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A Genomewide Screen for Late-Onset Alzheimer Disease in a Genetically Isolated Dutch Population
Abstract
Alzheimer disease (AD) is the most common cause of dementia. We conducted a genome screen of 103 patients with late-onset AD who were ascertained as part of the Genetic Research in Isolated Populations (GRIP) program that is conducted in a recently isolated population from the southwestern area of The Netherlands. All patients and their 170 closely related relatives were genotyped using 402 microsatellite markers. Extensive genealogy information was collected, which resulted in an extremely large and complex pedigree of 4,645 members. The pedigree was split into 35 subpedigrees, to reduce the computational burden of linkage analysis. Simulations aiming to evaluate the effect of pedigree splitting on false-positive probabilities showed that a LOD score of 3.64 corresponds to 5% genomewide type I error. Multipoint analysis revealed four significant and one suggestive linkage peaks. The strongest evidence of linkage was found for chromosome 1q21 (heterogeneity LOD [HLOD]=5.20 at marker D1S498). Approximately 30 cM upstream of this locus, we found another peak at 1q25 (HLOD=4.0 at marker D1S218). These two loci are in a previously established linkage region. We also confirmed the AD locus at 10q22-24 (HLOD=4.15 at marker D10S185). There was significant evidence of linkage of AD to chromosome 3q22-24 (HLOD=4.44 at marker D3S1569). For chromosome 11q24-25, there was suggestive evidence of linkage (HLOD=3.29 at marker D11S1320). We next tested for association between cognitive function and 4,173 single-nucleotide polymorphisms in the linked regions in an independent sample consisting of 197 individuals from the GRIP region. After adjusting for multiple testing, we were able to detect significant associations for cognitive function in four of five AD-linked regions, including the new region on chromosome 3q22-24 and regions 1q25, 10q22-24, and 11q25. With use of cognitive function as an endophenotype of AD, our study indicates the that the RGSL2, RALGPS2, and C1orf49 genes are the potential disease-causing genes at 1q25. Our analysis of chromosome 10q22-24 points to the HTR7, MPHOSPH1, and CYP2C cluster. This is the first genomewide screen that showed significant linkage to chromosome 3q23 markers. For this region, our analysis identified the NMNAT3 and CLSTN2 genes. Our findings confirm linkage to chromosome 11q25. We were unable to confirm SORL1; instead, our analysis points to the OPCML and HNT genes.
... NMNAT3 is located on chromosome 3q23. The SNP rs952797, which is downstream of the gene encoding NMNAT3 and upstream of the gene encoding CLSTN2, was demonstrated to be associated with AD (59). The NMNAT3 gene is key in nucleotide adenylyltransferase (NAD) synthesis and involved in AD (60). ...
... HTR7 is a G protein-coupled receptor for serotonin. According to Liu et al (59) HTR7 was associated with LOAD on chromosome 10q22-24. In their association study three SNPs, rs17129662, rs11185978 and rs7071717 together at 91.7 Mb, demonstrated an association with multiple cognitive domains in 197 unrelated subjects (59). ...
... According to Liu et al (59) HTR7 was associated with LOAD on chromosome 10q22-24. In their association study three SNPs, rs17129662, rs11185978 and rs7071717 together at 91.7 Mb, demonstrated an association with multiple cognitive domains in 197 unrelated subjects (59). Perez-García and Meneses (67) revealed that selective 5-HTR7 agonists are useful in the treatment of dysfunctional memory in aged-associated decline and AD. ...
Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder and it is the most common form of dementia in the elderly. Early onset AD is caused by mutations in three genes: Amyloid-β precursor protein, presenilin 1 (PSEN1) and PSEN2. Late onset AD (LOAD) is complex and apolipoprotein E is the only unanimously accepted genetic risk factor for its development. Various genes implicated in AD have been identified using advanced genetic technologies, however, there are many additional genes that remain unidentified. The present review highlights the genetics of early and LOAD and summarizes the genes involved in different signaling pathways. This may provide insight into neurodegenerative disease research and will facilitate the development of effective strategies to combat AD.
... Within neurodegenerative diseases, OPCML has been implicated in Alzheimer's disease in a GWAS carried out in patients affected by the late-onset form [123]. In line with these findings, altered OPCML mRNA levels were identified in the hippocampus of two mouse models of disease [124]. ...
... Furthermore, a signal for association with NTM has been discovered for childhood aggressiveness in attention deficit hyperactivity disorder, although the signal did not reach statistical significance [165]. A GWAS in a genetically isolated population from the Netherland linked four SNPs placed within intron 1 of the NTM gene to late-onset Alzheimer's disease [123]. ...
In the brain, cell adhesion molecules (CAMs) are critical for neurite outgrowth, axonal fasciculation, neuronal survival and migration, and synapse formation and maintenance. Among CAMs, the IgLON family comprises five members: Opioid Binding Protein/Cell Adhesion Molecule Like (OPCML or OBCAM), Limbic System Associated Membrane Protein (LSAMP), neurotrimin (NTM), Neuronal Growth Regulator 1 (NEGR1), and IgLON5. IgLONs exhibit three N-terminal C2 immunoglobulin domains; several glycosylation sites; and a glycosylphosphatidylinositol anchoring to the membrane. Interactions as homo- or heterodimers in cis and in trans, as well as binding to other molecules, appear critical for their functions. Shedding by metalloproteases generates soluble factors interacting with cellular receptors and activating signal transduction. The aim of this review was to analyse the available data implicating a role for IgLONs in neuropsychiatric disorders. Starting from the identification of a pathological role for antibodies against IgLON5 in an autoimmune neurodegenerative disease with a poorly understood mechanism of action, accumulating evidence links IgLONs to neuropsychiatric disorders, albeit with still undefined mechanisms which will require future thorough investigations.
... In the human brain, the 5-HT7R is highly expressed in the hippocampus and cerebral cortex, areas that are primarily affected by AD and FTLD (Hedlund and Sutcliffe, 2004). Moreover, genome-wide screens have revealed single-nucleotide polymorphisms located in close proximity to the 5-HT7R gene in patients with AD (Liu et al., 2007). The 5-HT7R is coupled to two heterotrimeric G-proteins, Gs and G12. ...
... NFT accumulation (Bowen et al., 2008). Moreover, genome-wide association studies found single-nucleotide polymorphisms located in close proximity to the 5-HT7R gene in a Dutch population of patients with late-onset AD (Liu et al., 2007). That finding suggested that mutations within the 5-HT7R gene might be etiologically relevant, at least in subpopulations of patients with AD. ...
Tauopathies comprise a heterogeneous family of neurodegenerative diseases characterized by pathological accumulation of hyperphosphorylated Tau protein. Pathological changes in serotonergic signaling have been associated with tauopathy etiology, but the underlying mechanisms remain poorly understood. Here, we studied the role of the serotonin receptor 7 (5-HT7R), in a mouse model of tauopathy induced by overexpressing the human Tau[R406W] mutant associated with inherited forms of frontotemporal dementia. We showed that the constitutive 5-HT7R activity is required for Tau hyperphosphorylation and formation of highly bundled Tau structures (HBTS) through G-protein-independent, CDK5-dependent mechanism. We also showed that 5-HT7R physically interacts with CDK5. At the systemic level, 5-HT7R-mediated CDK5 activation induces HBTS leading to neuronal death, reduced long-term potentiation (LTP), and impaired memory in mice. Specific blockade of constitutive 5-HT7R activity in neurons that overexpressed Tau[R406W] prevents Tau hyperphosphorylation, aggregation, and neurotoxicity. Moreover, 5-HT7R knockdown in the prefrontal cortex fully abrogates Tau[R406W]-induced LTP deficits and memory impairments. Thus, 5-HT7R/CDK5 signaling emerged as a new, promising target for tauopathy treatments.
... A total of five SNPs (i.e., rs9325507, rs3814220, rs12765878, rs11191865, rs9420707) were selected for further genotyping. These SNPs were analyzed in tumors or other diseases, such as breast and prostate cancer [15], aplastic anemia [13], and late-onset alzheimer disease [16]. Genomic DNA was extracted from peripheral blood of cases and controls using the GoldMag whole blood genomic DNA purification kit (GoldMag Co. Ltd., Xi'an, China), as recommended by the manufacturer's instructions [17]. ...
... However, rs9325507 and rs3814220 were studied in human leukocyte telomere length (LTL), results produced the P value less than 5 × 10 −7 , confirming that these locus are associated with LTL [24]. The connection of rs12765878 and late-onset alzheimer disease in a genetically isolated Dutch population was investigated through genome-wide screen [16]. Rs11191865 is a SNP involvement in systemic sclerosis (SSc)-related interstitial lung disease (ILD) (OR = 1.09, 95% CI 1.00-1.19, ...
Background
Laryngeal carcinoma (LC) is one of common diagnosed head and neck malignancies. Telomere length has been reported involved in malignant transformation and tumorigenesis. We speculate that single nucleotide polymorphisms (SNPs) in telomere length-related gene oligonucleotide/oligosaccharide-binding folds containing 1 (OBFC1) may have an association with LC in Chinese Han male population.
Methods
To prove this hypothesis, we performed a case–control study to analyze the OBFC1 polymorphisms in 172 LC patients and 180 healthy controls. A total of five SNPs (i.e., rs9325507, rs3814220, rs12765878, rs11191865, rs9420707) were selected for further genotyping.
Results
There was a significant difference in rs9325507 T allele frequency (OR = 0.88, 95% CI 0.64–1.21, P = 0.036) and rs11191865 A allele frequency (OR = 0.86, 95% CI 0.62–1.18, P = 0.009) between patient and control groups. In addition, the rs9325507 T/C genotype, rs3814220 G/A genotype, rs12765878 C/T genotype and rs11191865 A/G genotype had a lower risk of LC based on the results of logistic regression model analysis.
Conclusions
The results indicate a potential association between OBFC1 and LC risk in Chinese Han male population. Further work is required to confirm these results and explore the mechanisms of these effects.
... Among the five IgLON family members, both NEGR1 and OPCML have been linked to major depressive disorder [16][17][18][19][20], schizophrenia [21][22][23][24][25][26], autism [27,28], anorexia nervosa [29,30], and Alzheimer's disease [31,32]. Other pathologies and disorders ranging from dyslexia to Huntington's disease and obesity were attributed to alterations in one gene or the other [33]. ...
The immunoglobulin LAMP/OBCAM/NTM (IgLON) family of cell adhesion molecules comprises five members known for their involvement in establishing neural circuit connectivity, fine-tuning, and maintenance. Mutations in IgLON genes result in alterations in these processes and can lead to neuropsychiatric disorders. The two IgLON family members NEGR1 and OPCML share common links with several of them, such as schizophrenia, autism, and major depressive disorder. However, the onset and the underlying molecular mechanisms have remained largely unresolved, hampering progress in developing therapies. NEGR1 and OPCML are evolutionarily conserved in teleosts like the zebrafish (Danio rerio), which is excellently suited for disease modelling and large-scale screening for disease-ameliorating compounds. To explore the potential applicability of zebrafish for extending our knowledge on NEGR1- and OPCML-linked disorders and to develop new therapeutic strategies, we investigated the spatio-temporal expression of the two genes during early stages of development. negr1 and opcml are expressed maternally and subsequently in partially distinct domains of conserved brain regions. Other areas of expression in zebrafish have not been reported in mammals to date. Our results indicate that NEGR1 and OPCML may play roles in neural circuit development and function at stages earlier than previously anticipated. A detailed functional analysis of the two genes based on our findings could contribute to understanding the mechanistic basis of related psychiatric disorders.
... The discovery of IDE as an Aβ degrading enzyme [25] posited this enzyme, highly expressed in the brain [26], as a candidate pathophysiological link between AD and T2D. In fact, there is compelling evidence that the gene region around IDE might be genetically associated with both AD [27][28][29][30][31][32][33][34][35] and T2D [36][37][38][39]. Preclinical studies reported increased Aβ peptide accumulation in the brain of IDE-deficient mice at 3 months of age [40] and a clear diabetic phenotype in those mice at 6 months [41]. ...
The insulin-degrading enzyme (IDE) is an evolutionarily conserved zinc-dependent metallopeptidase highly expressed in the brain, where its specific functions remain poorly understood. Besides insulin, IDE is able to cleave many substrates in vitro, including amyloid beta peptides, making this enzyme a candidate pathophysiological link between Alzheimer's disease (AD) and type 2 diabetes (T2D). These antecedents led us to address the impact of IDE absence in hippocampus and olfactory bulb. A specific induction of microgliosis was found in the hippocampus of IDE knockout (IDE-KO) mice, without any effects in neither hippocampal volume nor astrogliosis. Performance on hippocampal-dependent memory tests is influenced by IDE gene dose in 12-month-old mice. Furthermore, a comprehensive characterization of the impact of IDE haploinsufficiency and total deletion in metabolic, behavioral, and molecular parameters in the olfactory bulb, a site of high insulin receptor levels, reveals an unambiguous barcode for IDE-KO mice at that age. Using wildtype and IDE-KO primary microglial cultures, we performed a functional analysis at the cellular level. IDE absence alters microglial responses to environmental signals, resulting in impaired modulation of phenotypic states, with only transitory effects on amyloid-β management. Collectively, our results reveal previously unknown physiological functions for IDE in microglia that, due to cell-compartment topological reasons, cannot be explained by its enzymatic activity, but instead modulate their multidimensional response to various damaging conditions relevant to aging and AD conditions.
Supplementary Information
The online version contains supplementary material available at 10.1186/s12974-023-02914-7.
... Variants in NMNAT2 have been associated with polyneuropathy with erythromelalgia, 7 while genome-wide association studies have suggested that variants in NMNAT3 are associated with Alzheimer's disease. 8 More work is needed to better understand the genetic causality of variants in the NMNAT2 and NMNAT3 genes. ...
Nicotinamide nucleotide adenylyltransferase 1 (NMNAT1) is a ubiquitously expressed enzyme involved in nuclear NAD+ production throughout the body. However, mutations in the NMNAT1 gene lead to retina-specific disease with few reports of systemic effects. We have previously demonstrated that AAV-mediated gene therapy using self-complementary AAV (scAAV) to ubiquitously express NMNAT1 throughout the retina prevents retinal degeneration in a mouse model of NMNAT1-associated disease. We aimed to develop a better understanding of the cell types in the retina that contribute to disease pathogenesis in NMNAT1-associated disease, and to identify the cell types that require NMNAT1 expression for therapeutic benefit. To achieve this goal, we treated Nmnat1V9M/V9M mice with scAAV using cell type-specific promoters to restrict NMNAT1 expression to distinct retinal cell types. We hypothesized that photoreceptors are uniquely vulnerable to NAD+ depletion due to mutations in NMNAT1. Consistent with this hypothesis, we identified that treatments that drove NMNAT1 expression in the photoreceptors led to preservation of retinal morphology. These findings suggest that gene therapies for NMNAT1-associated disease should aim to express NMNAT1 in the photoreceptor cells.
... In founder populations, affected individuals are more likely to have the causal mutation on longer haplotypes that are homozygous by recent decent, aiding in mutation discovery (Bourgain and Genin, 2005;Libiger and Schork, 2007). Some founder populations have extensive records allowing for reconstruction of deep and large genealogies (Falchi, et al., 2004;Liu, et al., 2007;Ober, et al., 2001;Vézina and Bournival, 2020). Gene-dropping simulations (Chen, et al., 2015;Maccluer, et al., 1986) can be performed within these genealogies, wherein ancestral genotypes are passed down a fixed pedigree structure. ...
Founder populations with deep genealogical data are well suited for investigating genetic variants contributing to diseases. Here, we present a major update of the genealogical analysis R package GENLIB, centered around a new function which can simulate the transmission of haplotypes from founders to probands along very large and complex user-specified genealogies.
Availability and implementation:
The latest update of the GENLIB package (v1.1.9) contains the new gen.simuHaplo() function and is available on the CRAN repository and from https://github.com/R-GENLIB/GENLIB. Examples can be accessed at https://github.com/R-GENLIB/simuhaplo_functions.
Supplementary information:
Supplementary data are available at Bioinformatics online.
... Finally, rs9787911 has been found to be nominally associated with AD in the Japanese population (72). The mapped gene NTM at 11q25 encodes a protein that may promote neurite outgrowth and adhesion via a hemophilic mechanism (73) and a linkage at 11q25 for AD has been discovered by two studies (74,75). ...
Introduction
In the last decade researchers have attempted to investigate the shared genetic architecture of longevity and age-related diseases and assess whether the increased longevity in certain people is due to protective alleles in the risk genes for a particular condition or whether there are specific “longevity” genes increasing the lifespan independently of age-related conditions' risk genes. The aim of this study was to investigate the shared genetic component between longevity and two age-related conditions.
Methods
We performed a cross-trait meta-analysis of publicly available genome-wide data for Alzheimer's disease, coronary artery disease and longevity using a subset-based approach provided by the R package ASSET.
Results
Despite the lack of strong genetic correlation between longevity and the two diseases, we identified 38 genome-wide significant lead SNPs across 22 independent genomic loci. Of them 6 were found to be potentially shared among the three traits mapping to genes including DAB2IP, DNM2, FCHO1, CLPTM1, and SNRPD2. We also identified 19 novel genome-wide associations for the individual traits in this study. Functional annotations and biological pathway enrichment analyses suggested that pleiotropic variants are involved in clathrin-mediated endocytosis and plasma lipoprotein and neurotransmitter clearance processes.
Discussion
In summary, we have been able to advance in the knowledge of the genetic overlap existing among longevity and the two most common age-related disorders.
... NTM (Neurotrimin) gene encodes a member of the IgLON (LAMP, OBCAM, NTM) family of immunoglobulin (Ig) domain-containing glycosylphosphatidylinositol (GPI)-anchored cell adhesion molecules. A study performed in humans suggested that NTM gene is associated with the level of the intelligence quotient (IQ) and genome wide association studies identified an association between NTM variation and cognitive function performances in humans 81,82 . ...
Wild boar (Sus scrofa L.) is one of the large mammals most spread worldwide, highly adaptable, and its population rapidly increased in many areas in Europe, including Italy, where Tuscany is considered particularly suitable for wild boar. Wild boars are potential hosts for different etiological agents, such as Brucella spp., Leptospira spp. and Pseudorabies virus and they can contribute to maintain and/or to disseminate some bacterial or viral pathogens to humans and domestic animals, above all-in free-range farms. In order to identify hypothetical genomic regions associated with these infection diseases, 96 samples of wild boars hunted in Tuscany during the 2018–2019 and 2019–2020 hunting seasons were considered. Diagnosis was achieved by serological tests and 42 Pseudorabies, 31 Leptospira and 15 Brucella positive animals were identified. All animals were genotyped with Geneseek Genomic Profiler Porcine HD (70 k) and a genome-wide scan was then performed. Significant markers were highlighted for Pseudorabies (two SNPs), Brucella (seven SNPs), and Leptospira (four SNPs) and they were located within, or nearby, 29 annotated genes on chromosome 6, 9, 12, 13, 14 and 18. Eight genes are implicated in viral (SEC14L1, JMJD6, SRSF2, TMPRSS2, MX1, MX2) or bacterial (COL8A1, SPIRE1) infections, seven genes (MFSD11, METTL23, CTTNBP2, BACE2, IMPA2, MPPE1 and GNAL) are involved in mental disorders and one gene (MGAT5B) is related to the Golgi complex. Results presented here provide interesting starting points for future research, validation studies and fine mapping of candidate genes involved in bacterial and viral infections in wild boar.
... Overexpression of CHRM3 or activation of CHRM3 by carbachol promoted cell proliferation, migration, and castration resistance in prostate cancer [37]. CLSTN2 is associated with episodic memory and late-onset Alzheimer's disease [38,39]. NELL1 has been found to be associated with a variety of tumors, which may inhibit the progress of cancer. ...
Previous studies have found that gene expression levels are associated with prognosis and some genes can be used to predict the survival risk of glioblastoma (GBM) patients. However, most of them just built the survival-related gene signature, and personal survival risk can be evaluated only in group. This study aimed to find the prognostic survival related genes of GBM, and construct survival risk prediction model, which can be used to evaluate survival risk by individual. We collected gene expression data and clinical information from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Cox regression analysis and LASSO-cox regression analysis were performed to get survival-related genes and establish the overall survival prediction model. The ROC curve and Kaplan Meier analysis were used to evaluate the prediction ability of the model in training set and two independent cohorts. We also analyzed the biological functions of survival-related genes by GO and KEGG enrichment analysis. We identified 99 genes associated with overall survival and selected 16 genes (IGFBP2, GPRASP1, C1R, CHRM3, CLSTN2, NELL1, SEZ6L2, NMB, ICAM5, HPCAL4, SNAP91, PCSK1N, PGBD5, INA, UCHL1 and LHX6) to establish the survival risk prediction model. Multivariate Cox regression analysis indicted that the risk score could predict overall survival independent of age and gender. ROC analyses showed that our model was more robust than four existing signatures. The sixteen genes can also be potential transcriptional biomarkers and the model can assist doctors on clinical decision-making and personalized treatment of GBM patients.
... A single-nucleotide polymorphism located 126 kb downstream of the NMNAT3 gene has been identified in a dutch cohort of familial late-onset AD, suggesting that this isoform might be relevant to AD. 85 ...
The enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT) catalyzes a reaction central to all known NAD biosynthetic routes. In mammals, three isoforms with distinct molecular and catalytic properties, different subcellular and tissue distribution have been characterized. Each isoform is essential for cell survival, with a critical role in modulating NAD levels in a compartment‐specific manner. Each isoform supplies NAD to specific NAD‐dependent enzymes, thus regulating their activity with impact on several biological processes, including DNA repair, proteostasis, cell differentiation, and neuronal maintenance. The nuclear NMNAT1 and the cytoplasmic NMNAT2 are also emerging as relevant targets in specific types of cancers and NMNAT2 has a key role in the activation of antineoplastic compounds. This review recapitulates the biochemical properties of the three isoforms and focuses on recent advances on their protective function, involvement in human diseases and role as druggable targets.
... The PK2 E8Q mice are also a valuable tool to study diseases related to synapse formation, stability, and function in autism (15). One of the PK-interacting proteins we found reduced in the synaptosome fraction in the PK2 E8Q mice was Mink1, which is associated with Alzheimer's disease, Alzheimer's Disease 15, suggesting that the reduction of Mink1 protein level in these patients with Alzheimer's disease may lead to reduced synapse stability due to the reduced PK function (39)(40)(41)(42). Consistent with this, we found that the PCP components are a direct target of amyloid oligomer-induced synapse degeneration in a mouse model of Alzheimer's disease (in press at Science Advances). ...
Whether there exists a common signaling mechanism that assembles all glutamatergic synapses is unknown. We show here that knocking out Prickle1 and Prickle2 reduced the formation of the PSD-95–positive glutamatergic synapses in the hippocampus and medial prefrontal cortex in postnatal development by 70–80%. Prickle1 and Prickle2 double knockout in adulthood lead to the disassembly of 70 to 80% of the postsynaptic-density(PSD)-95–positive glutamatergic synapses. PSD-95–positive glutamatergic synapses in the hippocampus of Prickle2E8Q/E8Q mice were reduced by 50% at postnatal day 14. Prickle2 promotes synapse formation by antagonizing Vangl2 and stabilizing the intercellular complex of the planar cell polarity (PCP) components, whereas Prickle2 E8Q fails to do so. Coculture experiments show that the asymmetric PCP complexes can determine the presynaptic and postsynaptic polarity. In summary, the PCP components regulate the assembly and maintenance of a large number of glutamatergic synapses and specify the direction of synaptic transmission.
... The top risk marker in the AD predictor was SMARCA4, which participated in cellular biological processes by altering the contact of DNA histone in the nucleosome (Euskirchen et al., 2012). RALGPS2 was with the largest betweenness in AD and as a potential pathogenic index of AD (Liu et al., 2007). The marker with the highest absolute MCMC difference in AD was CDCA7L, as the regulator of caspase-3, which played a significant role in cell death progression (Yosefzon et al., 2018). ...
Background: Neurodegenerative Diseases (NDs) are age-dependent and include Alzheimer’s disease (AD), Parkinson’s disease (PD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD), and so on. There have been numerous studies showing that accelerated aging is closely related (even the driver of) ND, thus promoting imbalances in cellular homeostasis. However, the mechanisms of how different ND types are related/triggered by advanced aging are still unclear. Therefore, there is an urgent need to explore the potential markers/mechanisms of different ND types based on aging acceleration at a system level.
Methods: AD, PD, PSP, FTD, and aging markers were identified by supervised machine learning methods. The aging acceleration differential networks were constructed based on the aging score. Both the enrichment analysis and sensitivity analysis were carried out to investigate both common and specific mechanisms among different ND types in the context of aging acceleration.
Results: The extracellular fluid, cellular metabolisms, and inflammatory response were identified as the common driving factors of cellular homeostasis imbalances during the accelerated aging process. In addition, Ca ion imbalance, abnormal protein depositions, DNA damage, and cytoplasmic DNA in macrophages were also revealed to be special mechanisms that further promote AD, PD, PSP, and FTD, respectively.
Conclusion: The accelerated epigenetic aging mechanisms of different ND types were integrated and compared through our computational pipeline.
... This snp was in linkage disequilibrium with APOE4 on chr19, which supported the APOE locus as the major susceptibility gene for LOAD. Another GWAS in the Netherlands with 103 LOAD patients and 170 first-degree family members from a pedigree of 4645 samples revealed a significant linkage with RGSL2, RALGPS2, C1orf49, HTR7, MPHOSPH1, CYP2C and CLSTN2 genes (Liu et al. 2007). However, several of these studies and associations were only the tip of an iceberg, as many of these putative associations were needed to validate by replication studies of huge samples. ...
Background
Patients with sporadic Alzheimer’s do not possess an identified causative variant and hold an estimated heritability of 92–100%. Majority of disease causing, or protective mutations were uncommon in a generic group of the population, whereas dominant variants were well identified. Development of next-generation sequencing along with genome-wide association studies allowed to accurately identify the lesser-known disease-causing variants essential for the early detection of AD in sporadic patients to provide genetic counsel and prophylactic treatment.Objective
The objective of the review is to bring the focus to the potentiality of large-scale GWAS (Genome-Wide Association Studies) analysis for the detection of novel genes for the sporadic Alzheimer’s disease.ResultsIdentification of infrequently studied genes like LILRB2, LIPC, ITGAX, HLA-A, CASP8, ABCA7, ADAM10, BIN1, CD33, CLU, EPHA1, GAB2, PICALM, TREM2, SORL1, MAPT, HLA for the sporadic AD, that interact with predominant AD genes and engages in pathways mediating disease progression.ConclusionA multi-population large-scale un-targeted whole-genome GWAS or WES (whole exome sequencing) analysis is needed to identify several genes and variants besides the predominantly studied APOE for the sporadic case of Alzheimer’s.
... NEGR1 is also linked to major depressive disorder (MDD) as well as schizophrenia (SZ), dyslexia, autism spectrum disorder (ASD), cognitive disabilities, and lower white matter integrity across the brain [12,[33][34][35]. By contrast, NTM is linked to intelligence and cognitive function [36]; LSAMP to mood disorders [11,37] and heart disease [38]; OBCAM, a tumor-suppressor [1], to cognitive deficits [39]; and IGLON5 to encephalopathy, sleep dysfunction, chronic neurodegeneration, and auto-immune disorders [40]. ...
Neuronal growth regulator 1 (NEGR1) and neurotrimin (NTM) are abundant cell-surface proteins found in brain and form part of the IgLON (Immunoglobulin LSAMP, OBCAM, Neurotrimin) family. In humans, NEGR1 is implicated in obesity and mental disorders, while NTM is linked to intelligence and cognitive function. IgLONs dimerize homophilically and heterophilically, and they are thought to shape synaptic connections and neural circuits by acting in trans (spanning cellular junctions) and/or in cis (at the same side of a junction). Here, we reveal homodimeric structures of NEGR1 and NTM. They assemble into V-shaped complexes via their Ig1 domains, and disruption of the Ig1-Ig1 interface abolishes dimerization in solution. A hydrophobic ridge from one Ig1 domain inserts into a hydrophobic pocket from the opposing Ig1 domain producing an interaction interface that is highly conserved among IgLONs but remarkably plastic structurally. Given the high degree of sequence conservation at the interaction interface, we tested whether different IgLONs could elicit the same biological effect in vivo. In a small scale study, administering different soluble IgLONs directly into the brain and monitoring feeding, only NEGR1 altered food intake significantly. Taking NEGR1 as a prototype, our studies thus indicate that while IgLONs share a conserved mode of interaction and are able to bind each other as homomers and heteromers, they are structurally plastic and can exert unique biological action.
... This remained a major challenge in understanding the pathogenesis of suicide, in-spite of the fact that these SNPs may be important and may provide an opportunity for discovery of novel biopathological pathways or strengthening known pathways in biomarker discovery for suicide risk and therapeutic intervention. Founder effect events in historically isolated small populations are useful in finding genes not only in Mendelian disorders but also in polygenes of several complex disease phenotypes with the advantage of narrowing down on the sub-phenotype heterogeneity [31][32][33][34]. To address this issue, we designed the present study in a historical small isolated endogamous Idu Mishmi population having the highest rate of suicide attempt (14.2%) compared to general urban population (0.4-4.2%) with depression as a significant covariate described in our earlier studies [26,27]. ...
Background:
Genetic diathesis of suicide is supported by family and twin studies. Few candidate gene pathways are known, but does not explain fully the complexity of suicide genetic risk. Recent investigations opting for Genome-Wide Association Studies (GWAS) resulted in finding additional targets, but replication remained a challenge. In this respect small isolated population approach in several complex disease phenotypes is found encouraging. The present study is an attempt to re-test some of the reported significant SNPs for suicide among a small historical high- risk isolated population from Northeast India.
Methods:
Two hundred ten cases (inclusive of depressed, suicide attempter and depressed + suicide attempter) and 249 controls were considered in the present study which were evaluated for the psychiatric parameters. Sixteen reported significant SNPs for suicide behaviour were re-tested using association approach under various genetic models. Networking by GeneMANIA tool was used for function prediction of the associated genes.
Results:
Seven SNPs (of 6 genes) remained significant in different genetic models. On networking genes with significant SNPs IL7, RHEB, CTNN3, KCNIP4, ARFGEF3 are found in interaction with already known candidate gene pathways while SNP rs1109089 (RHEB) gained further support from earlier expression studies. NUGGC gene is in complete isolation.
Conclusions:
Small population approach in replicating significant SNPs is useful in complex phenotypes like suicide. This study explored the region-specific demographics of India by identifying vulnerable population for suicide via genetic association analysis in bringing into academic and administrative forum, the importance of suicide as a disease and its biological basis.
... As these studies utilized a relatively small number of samples, only a single SNP in APOE reached genome-wide significance (typically considered p < 5.0 x 10 -8 , based on a Bonferroni correction for testing all independent SNPs in the human genome [83]). In fact, seven of the earliest GWAS, each of which used less than 2,000 cases, identified only APOE as significantly associated with AD [84][85][86][87][88][89][90]. This is likely due to small sample numbers, as GWAS requires a large sample size for sufficient statistical power to detect small-effect associations. ...
Advances in genetic and genomic technologies over the last thirty years have greatly enhanced our knowledge concerning the genetic architecture of Alzheimer's disease (AD). Several genes including APP, PSEN1, PSEN2, and APOE have been shown to exhibit large effects on disease susceptibility, with the remaining risk loci having much smaller effects on AD risk. Notably, common genetic variants impacting AD are not randomly distributed across the genome. Instead, these variants are enriched within regulatory elements active in human myeloid cells, and to a lesser extent liver cells, implicating these cell and tissue types as critical to disease etiology. Integrative approaches are emerging as highly effective for identifying the specific target genes through which AD risk variants act and will likely yield important insights related to potential therapeutic targets in the coming years. In the future, additional consideration of sex- and ethnicity-specific contributions to risk as well as the contribution of complex gene-gene and gene-environment interactions will likely be necessary to further improve our understanding of AD genetic architecture.
... It has exodeubiquitinase activity with a preference for long polyubiquitin chains and may play a regulatory role at the level of protein turnover [39]. This genetic region was previously reported to be linked to late-onset Alzheimer's disease [40,41]. SNP rs4815428 is located in TMC2, which encodes transmembrane channel-like protein 2. TMC2 is a potential ion channel required for the mechano-transduction of cochlear hair cells [42]. ...
Hypertension occurs at a higher rate in African Americans than in European Americans. Based on the assumption that causal variants are more frequently found on DNA segments inherited from the ancestral population with higher disease risk, we employed admixture mapping to identify genetic loci with excess local African ancestry associated with blood pressure. Chromosomal regions 1q21.2–21.3, 4p15.1, 19q12 and 20p13 were significantly associated with diastolic blood pressure (β = 5.28, -7.94, -6.82 and 5.89, P-value = 6.39E-04, 2.07E-04, 6.56E-05 and 5.04E-04, respectively); 1q21.2–21.3 and 19q12 were also significantly associated with mean arterial pressure (β = 5.86 and -6.40, P-value = 5.32E-04 and 6.37E-04, respectively). We further selected SNPs that had large allele frequency differences within these regions and tested their association with blood pressure. SNP rs4815428 was significantly associated with diastolic blood pressure after Bonferroni correction (β = -2.42, P-value = 9.57E-04), and it partially explained the admixture mapping signal at 20p13. SNPs rs771205 (β = -1.99, P-value = 3.37E-03), rs3126067, rs2184953 and rs58001094 (the latter three exhibit strong linkage disequilibrium, β = -2.3, P-value = 1.4E-03) were identified to be significantly associated with mean arterial pressure, and together they fully explained the admixture signal at 1q21.2–21.3. Although no SNP at 4p15.1 showed large ancestral allele frequency differences in our dataset, we detected association at low-frequency African-specific variants that mapped predominantly to the gene PCDH7, which is most highly expressed in aorta. Our results suggest that these regions may harbor genetic variants that contribute to the different prevalence of hypertension.
... Also, we identified two sets of host genes, one previously associated with memory, cognition or other neurodevelopmental processes and the other set identified here as candidates for roles in cognition (Table S4). Examples of known human genes associated with memory also identified in our study include: NTM and KLHl20 that are associated with Alzheimer's disease and DOCK8 and KANK1 that are associated with neurodevelopmental disorders including memory potential [29][30][31]. Examples of known mouse genes associated with memory include Specc1 that was identified in a mouse genetic screen for avoidance learning [32], Prdx6 that was associated with neurogenesis and Alzheimer's disease in mice [33,34] and knock-out mice for Abl2, Nrg3, Shank2, Gria1, and Fgf14 that caused neurodevelopmental defects [35][36][37][38][39]. The other set contains 135 genes not previously associated with memory of which 65 have brain expression [40] (http:// connectivity.brain-map.org/). ...
Background:
Recent evidence has linked the gut microbiome to host behavior via the gut-brain axis [1-3]; however, the underlying mechanisms remain unexplored. Here, we determined the links between host genetics, the gut microbiome and memory using the genetically defined Collaborative Cross (CC) mouse cohort, complemented with microbiome and metabolomic analyses in conventional and germ-free (GF) mice.
Results:
A genome-wide association analysis (GWAS) identified 715 of 76,080 single-nucleotide polymorphisms (SNPs) that were significantly associated with short-term memory using the passive avoidance model. The identified SNPs were enriched in genes known to be involved in learning and memory functions. By 16S rRNA gene sequencing of the gut microbial community in the same CC cohort, we identified specific microorganisms that were significantly correlated with longer latencies in our retention test, including a positive correlation with Lactobacillus. Inoculation of GF mice with individual species of Lactobacillus (L. reuteri F275, L. plantarum BDGP2 or L. brevis BDGP6) resulted in significantly improved memory compared to uninoculated or E. coli DH10B inoculated controls. Untargeted metabolomics analysis revealed significantly higher levels of several metabolites, including lactate, in the stools of Lactobacillus-colonized mice, when compared to GF control mice. Moreover, we demonstrate that dietary lactate treatment alone boosted memory in conventional mice. Mechanistically, we show that both inoculation with Lactobacillus or lactate treatment significantly increased the levels of the neurotransmitter, gamma-aminobutyric acid (GABA), in the hippocampus of the mice.
Conclusion:
Together, this study provides new evidence for a link between Lactobacillus and memory and our results open possible new avenues for treating memory impairment disorders using specific gut microbial inoculants and/or metabolites. Video Abstract.
... Polymorphisms in the IgLON1 and IgLON2 gene have been found to be associated with late onset Alzheimers disease (28), whereas IgLON3 has been linked to schizophrenia and depression (29). This is intriguing knowledge considering the phenotype of anti-IgLON5 disease with prominent symptoms such as dementia and behavioral symptoms, alongside tau depositions, and may further strengthen the hypothesis that damage to the IgLON5 protein is an underlying mechanism of the disease. ...
Background: Anti-IgLON5 disease is a novel disorder with a complex interplay between inflammation and neurodegeneration. Patients develop antibodies against IgLON5 but also deposition of neuronal tau protein. Symptoms often have an insidious onset, slow progression and mimic other neurological disorders. Here we report a case with severely prolonged 11-year disease course and provide a review of current reported cases with focus on presentation, work-up, treatment, and outcome.
Method: All reported cases of anti-IgLON5 disease were evaluated. Cases reported twice (in case series and as single case reports), were carefully excluded.
Results: Most patients display a characteristic sleep disorder with severe insomnia, non rapid eye movement (NREM) parasomnia, with finalistic movements and sleep disordered breathing (stridor and obstructive sleep apnea). Other symptoms are bulbar involvement, gait instability, movement disorders, oculomotor abnormalities, dysautonomia, and peripheral symptoms. Antibodies are present in both serum and CSF and there is a strong correlation with human leukocyte antigen (HLA) DRB1*10:01 and HLA-DQB1*05:01. Neuropathological examination reveals neurodegeneration with neuronal tau deposits in regions that correlate with the clinical presentation (e.g., predominantly hypothalamus and tegmentum of the brain stem). Majority of cases respond partially to immunotherapy. Cases, who received no treatment or treatment with IV corticosteroids alone, had a higher mortality than cases treated with more potent immunotherapy.
Conclusion: The clinical spectrum of Anti-IgLON5 disease continues to expand. Further studies are needed to elucidate the pathophysiology, therapeutic strategies and outcome in this novel disorder. Aggressive immunotherapy seems to increase survival.
... Several studies have reported that Nmnat1 and Nmnat2 have neuroprotective roles and can restore behavioral impairment in AD-like tauopathy mouse models [75][76][77][78]. In addition, a genome-wide screening for late-onset AD in a genetically isolated Dutch population identified significant linkage to the loci of NMNAT3 [79]. As an alternative function of Nmnat, studies using Drosophila revealed that the Drosophila Nmnat (dNmnat) was a stress-response protein that acted as a chaperone. ...
Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme that mediates various redox reactions. Particularly, mitochondrial NAD plays a critical role in energy production pathways, including the tricarboxylic acid (TCA) cycle, fatty acid oxidation, and oxidative phosphorylation. NAD also serves as a substrate for ADP-ribosylation and deacetylation by poly(ADP-ribose) polymerases (PARPs) and sirtuins, respectively. Thus, NAD regulates energy metabolism, DNA damage repair, gene expression, and stress response. Numerous studies have demonstrated the involvement of NAD metabolism in neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and retinal degenerative diseases. Mitochondrial dysfunction is considered crucial pathogenesis for neurodegenerative diseases such as AD and PD. Maintaining appropriate NAD levels is important for mitochondrial function. Indeed, decreased NAD levels are observed in AD and PD, and supplementation of NAD precursors ameliorates disease phenotypes by activating mitochondrial functions. NAD metabolism also plays an important role in axonal degeneration, a characteristic feature of peripheral neuropathy and neurodegenerative diseases. In addition, dysregulated NAD metabolism is implicated in retinal degenerative diseases such as glaucoma and Leber congenital amaurosis, and NAD metabolism is considered a therapeutic target for these diseases. In this review, we summarize the involvement of NAD metabolism in axon degeneration and various neurodegenerative diseases and discuss perspectives of nutritional intervention using NAD precursors.
... The homozygous region of the French Trotter overlapped at position 39.5-41.1 Mb with islands of Shagya and Purebred Arabians, in which among others the genes NTM and OPCML are located. These genes, associated with intelligence and cognitive functions in humans [71,72], and hypothesized to modulate temperament in horses were highlighted by Gurgul et al. [7] focusing on signals of diversifying selection between light versus draught horses. Additionally, the authors found high linkage disequilibrium (LD) in the chromosomal area between 40.1 Mb and 52.2 Mb in Arabian and Malopolski horse, which corresponded with the extended ROH island of the French Trotter at 39.6 Mb and 52.5 Mb [7]. ...
Intensive artificial and natural selection have shaped substantial variation among
European horse breeds. Whereas most equine selection signature studies employ divergent genetic population structures in order to derive specific inter-breed targets of selection, we screened a total of 1476 horses originating from 12 breeds for the loss of genetic diversity by runs of homozygosity (ROH) utilizing a 670,000 single nucleotide polymorphism (SNP) genotyping array. Overlapping homozygous regions (ROH islands) indicating signatures of selection were identified by breed and similarities/dissimilarities between populations were evaluated. In the entire dataset, 180 ROH islands were identified, whilst 100 islands were breed specific, all other overlapped in 36 genomic
regions with at least one ROH island of another breed. Furthermore, two ROH hot spots were determined at horse chromosome 3 (ECA3) and ECA11. Besides the confirmation of previously documented target genes involved in selection for coat color (MC1R, STX17, ASIP), body size (LCORL/NCAPG, ZFAT, LASP1, HMGA2), racing ability (PPARGC1A), behavioral traits (GRIN2B, NTM/OPCML) and gait patterns (DMRT3), several putative target genes related to embryonic morphogenesis (HOXB), energy metabolism (IGFBP1, IGFBP3), hair follicle morphogenesis (KRT25, KRT27, INTU) and autophagy (RALB) were highlighted. Furthermore, genes were pinpointed which might be involved in environmental adaptation of specific habitats (UVSSA, STXBP4, COX11, HLF, MMD).
... In humans, genetic abnormalities of individual IgLONs have been implicated in a variety of disorders. Four single-nucleotide polymorphisms (SNPs) in intron 1 of the NTRI gene and one SNP in intron 1 of the OPCML gene have been found to be associated with late-onset Alzheimer's disease (Liu et al., 2007), while modulation of OPCML expression is associated with cancer progression (Cui et al., 2008). Genetic variants in the NTRI gene have also been implicated in childhood aggressiveness in children with attention deficit/hyperactivity disorder (Brevik et al., 2016) and developmental delay (Minhas et al., 2013), whereas SNPs of LSAMP have been associated with schizophrenia and depression (Karis et al., 2018;Koido et al., 2014). ...
In the developing brain, cell-surface proteins play crucial roles, but their protein-protein interaction network remains largely unknown. A proteomic screen identified 200 interactions, 89 of which were not previously published. Among these interactions, we find that the IgLONs, a family of five cell-surface neuronal proteins implicated in various human disorders, interact as homo- and heterodimers. We reveal their interaction patterns and report the dimeric crystal structures of Neurotrimin (NTRI), IgLON5, and the neuronal growth regulator 1 (NEGR1)/IgLON5 complex. We show that IgLONs maintain an extended conformation and that their dimerization occurs through the first Ig domain of each monomer and is Ca2+ independent. Cell aggregation shows that NTRI and NEGR1 homo- and heterodimerize in trans. Taken together, we report 89 unpublished cell-surface ligand-receptor pairs and describe structural models of trans interactions of IgLONs, showing that their structures are compatible with a model of interaction across the synaptic cleft.
... Mb), divergently selected between the draft and light horses, apart from two pseudogenes and one uncharacterized protein coding gene we found two genes (namely: NTM, coding for neurotrimin and OPCML, coding for opioid binding protein) that were involved in central nervous system functioning. The study performed in humans suggested that NTM gene (coding for Neurotrimin) locus is associated with the level of IQ and two other genome wide association studies (GWAS) reported an association between NTM variation and cognitive function performances in humans [32,33]. The diversifying selection signature at this locus between the draft and light horses may potentially contribute to their differing temperaments and/or potentially, the ability to develop different gaits as a function of motor coordination managed by the brain. ...
The genetic differentiation of the current horse population was evolutionarily created by natural or artificial selection which shaped the genomes of individual breeds in several unique ways. The availability of high throughput genotyping methods created the opportunity to study this genetic variation on a genome-wide level allowing detection of genome regions divergently selected between separate breeds as well as among different horse types sharing similar phenotypic features. In this study, we used the population differentiation index (FST) that is generally used for measuring locus-specific allele frequencies variation between populations, to detect selection signatures among six horse breeds maintained in Poland. These breeds can be classified into three major categories, including light, draft and primitive horses, selected mainly in terms of type (utility), exterior, performance, size, coat color and appearance. The analysis of the most pronounced selection signals found in this study allowed us to detect several genomic regions and genes connected with processes potentially important for breed phenotypic differentiation and associated with energy homeostasis during physical effort, heart functioning, fertility, disease resistance and motor coordination. Our results also confirmed previously described association of loci on ECA3 (spanning LCORL and NCAPG genes) and ECA11 (spanning LASP1 gene) with the regulation of body size in our draft and primitive (small size) horses. The efficiency of the applied FST-based approach was also confirmed by the identification of a robust selection signal in the blue dun colored Polish Konik horses at the locus of TBX3 gene, which was previously shown to be responsible for dun coat color dilution in other horse breeds. FST-based method showed to be efficient in detection of diversifying selection signatures in the analyzed horse breeds. Especially pronounced signals were observed at the loci responsible for fixed breed-specific features. Several candidate genes under selection were proposed in this study for traits selected in separate breeds and horse types, however, further functional and comparative studies are needed to confirm and explain their effect on the observed genetic diversity of the horse breeds. © 2019 Gurgul et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
... This means that mitochondrial NAD + is critically important to maintain cell health in the CNS. Moreover, NMNAT2 mRNA levels have been reported to decline in models of Alzheimer's disease and precede neurodegeneration (Ljungberg et al. 2012), while a single-nucleotide polymorphism in NMNAT3 has been identified in a Dutch cohort of familial Alzheimer's disease (Liu et al. 2007). ...
Aging is a major risk factor for many types of cancer, and the molecular mechanisms implicated in aging, progeria syndromes, and cancer pathogenesis display considerable similarities. Maintaining redox homeostasis, efficient signal transduction, and mitochondrial metabolism are essential for genome integrity and preventing progression to cellular senescence or tumorigenesis. NAD+ is a central signaling molecule involved in these and other cellular processes implicated in age-related diseases and cancer. Growing evidence implicates NAD+ decline as a major feature of accelerated aging progeria syndromes and normal aging. Administration of NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) offer promising therapeutic strategies to improve health, progeria comorbidities, and cancer therapies. This review summarizes insights from the study of aging and progeria syndromes and discusses the implications and therapeutic potential of the underlying molecular mechanisms involved in aging and how they may contribute to tumorigenesis. Expected final online publication date for the Annual Review of Cancer Biology Volume 3 is March 4, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
... Several studies have also reported that Nmnat1 and Nmnat2 have neuroprotective roles and restore behavioral impairments in AD-like Tauopathy mouse models (Cheng et al., 2013;Ljungberg et al., 2012;Musiek et al., 2016;Rossi et al., 2018). Additionally, a genome-wide screen for late-onset AD in a genetically isolated Dutch population identified a significant linkage to the loci of NMNAT3 (Liu et al., 2007). ...
Nicotinamide adenine dinucleotide (NAD) is an important co-factor involved in numerous physiological processes, including metabolism, post-translational protein modification, and DNA repair. In living organisms, a careful balance between NAD production and degradation serves to regulate NAD levels. Recently, a number of studies have demonstrated that NAD levels decrease with age, and the deterioration of NAD metabolism promotes several aging-associated diseases, including metabolic and neurodegenerative diseases and various cancers. Conversely, the upregulation of NAD metabolism, including dietary supplementation with NAD precursors, has been shown to prevent the decline of NAD and exhibits beneficial effects against aging and aging-associated diseases. In addition, many studies have demonstrated that genetic and/or nutritional activation of NAD metabolism can extend the lifespan of diverse organisms. Collectively, it is clear that NAD metabolism plays important roles in aging and longevity. In this review, we summarize the basic functions of the enzymes involved in NAD synthesis and degradation, as well as the outcomes of their dysregulation in various aging processes. In addition, a particular focus is given on the role of NAD metabolism in the longevity of various organisms, with a discussion of the remaining obstacles in this research field.
... Lsamp has been shown to be implicated in hippocampal plasticity and adaptation in changing environments (Qiu et al., 2010;Heinla et al., 2015). Polymorphisms and expressional alterations in the Lsamp gene in humans have been linked to a spectrum of neuropsychiatric disorders (Must et al., 2008;Behan et al., 2009;Koido et al., 2012Koido et al., , 2014 whereas polymorphisms in the Ntm gene have been found to be associated with cognitive functions (Liu et al., 2007) and intelligence (Pan et al., 2010) and expressional alterations in the dorsolateral prefrontal cortex have been found in schizophrenic brains (Karis et al., 2018). ...
... In a study on late-onset Alzheimer's disease, four SNPs (rs1629316, rs1547897, rs11222931, and rs11222932) in intron 1 of the Ntm gene (11q25) and one SNP (rs11223225) in intron 1 of the OBCAM gene (located on the same chromosome as Ntm < 80 kb apart) have been found to be associated with late-onset Alzheimer's disease (Liu et al., 2007). Genome-linkage studies in two independent Dutch populations indicate that depression is also associated with a locus on chromosome 11q25 suggesting a link to OBCAM (Schol-Gelok et al., 2010). ...
Immunoglobulin superfamily (IgSF) cell adhesion molecules (CAMs) are cell surface glycoproteins that not only mediate interactions between neurons but also between neurons and other cells in the nervous system. While typical IgSF CAMs are transmembrane molecules, this superfamily also includes CAMs, which do not possess transmembrane and intracellular domains and are instead attached to the plasma membrane via a glycosylphosphatidylinositol (GPI) anchor. In this review, we focus on the role GPI-anchored IgSF CAMs have as signal transducers and ligands in neurons, and discuss their functions in regulation of neuronal development, synapse formation, synaptic plasticity, learning, and behavior. We also review the links between GPI-anchored IgSF CAMs and brain disorders.
... The European ancestry families included 2 large Dutch families from the Erasmus Rucphen Family study. 5 Most of these families were recently analyzed for genetic linkage, an analysis that will be used in the analysis of the sequence data. 6,7 By design, no e4/e4 individuals were selected for sequencing, and we prioritized e3/e4 individuals with earlier disease onset. ...
... 12 Interestingly, mutations in NMNAT1 have been recently identified as a cause of Leber congenital amaurosis, a degenerative disease of the young human retina, 13 and genome-wide and linkage analysis have demonstrated an association between NMNAT3 and late-onset Alzheimer's disease. 14 The above observations suggest that all three NMNAT isoforms are likely important for the survival of both, peripheral axons and CNS neurons and their processes. Nevertheless, the neuroprotective role of each of these proteins following neonatal H-I remains poorly understood. ...
Objective
To determine whether the NAD+ biosynthetic protein, nicotinamide mononucleotide adenylyltransferase‐3 (NMNAT3), is a neuroprotective inducible enzyme capable of decreasing cerebral injury after neonatal hypoxia‐ischemia (H‐I) and reducing glutamate receptor‐mediated excitotoxic neurodegeneration of immature neurons.
Methods
Using NMNAT3‐overexpressing mice we investigated whether increases in brain NMNAT3 reduced cerebral tissue loss following H‐I. We then employed biochemical methods from injured neonatal brains to examine the inducibility of NMNAT3 and the mechanism of NMNAT3‐dependent neuroprotection. Using AAV8‐mediated vectors for in vitro neuronal NMNAT3 knockdown, we then examine the endogenous role of this protein on immature neuronal survival prior and following NMDA receptor‐mediated excitotoxicity.
Results
NMNAT3 mRNA and protein levels increased after neonatal H‐I. In addition, NMNAT3 overexpression decreased cortical and hippocampal tissue loss 7 days following injury. We further show that the NMNAT3 neuroprotective mechanism involves a decrease in calpastatin degradation, and a decrease in caspase‐3 activity and calpain‐mediated cleavage. Conversely, NMNAT3 knockdown of cortical and hippocampal neurons in vitro caused neuronal degeneration and increased excitotoxic cell death. The neurodegenerative effects of NMNAT3 knockdown were counteracted by exogenous upregulation of NMNAT3.
Conclusions
Our observations provide new insights into the neuroprotective mechanisms of NMNATs in the injured developing brain, adding NMNAT3 as an important neuroprotective enzyme in neonatal H‐I via inhibition of apoptotic and necrotic neurodegeneration. Interestingly, we find that endogenous NMNAT3 is an inducible protein important for maintaining the survival of immature neurons. Future studies aimed at uncovering the mechanisms of NMNAT3 upregulation and neuroprotection may offer new therapies against the effects of hypoxic‐ischemic encephalopathy.
... In AD, NMNAT2 transcript levels negatively correlate with cognitive dysfunction and AD pathology [15 ]. Genomewide association studies have indicated a SNP (rs952797) located 126 kb downstream of the NMNAT3 gene that is associated with late-onset AD [16]. Although these association studies do not demonstrate a causal relationship, they do recommend NMNAT as an important contributor to neuronal health. ...
Nicotinamide mononucleotide adenylyl transferases (NMNATs) are a family of highly conserved proteins indispensable for cellular homeostasis. NMNATs are classically known for their enzymatic function of catalyzing NAD⁺ synthesis, but also have gained a reputation as essential neuronal maintenance factors. NMNAT deficiency has been associated with various human diseases with pronounced consequences on neural tissues, underscoring the importance of the neuronal maintenance and protective roles of these proteins. New mechanistic studies have challenged the role of NMNAT-catalyzed NAD⁺ production in delaying Wallerian degeneration and have specified new mechanisms of NMNAT’s chaperone function critical for neuronal health. Progress in understanding the regulation of NMNAT has uncovered a neuronal stress response with great therapeutic promise for treating various neurodegenerative conditions.
Disorders of behavior represent some of the most common and disabling diseases affecting humankind; however, despite their worldwide distribution, genetic influences on these illnesses are often overlooked by families and mental health professionals. Psychiatric genetics is a rapidly advancing field, elucidating the varied roles of specific genes and their interactions in brain development and dysregulation. Principles of Psychiatric Genetics includes 22 disorder-based chapters covering, amongst other conditions, schizophrenia, mood disorders, anxiety disorders, Alzheimer's disease, learning and developmental disorders, eating disorders and personality disorders. Supporting chapters focus on issues of genetic epidemiology, molecular and statistical methods, pharmacogenetics, epigenetics, gene expression studies, online genetic databases and ethical issues. Written by an international team of contributors, and fully updated with the latest results from genome-wide association studies, this comprehensive text is an indispensable reference for psychiatrists, neurologists, psychologists and anyone involved in psychiatric genetic studies.
Background:
5XFAD humanized mutant mice and Trem2 knockout (T2KO) mice are two mouse models relevant to the study of Alzheimer's disease (AD)-related pathology.
Objective:
To determine hippocampal transcriptomic and polyadenylation site usage alterations caused by genetic mutations engineered in 5XFAD and T2KO mice.
Methods:
Employing a publicly available single-nucleus RNA sequencing dataset, we used Seurat and Sierra analytic programs to identify differentially expressed genes (DEGs) and differential transcript usage (DTU), respectively, in hippocampal cell types from each of the two mouse models. We analyzed cell type-specific DEGs further using Ingenuity Pathway Analysis (IPA).
Results:
We identified several DEGs in both neuronal and glial cell subtypes in comparisons of wild type (WT) versus 5XFAD and WT versus T2KO mice, including Ttr, Fth1, Pcsk1n, Malat1, Rpl37, Rtn1, Sepw1, Uba52, Mbp, Arl6ip5, Gm26917, Vwa1, and Pgrmc1. We also observed DTU in common between the two comparisons in neuronal and glial subtypes, specifically in the genes Prnp, Rbm4b, Pnisr, Opcml, Cpne7, Adgrb1, Gabarapl2, Ubb, Ndfip1, Car11, and Stmn4. IPA identified 3 statistically significant canonical pathways that appeared in multiple cell types and that overlapped between 5XFAD and T2KO comparisons to WT, including 'FXR/RXR Activation', 'LXR/RXR Activation', and 'Acute Phase Response Signaling'.
Conclusion:
DEG, DTU, and IPA findings, derived from two different mouse models of AD, highlight the importance of energy imbalance and inflammatory processes in specific hippocampal cell types, including subtypes of neurons and glial cells, in the development of AD-related pathology. Additional studies are needed to further characterize these findings.
Background
Suicide with complex etiology and increased global prevalence is a challenge in genome-based biomarker discovery. The present study explores whole-genome association in a small, isolated, historical tribal population of Idu Mishmi from Dibang Valley of Arunachal Pradesh, India with a high rate of suicide.
Methods
Microarray genotyping (∼660,000 markers) was performed on 72 well-annotated un-related cases and controls for suicide risk. A logistic regression model adjusted for age, sex and descent was used to identify known/novel genetic markers implicated in suicide risk. STRING network analysis was implemented on significant genes found from this study, earlier re-tested SNPs genes in the same population and reported candidate genes for functional inference.
Results
We found 12 SNPs (all intronic, some downstream or upstream transcript variants) from nine genes with suggestive significance (p-value <0.00001) in the pathogenesis of suicide. Among the 12 SNPs, the variant (rs6454748) of GABRR2 gene was earlier reported for alcohol abuse. Genes GRM7, SIRT2 and RAPGEF4 from this study are strongly embedded within candidate/known genes in the STRING network and all genes we found in this study were implicated earlier with some other psychiatry disorders.
Limitation
Small sample size and considering GWAS significance threshold criteria at p-value < 0.00001 instead of stringent <10⁻⁸ in view of the exploratory nature of the study.
Conclusion
The present study illustrated the advantage of small, historical populations in eliciting genetics of complex diseases like suicide. Besides, network analysis provided an opportunity in validation of earlier candidate genes and pathways, besides proposing novel pathways in suicide risk. This study provided a framework of gene functional interactions for further exploration.
Wild boar (Sus scrofa L.) is one of the large mammals most spread worldwide, highly adaptable, and its population has rapidly increased in many areas in Europe. Central Italy, as well as Tuscany, is an area particularly suitable for wild boar. Wild boars are potential hosts for different etiological agents, such as Brucella spp., Leptospira spp. and Pseudorabies virus and can contribute to maintain and/or to disseminate some bacterial or viral pathogens to humans and domestic animals, above all-in free-range farms. In order to identify hypothetical genomic regions associated with these infection diseases, 96 samples of wild boars hunted in Tuscany during the 2018–2019 and 2019-2020 hunting seasons were considered. Diagnosis was achieved by serological tests and 42 Pseudorabies, 31 Leptospira and 15 Brucella positive animals were identified. All animals were genotyped with Geneseek Genomic Profiler Porcine HD (70k) and a genome-wide scan was then performed. Significant markers were highlighted for Pseudorabies (two SNPs), Brucella (seven SNPs), and Leptospira (four SNPs) and they were located within, or nearby, 29 annotated genes on chromosome 6, 9, 12, 13, 14 and 18. Eight genes are implicated in viral (SEC14L1, JMJD6, SRSF2, TMPRSS2, MX1, MX2) or bacterial (COL8A1, SPIRE1) infections, seven genes (MFSD11, METTL23, CTTNBP2, BACE2, IMPA2, MPPE1 and GNAL) are involved in mental disorders and one gene (MGAT5B) is related to the Golgi complex. Results presented here provide interesting starting points for future research, validation studies and fine mapping of candidate genes involved in bacterial and viral infections in wild boar.
Knowledge on the genetic aetiology of Alzheimer's disease has greatly increased over the past 20 years. We are now finding that more genetic variants than previously thought play a role in disease susceptibility.
Key Concepts
Advances in genetic research into a complex disorder.
Alzheimer's disease (AD) is the most common form of dementia and is genetically heterogeneous.
The APOE gene has the largest effect size on risk for AD, and is the most replicated finding.
Understanding of the genetic risk factors for AD has been greatly increased by advancements in technology.
Multiple gene have now been identified as being involved in the aetiology of AD, and have highlight biological pathways that may be affected.
Still, these genes do not account for all of the estimated genetic aetiology and therefore variants with even smaller effect size are being investigated through polygenic risk score analysis.
Background Identifying genetic interactions in data obtained from genome-wide association studies (GWASs) can help in understanding the genetic basis of complex diseases. The large number of single nucleotide polymorphisms (SNPs) in GWASs however makes the identification of genetic interactions computationally challenging. We developed the Bayesian Combinatorial Method (BCM) that can identify pairs of SNPs that in combination have high statistical association with disease. Results We applied BCM to two late-onset Alzheimer’s disease (LOAD) GWAS datasets to identify SNP-SNP interactions between a set of known SNP associations and the dataset SNPs. For evaluation we compared our results with those from PLINK, an established method. Gene Ontology analysis of genes from the top 200 dataset SNPs for both GWAS datasets showed overrepresentation of LOAD-related terms. Four genes were common to both datasets: APOE and APOC1, which have well established associations with LOAD, and CAMK1D and FBXL13, not previously linked to LOAD but having evidence of involvement in LOAD. Supporting evidence was also found for additional genes from the top 30 dataset SNPs. Conclusion BCM performed well in identifying several SNPs having evidence of involvement in the pathogenesis of LOAD that would not have been identified by univariate analysis due to small main effect. These results provide support for applying BCM to identify potential genetic variants such as SNPs from high dimensional GWAS datasets.
Germline copy number variants (CNVs) and single-nucleotide polymorphisms (SNPs) form the basis of inter-individual genetic variation. Although the phenotypic effects of SNPs have been extensively investigated, the effects of CNVs is relatively less understood. To better characterize mechanisms by which CNVs affect cellular phenotype, we tested their association with variable CpG methylation in a genome-wide manner. Using paired CNV and methylation data from the 1000 genomes and HapMap projects, we identified genome-wide associations by methylation quantitative trait locus (mQTL) analysis. We found individual CNVs being associated with methylation of multiple CpGs and vice versa. CNV-associated methylation changes were correlated with gene expression. CNV-mQTLs were enriched for regulatory regions, transcription factor-binding sites (TFBSs), and were involved in long-range physical interactions with associated CpGs. Some CNV-mQTLs were associated with methylation of imprinted genes. Several CNV-mQTLs and/or associated genes were among those previously reported by genome-wide association studies (GWASs). We demonstrate that germline CNVs in the genome are associated with CpG methylation. Our findings suggest that structural variation together with methylation may affect cellular phenotype.
Background Identifying genetic interactions in data obtained from genome-wide association studies (GWASs) can help in understanding the genetic basis of complex diseases. The large number of single nucleotide polymorphisms (SNPs) in GWASs however makes the identification of genetic interactions computationally challenging. We developed the Bayesian Combinatorial Method (BCM) that can identify pairs of SNPs that in combination have high statistical association with disease. Results We applied BCM to two late-onset Alzheimer’s disease (LOAD) GWAS datasets to identify SNP-SNP interactions between a set of known SNP associations and the dataset SNPs. For evaluation we compared our results with those from logistic regression, as implemented in PLINK. Gene Ontology analysis of genes from the top 200 dataset SNPs for both GWAS datasets showed overrepresentation of LOAD-related terms. Four genes were common to both datasets: APOE and APOC1, which have well established associations with LOAD, and CAMK1D and FBXL13, not previously linked to LOAD but having evidence of involvement in LOAD. Supporting evidence was also found for additional genes from the top 30 dataset SNPs. Conclusion BCM performed well in identifying several SNPs having evidence of involvement in the pathogenesis of LOAD that would not have been identified by univariate analysis due to small main effect. These results provide support for applying BCM to identify potential genetic variants such as SNPs from high dimensional GWAS datasets.
Familial clustering of schizophrenia (SCZ), bipolar disorder (BPD), and major depressive disorder (MDD) was investigated systematically (Aukes et al., Genet Med 2012, 14, 338‐341) and any two or even three of these disorders could co‐exist in some families. Furthermore, evidence from symptomatology and psychopharmacology also imply the existence of intrinsic connections between these three major psychiatric disorders. A total of 71,445 SNPs on chromosome 1 were genotyped on 119 SCZ, 253 BPD (type‐I), 177 MDD cases and 1000 controls and further validated in 986 SCZ patients in the population of Shandong province of China. Outstanding psychosis genes are systematically revealed( ATP1A4, ELTD1, FAM5C, HHAT, KIF26B, LMX1A, NEGR1, NFIA, NR5A2, NTNG1, PAPPA2, PDE4B, PEX14, RYR2, SYT6, TGFBR3, TTLL7 and USH2A). Unexpectedly, flanking genes for up to 97.09% of the associated SNPs were also replicated in an enlarged cohort of 986 SCZ patients. From the perspective of etiological rather than clinical psychiatry, bipolar and major depressive disorder could be subtypes of schizophrenia. Meanwhile, the varied clinical feature and prognosis might be the result of interaction of genetics and epigenetics, for example, irreversible or reversible shut down, and over or insufficient expression of certain genes. Also, similar evidence has emerged from other chromosomes such as chr3, chr4, chr5, chr6, chr7 and chr8 (J Comp Neurol 2018; 526(1):59‐79; J Comp Neurol 2019; 527(2): 392‐405. Am J Transl Res 2017; 9(5):2473‐91; Curr Mol Med 2016; 16(9):840‐54; Behav Brain Res 2015; 293:241‐51; Mol Neurobiol 2017; 54(8):5868‐82).
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Here we reported novel apigenin-rivastigmine hybrids were rationally designed and synthesized by the multi-target-directed ligands (MTDLs) strategy, their activity in vitro results revealed that compound 3d showed significant antioxidant potency (ORAC = 1.3 eq), and it was a reversible huAChE (IC50 = 6.8 μM) and huBChE (IC50 = 16.1 μM) inhibitor. 3d also served as a selective metal chelator, and it significantly inhibited and disaggregated self-mediated and Cu2+-mediated Aβ1-42 aggregation, and also inhibited hAChE-mediated induced Aβ1-40 aggregation. Compound 3d exhibited remarkable neuroprotective effect and hepatoprotective activity. In addition, compound 3d presented favourable blood-brain barrier penetration in vitro and drug-like property. Further, the in vivo assay displayed that 3d indicated remarkable dyskinesia recovery rate and response efficiency on AD zebrafish, and exhibited surprising protective effect on Aβ1-40-mediated zebrafish vascular injury. More importantly, 3d did not indicate obvious acute toxicity at dose up to 2000 mg/kg, and could improve scopolamine-induced memory impairment. Subsequently, the regulation of multi-targets for 3d were further confirmed through transcriptome sequencing of brain hippocampi, which also offered novel potential targets and opened a new way to treat Alzheimer's disease. More interestingly, the metabolism of 3din vitro indicated that 4 metabolites in rat liver microsome metabolism, 2 metabolites in human liver microsome metabolism, and 4 metabolites in intestinal flora metabolism, which offered supports for the preclinical study of 3d. Overall, this study exhibited that compound 3d was a promising advanced compound targeted multiple factors associated with AD.
Background:
Schizophrenia (SCZ) and dementia, often related, are two of the most common neuropsychiatric diseases; epidemiological studies have shown that SCZ patients present a 2-fold increased risk for dementia compared to non-schizophrenic individuals. We explored the presence of rare and novel damaging gene variants in patients diagnosed with late-onset dementia of Alzheimer's type (DAT) or SCZ.
Methods:
We included 7 DAT and 12 SCZ patients and performed high-depth targeted sequencing of 184 genes.
Results:
We found novel and rare damaging variants in 18 genes in these Mexican patients. Carriers of these variants showed extreme phenotypes, including, treatment-resistant SCZ or cognitive decline. Furthermore, we found a variation on ABCC1 as a possible link between psychosis and cognitive impairment.
Discussion:
As an exploratory analysis, we report some interesting variations that should be corroborated in larger sample size studies.
The genetic correlates of extreme impulsive violence are poorly understood, and there have been no studies that have systematically characterized a large group of affected individuals both clinically and genetically. We performed a genome‐wide rare copy number variant (CNV) analysis in 281 males from 4 Czech prisons who met strict clinical criteria for extreme impulsive violence. Inclusion criteria included age > 18 years, an ICD 10 diagnosis of Dissocial Personality Disorder, and the absence of an organic brain disorder. Participants underwent a structured psychiatric assessment to diagnose extreme impulsive violence and then provided a blood sample for genetic analysis. DNA was genotyped and CNVs were identified using Illumina HumanOmni2.5 SNP array platform. Comparing with 15,500 external population controls we identified 828 rare CNVs (frequency ≤ 0.1% among control samples) in 264 participants. The CNVs impacted 754 genes, with 124 genes impacted more than once (2‐25‐times). Many of these genes are associated with autosomal dominant or X‐linked disorders affecting adult behaviour, cognition, learning, intelligence, specifically expressed in the brain, and relevant to synapses, neurodevelopment, neurodegeneration, obesity and neuropsychiatric phenotypes. Specifically we identified 31 CNVs of clinical relevance in 31 individuals, 59 likely clinically relevant CNVs in 49 individuals, and 17 recurrent CNVs in 65 individuals. Thus, 123 of 281 (44%) individuals had one to several rare CNVs that were likely relevant to impulsive violence. Extreme impulsive violence is genetically heterogeneous and genomic analysis is likely required to identify, further research and specifically treat the causes in affected individuals.
The Alzheimer's Disease Sequencing Project (ADSP) performed whole genome sequencing (WGS) of 584 subjects from 111 multiplex families at three sequencing centers. Genotype calling of single nucleotide variants (SNVs) and insertion-deletion variants (indels) was performed centrally using GATK-HaplotypeCaller and Atlas V2. The ADSP Quality Control (QC) Working Group applied QC protocols to project-level variant call format files (VCFs) from each pipeline, and developed and implemented a novel protocol, termed "consensus calling," to combine genotype calls from both pipelines into a single high-quality set. QC was applied to autosomal bi-allelic SNVs and indels, and included pipeline-recommended QC filters, variant-level QC, and sample-level QC. Low-quality variants or genotypes were excluded, and sample outliers were noted. Quality was assessed by examining Mendelian inconsistencies (MIs) among 67 parent-offspring pairs, and MIs were used to establish additional genotype-specific filters for GATK calls. After QC, 578 subjects remained. Pipeline-specific QC excluded ~12.0% of GATK and 14.5% of Atlas SNVs. Between pipelines, ~91% of SNV genotypes across all QCed variants were concordant; 4.23% and 4.56% of genotypes were exclusive to Atlas or GATK, respectively; the remaining ~0.01% of discordant genotypes were excluded. For indels, variant-level QC excluded ~36.8% of GATK and 35.3% of Atlas indels. Between pipelines, ~55.6% of indel genotypes were concordant; while 10.3% and 28.3% were exclusive to Atlas or GATK, respectively; and ~0.29% of discordant genotypes were. The final WGS consensus dataset contains 27,896,774 SNVs and 3,133,926 indels and is publicly available.
The most frequent forms of Alzheimer’s disease (AD) are complex, and their distribution within families cannot be explained by a Mendelian model of inheritance. In fact, these forms of AD result from a combination of genetic and environmental factors, with the estimated heritability ranging from 58 to 79%. This chapter reviews the large body of research on genetic risk factors in AD. Linkage analyses and candidate gene association studies have notably identified APOE (the major genetic risk factor for AD) and SORL1. Most of the other loci known to be associated with AD have been identified in genome-wide association studies and (more recently) analyses of rare variants. These AD-associated loci and genes have highlighted a number of underlying biological mechanisms, which will be discussed briefly. Although some of these pathways (e.g., amyloid precursor protein (APP) metabolism and tau pathology) fit with the amyloid cascade hypothesis, others point out innate immunity and microglia.
Over the past 5 years, whole exome sequencing (WES) ignited a revolution in genomic science, triggering a wave of genetic discoveries that have dramatically improved our understanding of the human genetic landscape. In my research, I have used this innovative approach to explore different facets of the complex genetic architecture of Alzheimer’s disease (AD). First, given the phenotypic overlap between different neurodegenerative dementias such as frontotemporal dementia (FTD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD) and Alzheimer’s disease, I tested the hypothesis that Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT and PRNP) may influence sporadic Alzheimer’s disease. Second, genome-wide association studies (GWASs) have identified 9 main susceptibility loci for AD (CLU, PICALM, BIN1, EPHA1, ABCA7, MS4A6A, CD33, CR1, CD2AP). Although these have been consistently replicated, the risk variants underlying these GWASs hits still need to be identified, thus I have investigated the whole spectrum of protein-coding variability within these candidate loci. Third, the ‘Amyloid cascade hypothesis’ is the ‘Rosetta stone’ of AD pathology, therefore I have analyzed genes involved in APP-Aß metabolism. Fourth, the discovery of TREM2, the second most significant risk factor for AD. This tremendous finding has been the result of an extensive collaboration and the exome sequencing data that I have generated were the initial foundation of this work. Finally, an increasing body of evidence has shown that causative genes for complex Mendelian syndromes may harbor risk factors for common polygenic diseases. Thus, I have analyzed rare coding variants in Mendelian leukodystrophy genes, as potential susceptibility factors for Alzheimer’s disease. In conclusion, my research emphasizes the pivotal role of rare protein-coding variability in AD genetics. Whole exome sequencing has enabled researchers to explore the human genetic architecture in a comprehensive and unprecedented way, drawing maps of rare coding variability across the human genetic landscape. My doctoral thesis is a reflection of this exciting advancement.
Neurotrimin (Ntm) belongs to the IgLON family of cell adhesion molecules with Lsamp, Obcam and kilon that regulate the outgrowth of neurites mostly by forming heterodimers. IgLONs have been associated with psychiatric disorders, intelligence, body weight, heart disease and tumours. This study provides an initial behavioural and pharmacological characterization of the phenotype of Ntm-deficient mice. We expected to see at least some overlap with the phenotype of Lsamp-deficient mice as Ntm and Lsamp are the main interaction partners in the IgLON family and are colocalized in some brain regions. However, Ntm-deficient mice displayed none of the deviations in behaviour that we have previously shown in Lsamp-deficient mice, but differently from Lsamp-deficient mice, had a deficit in emotional learning in the active avoidance task. The only overlap was decreased sensitivity to the locomotor stimulating effect of amphetamine in both knockout models. Thus, despite being interaction partners, on the behavioural level Lsamp seems to play a much more central role than Ntm and the roles of these two proteins seem to be complementary rather than overlapping.
A candidate gene for the chromosome 1 Alzheimer's disease (AD) locus was
identified (STM2). The predicted amino acid sequence for STM2 is
homologous to that of the recently cloned chromosome 14 AD gene (S182).
A point mutation in STM2, resulting in the substitution of an isoleucine
for an asparagine (N141l), was identified in affected people from Volga
German AD kindreds. This N141l mutation occurs at an amino acid residue
that is conserved in human S182 and in the mouse S182 homolog. The
presence of missense mutations in AD subjects in two highly similar
genes strongly supports the hypothesis that mutations in both are
pathogenic.
Nicastrin, a transmembrane glycoprotein, forms high molecular weight complexes
with presenilin 1 and presenilin 2. Suppression of nicastrin expression in
Caenorhabditis elegans embryos induces a subset of notch/glp-1
phenotypes similar to those induced by simultaneous null mutations in both
presenilin homologues of C. elegans (sel-12 and hop-1).
Nicastrin also binds carboxy-terminal derivatives of -amyloid precursor
protein (APP), and modulates the production of the amyloid -peptide
(A) from these derivatives. Missense mutations in a conserved hydrophilic
domain of nicastrin increase A42 and A40
peptide secretion. Deletions in this domain inhibit A production. Nicastrin
and presenilins are therefore likely to be functional components of a multimeric
complex necessary for the intramembranous proteolysis of proteins such as
Notch/GLP-1 and APP.
Objective: To estimate the prevalence of dementia and its subtypes in the general population and examine the relation of the disease to education.
Design: Population based cross sectional study.
Setting: Ommoord, a suburb of Rotterdam.
Subjects: 7528 participants of the Rotterdam study aged 55-106 years.
Results: 474 cases of dementia were detected, giving an overall prevalence of 6.3%. Prevalence ranged from 0.4% (5/1181 subjects) at age 55-59 years to 43.2% (19/44) at 95 years and over. Alzheimer's disease was the main subdiagnosis (339 cases; 72%); it was also the main cause of the pronounced increase in dementia with age. The relative proportion of vascular dementia (76 cases; 16%), Parkinson's disease dementia (30; 6%), and other dementias (24; 5%) decreased with age. A substantially higher prevalence of dementia was found in subjects with a low level of education. The association with education was not due to confounding by cardiovascular disease.
Conclusions: The prevalence of dementia increases exponentially with age. About one third of the population aged 85 and over has dementia. Three quarters of all dementia is due to Alzheimer's disease. In this study an inverse dose-response relation was found between education and dementia—in particular, Alzheimer's disease.
Key messages
Key messagesOf all cases of dementia, 72% were cases of Alzheimer's diseaseThe pronounced increase in prevalence of dementia with age was due to a substantial increase in Alzheimer's diseaseAlzheimer's disease was more often diagnosed in less educated peopleThe association between dementia and education could not be explained by cardiovascular disease comorbidity
We have genotyped 292 affected sibling pairs (ASPs) with Alzheimer's disease (AD) according to NINCDS-ADRDA diagnostic criteria and with onset ages of >/=65 years using 237 microsatellite markers separated by an average distance of 16.3 cM. Data were analysed by SPLINK and MAPMAKER/SIBS on the whole sample of 292 ASPs and subsets of 162 ASPs where both members possessed an apolipoprotein E (APOE)straightepsilon4 allele and 63 pairs where neither possessed anstraightepsilon4 allele. Sixteen peaks with a multipoint lod score (MLS) >1 either in the whole sample, the straightepsilon4-positive or -negative subgroups were observed on chromosomes 1 (two peaks), 2, 5, 6, 9 (two peaks), 10 (two peaks), 12, 13, 14, 19, 21 and X (two peaks). Simulation studies revealed that these findings exceeded those expected by chance, although many are likely to be false positives. The highest lod scores on chromosomes 1 (MLS 2.67), 9 (MLS 2.38), 10 (MLS 2.27) and 19 (MLS 1.79) fulfilLander and Kruglyak's definition of 'suggestive' in that they would be expected to occur by chance once or less per genome scan. Several other peaks were only marginally less significant than this, in particular those on chromosomes 14 (MLS 2.16), 5 (MLS 2.00), 12, close to alpha2-macroglobulin (MLS 1.91), and 21, close to amyloid precursor protein (MLS 1.77). This is the largest genome scan to date in AD and shows for the first time that this is a genetically complex disorder involving several, perhaps many, genes in addition to APOE. Moreover, our data will be of interest to those hoping to identify positional candidate genes using information emerging from neurobiological studies of AD.
By using a variety of biochemical techniques, chromatin and chromatin fragments have been identified as probable physiological ligands for C-reactive protein. Studies using 14C-labeled C-reactive protein show that binding to chromatin is saturable with a Kd = 8 X 10(-7) M, a value indicating that the affinity of C-reactive protein for chromatin is at least four times its affinity for phosphorylcholine. At saturation, there is approximately one C-reactive protein-binding site for every 160 base pairs of DNA in chromatin. The interaction of C-reactive protein with chicken erythrocyte nucleosome core particle has been studied. Fifty per cent inhibition of the binding of C-reactive protein to phosphorylcholine is obtained at a core particle concentration of 1.25 X 10(-9) M, indicating that the affinity of C-reactive protein for one of the sites on core particles is at least 2400 times greater than the affinity of C-reactive protein for phosphorylcholine. The possibility that C-reactive protein may act as a scavenger for chromatin fragments released from damaged cells is discussed.
Several studies have reported an association of the apolipoprotein E allele epsilon 4 (APOE*4) to familial and sporadic late-onset Alzheimer's disease (LOAD). Here we report on the relationship between APOE*4 and early-onset Alzheimer's disease (EOAD) in a Dutch population-based study. The frequency of the APOE*4 allele was 2.3 times higher among EOAD cases compared to controls. Among patients, the allele frequency was 1.6 times higher in those with a positive family history than in those without. A significant increase in risk of EOAD was found for subjects homozygous for APOE*4 regardless of family history of dementia, but an increase in EOAD risk for APOE*4 heterozygotes could only be shown in subjects with a positive family history. Our study demonstrates a significant association between APOE*4 and EOAD which is modified by family history of dementia.
The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic
forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years
with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major
risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD
by age 80.
General and specific cognitive abilities were studied in intact Swedish same-sex twin pairs 80 or more years old for whom
neither twin had major cognitive, sensory, or motor impairment. Resemblance for 110 identical twin pairs significantly exceeded
resemblance for 130 fraternal same-sex twin pairs for all abilities. Maximum-likelihood model-fitting estimates of heritability
were 62 percent for general cognitive ability, 55 percent for verbal ability, 32 percent for spatial ability, 62 percent for
speed of processing, and 52 percent for memory. There was also evidence for the significant influence of idiosyncratic experience
as the environmental component that most determines individual differences in cognitive abilities late in life.
Results of previous studies suggest that memory complaints may predict cognitive decline and dementia among elderly people in whom cognitive impairment is already apparent. However, cognitive decline is often a gradual process, and elderly people may notice that their memory deteriorates before mental status tests are able to detect any change in cognitive functioning. Therefore, the authors hypothesized that memory complaints would predict incident Alzheimer's disease in elderly subjects with no signs of cognitive impairment.
In the community-based Amsterdam Study of the Elderly, a sample of 3,778 nondemented persons, 65 to 84 years old, was selected and divided into two cognitive categories: normal (Mini-Mental State scores of 26-30) and borderline and impaired (Mini-Mental State scores less than 26). At baseline, the presence or absence of memory complaints was assessed. At follow-up, incident cases of Alzheimer's disease were diagnosed in a two-step procedure.
After an average of 3.2 years, 2,169 persons were reevaluated, of whom 77 had incident Alzheimer's disease. Multivariate logistic regression analyses showed that memory complaints were associated with incident Alzheimer's disease in subjects with normal baseline cognition but not in subjects with impaired baseline cognition.
The findings of this study suggest that memory complaints are a relatively strong predictor of incident Alzheimer's disease in older persons in whom cognitive impairment is not yet apparent. Furthermore, they suggest that older persons may be aware of a decline in cognition at a time when mental status tests are still unable to detect a decline from premorbid functioning.
Plasma Aβ42 (amyloid β42 peptide) is invariably elevated in early-onset familial Alzheimer's disease (AD), and it is also
increased in the first-degree relatives of patients with typical late-onset AD (LOAD). To detect LOAD loci that increase Aβ42,
we used plasma Aβ42 as a surrogate trait and performed linkage analysis on extended AD pedigrees identified through a LOAD
patient with extremely high plasma Aβ. Here, we report linkage to chromosome 10 with a maximal lod score of 3.93 at 81 centimorgans
close to D10S1225. Remarkably, linkage to the same region was obtained independently in a genome-wide screen of LOAD sibling
pairs. These results provide strong evidence for a novel LOAD locus on chromosome 10 that acts to increase Aβ.
Efforts to find disease genes using high-density single-nucleotide polymorphism (SNP) maps will produce data sets that exceed the limitations of current computational tools. Here we describe a new, efficient method for the analysis of dense genetic maps in pedigree data that provides extremely fast solutions to common problems such as allele-sharing analyses and haplotyping. We show that sparse binary trees represent patterns of gene flow in general pedigrees in a parsimonious manner, and derive a family of related algorithms for pedigree traversal. With these trees, exact likelihood calculations can be carried out efficiently for single markers or for multiple linked markers. Using an approximate multipoint calculation that ignores the unlikely possibility of a large number of recombinants further improves speed and provides accurate solutions in dense maps with thousands of markers. Our multipoint engine for rapid likelihood inference (Merlin) is a computer program that uses sparse inheritance trees for pedigree analysis; it performs rapid haplotyping, genotype error detection and affected pair linkage analyses and can handle more markers than other pedigree analysis packages.
The apolipoprotein E type 4 allele (APOE-epsilon 4) is genetically associated with the common late onset familial and sporadic forms of Alzheimer's disease (AD). Risk for AD increased from 20% to 90% and mean age at onset decreased from 84 to 68 years with increasing number of APOE-epsilon 4 alleles in 42 families with late onset AD. Thus APOE-epsilon 4 gene dose is a major risk factor for late onset AD and, in these families, homozygosity for APOE-epsilon 4 was virtually sufficient to cause AD by age 80.
Efforts to find disease genes using high-density single-nucleotide polymorphism (SNP) maps will produce data sets that exceed the limitations of current computational tools. Here we describe a new, efficient method for the analysis of dense genetic maps in pedigree data that provides extremely fast solutions to common problems such as allele-sharing analyses and haplotyping. We show that sparse binary trees represent patterns of gene flow in general pedigrees in a parsimonious manner, and derive a family of related algorithms for pedigree traversal. With these trees, exact likelihood calculations can be carried out efficiently for single markers or for multiple linked markers. Using an approximate multipoint calculation that ignores the unlikely possibility of a large number of recombinants further improves speed and provides accurate solutions in dense maps with thousands of markers. Our multi-point engine for rapid likelihood inference (Merlin) is a computer program that uses sparse inheritance trees for pedigree analysis; it performs rapid haplotyping, genotype error detection and affected pair linkage analyses and can handle more markers than other pedigree analysis packages.
We investigate the contribution of the Iberian bat fauna to the cryptic diversity in Europe using mitochondrial (cytb and ND1) and nuclear (RAG2) DNA sequences. For each of the 28 bat species known for Iberia, samples covering a wide geographic range within Spain were compared to samples from the rest of Europe. In this general screening, almost 20% of the Iberian species showed important mitochondrial discontinuities (K2P distance values > 5%) either within the Iberian or between Iberian and other European samples. Within Eptesicus serotinus and Myotis nattereri, levels of genetic divergence between lineages exceeded 16%, indicating that these taxa represent a complex of several biological species. Other well-differentiated lineages (K2P distances between 5–10%) appeared within Hypsugo savii, Pipistrellus kuhlii and Plecotus auritus, suggesting the existence of further cryptic diversity. Most unsuspected lineages seem restricted to Iberia, although two have crossed the Pyrenees to reach, at leas...
Alzheimer's disease (AD) is a devastating neurodegenerative disorder of late life with complex inheritance. Mutations in three known genes lead to the rare early-onset autosomal dominant form of AD, while a common polymorphism (e4) in the gene encoding apolipoprotein E (APOE) is a risk factor for more typical late-onset (>60 years) AD. A recent study concluded that there are up to four additional genes with an equal or greater contribution to the disease. We performed a 9cM genome screen of 437 families with AD, the full National Institute of Mental Health (NIMH) sample, which has been carefully ascertained, evaluated and followed by our group over the last decade. Performing standard parametric and non-parametric linkage analyses, we observed a 'highly significant' linkage peak by Lander and Kruglyak criteria on chromosome 19q13, which probably represents APOE. Twelve additional locations-on 1q23, 3p26, 4q32, 5p14, 6p21, 6q27, 9q22, 10q24, 11q25, 14q22, 15q26 and 21q22-met criteria for 'suggestive' linkage [i.e. two-point lod score (TLS) ≥1.9 andl or multipoint lod score (MLS)≥2.2] in at least one of our analyses. Although some of these will surely prove to be false positives, these linkage signals should provide a valuable framework for future studies aimed at identifying additional susceptibility genes for late-onset AD.
We reanalyzed and compared current prevalence estimates of Alzheimer's disease in Europe. Studies characterized as follows qualified for comparison: dementia defined by the Diagnostic and Statistical Manual for Mental Disorders, 3rd edition, or equivalent criteria; Alzheimer's disease diagnosed by the National Institute of Neurological and Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association or equivalent criteria; case-finding through direct individual examination; appropriate sample size; and inclusion of institutionalized persons. Of the 23 European surveys of dementia considered, six fulfilled the inclusion criteria. When age and sex were considered, there were no major geographic differences in the prevalence of Alzheimer's disease across Europe. Overall European prevalence (per 100 population) for the age groups 30 to 59, 60 to 69, 70 to 79, and 80 to 89 years was, respectively, 0.02, 0.3, 3.2, and 10.8. Prevalence increased exponentially with advancing age and, in some populations, was consistently higher in women. Prevalence remained stable over 15 years in one study.
A LOCUS segregating with familial Alzheimer's disease (AD) has been
mapped to chromosome 21 (ref. 1), close to the amyloid precursor protein
(APP) gene2-5. Recombinants between the APP gene and the AD
locus have been reported6-8 which seemed to exclude it as the
site of the mutation causing familial AD. But recent genetic analysis of
a large number of AD families has demonstrated that the disease is
heterogeneous9. Families with late-onset AD do not show
linkage to chromosome 21 markers9,10. Some families with
early-onset AD show linkage to chromosome 21 markers, but some do
not8,9,11. This has led to the suggestion that there is
non-allelic genetic heterogeneity even within early onset familial
AD8,9. To avoid the problems that heterogeneity poses for
genetic analysis, we have examined the cosegregation of AD and markers
along the long arm of chromosome 21 in a single family with AD confirmed
by autopsy. Here we demonstrate that in this kindred, which shows
linkage to chromosome 21 markers, there is a point mutation in the APP
gene. This mutation causes an amino-acid substitution (Val-->Ile)
close to the carboxy terminus of the β-amyloid peptide. Screening
other cases of familial AD revealed a second unrelated family in which
this variant occurs. This suggests that some cases of AD could be caused
by mutations in the APP gene.
A powerful approach to mapping the genes for complex traits is to study isolated founder populations, in which genetic heterogeneity and environmental noise are likely to be reduced and in which extended genealogical data are often available. Using graph theory, we applied an approach that involved sampling from the large number of pairwise relationships present in an extended genealogy to reconstruct sets of subpedigrees that maximize the useful information for linkage mapping while minimizing calculation burden. We investigated, through simulation, the properties of the different sets in terms of bias in identity-by-descent (IBD) estimation and power decrease under various genetic models. We applied this approach to a small isolated population from Sardinia, the village of Talana, consisting of a unique large and complex pedigree, and performed a genomewide search through variance-com-ponents linkage analysis for serum lipid levels. We identified a region of significant linkage on chromosome 2 for total serum cholesterol and low-density lipoprotein (LDL) cholesterol. Through higher-density mapping, we obtained an increased linkage for both traits on 2q21.2-q24.1, with a LOD score of 4.3 for total serum cholesterol and of 3.9 for LDL cholesterol. A replication study was performed in an independent and larger set from a genetically differentiated isolated population of the same region of Sardinia, the village of Perdasdefogu. We obtained consistent linkage to the region for total serum cholesterol (LOD score 1.4) and LDL cholesterol (LOD score 2.2), with a level of concordance uncommon for complex traits, and refined the location of the quantitative-trait locus. Inter-estingly, the 2q21.1-22 region has also been linked to premature coronary heart disease in Finns, and, in the adjacent 2q14 region, significant linkage with triglycerides has been reported in Hutterites.
The past decade has witnessed hundreds of reports declaring or refuting genetic association with putative Alzheimer disease susceptibility genes. This wealth of information has become increasingly difficult to follow, much less interpret. We have created a publicly available, continuously updated database that comprehensively catalogs all genetic association studies in the field of Alzheimer disease (http://www.alzgene.org). We performed systematic meta-analyses for each polymorphism with available genotype data in at least three case-control samples. In addition to identifying the ε4 allele of APOE and related effects, we pinpointed over a dozen potential Alzheimer disease susceptibility genes (ACE, CHRNB2, CST3, ESR1, GAPDHS, IDE, MTHFR, NCSTN, PRNP, PSEN1, TF, TFAM and TNF) with statistically significant allelic summary odds ratios (ranging from 1.11-1.38 for risk alleles and 0.92-0.67 for protective alleles). Our database provides a powerful tool for deciphering the genetics of Alzheimer disease, and it serves as a potential model for tracking the most viable gene candidates in other genetically complex diseases.
We have genotyped 292 affected sibling pairs (ASPs) with Alzheimer's disease (AD) according to NINCDS– ADRDA diagnostic criteria and with onset ages of ≥65 years using 237 microsatellite markers separated by an average distance of 16.3 cM. Data were analysed by SPLINK and MAPMAKER/SIBS on the whole sample of 292 ASPs and subsets of 162 ASPs where both members possessed an apolipoprotein E (APOE) ε4 allele and 63 pairs where neither possessed an ε4 allele. Sixteen peaks with a multipoint lod score (MLS) >1 either in the whole sample, the ε4-positive or-negative subgroups were observed on chromosomes 1 (two peaks), 2, 5, 6, 9 (two peaks), 10 (two peaks), 12, 13, 14, 19, 21 and X (two peaks). Simulation studies revealed that these findings exceeded those expected by chance, although many are likely to be false positives. The highest lod scores on chromosomes 1 (MLS 2.67), 9 (MLS 2.38), 10 (MLS 2.27) and 19 (MLS 1.79) fulfil Lander and Kruglyak's definition of 'suggestive' in that they would be expected to occur by chance once or less per genome scan. Several other peaks were only marginally less significant than this, in particular those on chromosomes 14 (MLS 2.16), 5 (MLS 2.00), 12, close to α2-macroglobulin (MLS 1.91), and 21, close to amyloid precursor protein (MLS 1.77). This is the largest genome scan to date in AD and shows for the first time that this is a genetically complex disorder involving several, perhaps many, genes in addition to APOE. Moreover, our data will be of interest to those hoping to identify positional candidate genes using information emerging from neurobiological studies of AD.
Four different loci have been found to be involved in the development of familial Alzheimer disease (AD). The [varepsilon]4 allele of the apolipoprotein E gene on chromosome 19 is a susceptibility factor for AD, and in a small number of AD families, dominant mutations with high penetrance are operating in genes on chromosomes 1, 14 and 21. However, the disease in many familial AD cases cannot be explained by these genes; thus, other genetic factors involved in the etiology of AD should exist. Recently, an association between the cytochrome P450 2D6B (CYP2D6B) allele and the Lewy body variant of AD was reported. In the present study, 54 unrelated Swedish familial AD patients and 56 age- and sex-matched healthy controls were studied with respect to the two genetic polymorphisms of oxidative drug metabolism, CYP2D6 and CYP2C19. No significant association was found between the defect CYP2D6A and -B or CYP2C19m 1 and -m2 alleles and familial AD patients, with the exception of a lower frequency of CYP2D6B in the male AD cases.
(C) 1998 Lippincott Williams & Wilkins, Inc.
We performed a two-stage genome screen to search for novel risk factors for late-onset Alzheimer disease (AD). The first stage involved genotyping 292 affected sibling pairs using 237 markers spaced at approximately 20 cM intervals throughout the genome. In the second stage, we genotyped 451 affected sibling pairs (ASPs) with an additional 91 markers, in the 16 regions where the multipoint LOD score was greater than 1 in stage I. Ten regions maintained LOD scores in excess of 1 in stage II, on chromosomes 1 (peak B), 5, 6, 9 (peaks A and B), 10, 12, 19, 21, and X. Our strongest evidence for linkage was on chromosome 10, where we obtained a peak multipoint LOD score (MLS) of 3.9. The linked region on chromosome 10 spans approximately 44 cM from D10S1426 (59 cM) to D10S2327 (103 cM). To narrow this region, we tested for linkage disequilibrium with several of the stage II microsatellite markers. Of the seven markers we tested in family-based and case control samples, the only nominally positive association we found was with the 167 bp allele of marker D10S1217 (chi-square = 7.11, P = 0.045, df = 1).
The genetic make-up of genetically isolated populations may differ from a general population as a result of genetic drift and founder effects. We assessed the extent of this deviation in a recently isolated population located in the southwest of the Netherlands and studied as part of the Genetic Research in Isolated Population (GRIP) program. A gene-dropping experiment was performed in a large pedigree from this isolate, assuming different initial frequencies in the population founders came from. Allelic frequencies in the last generations of this pedigree were estimated. Simulation analysis showed large fluctuations, as measured by variation coefficient and sufficient loss probability, when initial frequencies were lower than or equal to 1%. For initial frequencies larger than 1% the fluctuations were small. We also analyzed mean heterozygosity and allele diversity of 592 markers in a random sample from the GRIP population. The results were compared with a general population (CEPH sample), old large isolate (Icelandic sample) and the small-sized population of Talana (Sardinia). GRIP mean heterozygosity and mean number of alleles were significantly lower as compared with CEPH and Iceland, but much higher when compared with the Talana population. We also concluded that the findings from the GRIP population for common variants (>1%) are likely to be extendable to other young isolates in Europe as well as to outbred populations.
Working memory (WM) encompasses both short-term memory (storage) and executive functions that play an essential role in all forms of cognition. In this study, the genetic structure of storage and executive functions engaged in both a spatial and verbal WM span task is investigated using a twin sample. The sample consists of 143 monozygotic (MZ) and 93 dizygotic (DZ) Japanese twin pairs, ages 16 to 29 years. In 155 (87 MZ, 62 DZ) of these pairs, cognitive ability scores from the Kyodai Japanese IQ test are also obtained. The phenotypic relationship between WM and cognitive ability is confirmed (r = 0.26–0.44). Individual differences in WM storage and executive functions are found to be significantly influenced by genes, with heritability estimates all moderately high (43%–49%), and estimates for cognitive ability comparable to previous studies (65%). A large part of the genetic variance in storage and executive functions in both spatial and verbal modalities is due to a common genetic factor that accounts for 11% to 43% of the variance. In the reduced sample, this common genetic factor accounts for 64% and 26% of the variance in spatial and verbal cognitive ability, respectively. Additional genetic variance in WM (7%–30%) is due to modality specific factors (spatial and verbal) and a storage specific factor that may be particularly important for the verbal modality. None of the variance in cognitive ability is accounted for by the modality and storage genetic factors, suggesting these may be specific to WM.
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Clinical criteria for the diagnosis of Alzheimer's disease include insidious onset and progressive impairment of memory and other cognitive functions. There are no motor, sensory, or coordination deficits early in the disease. The diagnosis cannot be determined by laboratory tests. These tests are important primarily in identifying other possible causes of dementia that must be excluded before the diagnosis of Alzheimer's disease may be made with confidence. Neuropsychological tests provide confirmatory evidence of the diagnosis of dementia and help to assess the course and response to therapy. The criteria proposed are intended to serve as a guide for the diagnosis of probable, possible, and definite Alzheimer's disease; these criteria will be revised as more definitive information become available.
Some cases of Alzheimer's disease are inherited as an autosomal dominant trait. Genetic linkage studies have mapped a locus (AD3) associated with susceptibility to a very aggressive form of Alzheimer's disease to chromosome 14q24.3. We have defined a minimal cosegregating region containing the AD3 gene, and isolated at least 19 different transcripts encoded within this region. One of these transcripts (S182) corresponds to a novel gene whose product is predicted to contain multiple transmembrane domains and resembles an integral membrane protein. Five different missense mutations have been found that cosegregate with early-onset familial Alzheimer's disease. Because these changes occurred in conserved domains of this gene, and are not present in normal controls, they are likely to be causative of AD3.
We report the cloning of a novel gene (E5-1) encoded on chromosome 1 which has substantial nucleotide and amino-acid sequence similarity to the S182 gene on chromosome 14q24.3. Mutations, including three new missense mutations in the S182 gene, are associated with the AD3 subtype of early-onset familial Alzheimer's disease (AD). Both the E5-1 and the S182 proteins are predicted to be integral membrane proteins with seven membrane-spanning domains, and a large exposed loop between the sixth and seventh transmembrane domains. Analysis of the nucleotide sequence of the open reading frame (ORF) of the E5-1 gene led to the discovery of two missense substitutions at conserved amino-acid residues in affected members of pedigrees with a form of familial AD that has a later age of onset than the AD3 subtype (50-70 years versus 30-60 years for AD3). These observations imply that the E5-1 gene on chromosome 1 and the S182 gene on chromosome 14q24.3 are members of a family of genes (presenilins) with related functions, and indicates that mutations in conserved residues of E5-1 could also play a role in the genesis of AD. Our results also indicate that still other AD susceptibility genes exist.
The binding of [3H]-U-69593 and [3H]-CI-977 to kappa-1 opioid receptors has been examined in the temporal cortex of postmortem brains from patients with Alzheimer's disease and age-matched controls using quantitative autoradiography. There was no significant difference between Alzheimer and control subjects in the level of [3H]-U-69593 and [3H]-CI-977 binding, but ChAT activity was markedly reduced (by 73% compared to controls). These results are not consistent with a presynaptic localisation of kappa-1 receptors on cholinergic terminals in human temporal cortex.
We determined whether a battery of neuropsychological tests could predict who would develop Alzheimer's disease (AD) in a group of 123 memory-impaired nondemented patients. Patients were followed longitudinally for 2 years with a research battery of neuropsychological tests. After 2 years, 29 developed probable AD, and 94 did not develop dementia. We used logistic regression analyses to examine the classification accuracy of subjects' performance at entry to the study on the research battery. The logistic regression model was significant with an accuracy of 89%, sensitivity of 76%, and specificity of 94%. Two tests contributed significantly to this model: the delayed recall from the Rey Auditory Verbal Learning Test and the Mental Control subtest of the Wechsler Memory Scale. These two tests alone produced the same accuracy, sensitivity, and specificity as the larger model. These results demonstrate that probable AD can be predicted with a high degree of accuracy and with a relatively brief battery of neuropsychological tests.
In complex disease studies, it is crucial to perform multipoint linkage analysis with many markers and to use robust nonparametric methods that take account of all pedigree information. Currently available methods fall short in both regards. In this paper, we describe how to extract complete multipoint inheritance information from general pedigrees of moderate size. This information is captured in the multipoint inheritance distribution, which provides a framework for a unified approach to both parametric and nonparametric methods of linkage analysis. Specifically, the approach includes the following: (1) Rapid exact computation of multipoint LOD scores involving dozens of highly polymorphic markers, even in the presence of loops and missing data. (2) Non-parametric linkage (NPL) analysis, a powerful new approach to pedigree analysis. We show that NPL is robust to uncertainty about mode of inheritance, is much more powerful than commonly used nonparametric methods, and loses little power relative to parametric linkage analysis. NPL thus appears to be the method of choice for pedigree studies of complex traits. (3) Information-content mapping, which measures the fraction of the total inheritance information extracted by the available marker data and points out the regions in which typing additional markers is most useful. (4) Maximum-likelihood reconstruction of many-marker haplotypes, even in pedigrees with missing data. We have implemented NPL analysis, LOD-score computation, information-content mapping, and haplotype reconstruction in a new computer package, GENEHUNTER. The package allows efficient multipoint analysis of pedigree data to be performed rapidly in a single user-friendly environment.
Four genetic loci have been identified as contributing to Alzheimer disease (AD), including the amyloid precursor protein gene, the presenilin 1 gene, the presenilin 2 gene, and the apolipoprotein E gene, but do not account for all the genetic risk for AD.
To identify additional genetic risk factors for late-onset AD.
A complete genomic screen was performed (N=280 markers). Critical values for chromosomal regional follow-up were a P value of .05 or less for affected relative pair analysis or sibpair analysis, a parametric lod score of 1.0 or greater, or both. Regional follow-up included analysis of additional markers and a second data set.
Clinic populations in the continental United States.
From a series of multiplex families affected with late-onset (> or =60 years) AD ascertained during the last 14 years (National Insititute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association diagnostic criteria) and for which DNA has been obtained, a subset of 16 families (135 total family members, 52 of whom were patients with AD) was used for the genomic screen. A second subset of 38 families (216 total family members, 89 of whom were patients with AD) was used for the follow-up analysis.
Linkage analysis results generated using both genetic model-dependent (lod score) and model-independent methods.
Fifteen chromosomal regions warranted initial follow-up. Follow-up analyses revealed 4 regions of continued interest on chromosomes 4, 6, 12, and 20, with the strongest results observed forchromosome 12. Peak 2-point affecteds-only lod scores (n=54) were 1.3, 1.6, 2.7, and 2.2 and affected relative pairs P values (n=54) were .04, .03, .14, and .04 for D12S373, D12S1057, D12S1042, and D12S390, respectively. Sibpair analysis (n=54) resulted in maximum lod scores (MLSs) of 1.5, 2.6, 3.2, and 2.3 for these markers, with a peak multipoint MLS of 3.5. A priori stratification by APOE genotype identified 27 families that had at least 1 member with AD whose genotype did not contain an APOE*4 allele. Analysis of these 27 families resulted in MLSs of 1.0, 2.4, 3.7, and 3.3 and a peak multipoint MLS of 3.9.
A complete genomic screen in families affected with late-onset AD identified 4 regions of interest after follow-up. Chromosome 12 gave the strongest and most consistent results with a peak multipoint MLS of 3.5, suggesting that this region contains a new susceptibility gene for AD. Additional analyses are necessary to identify the chromosome 12 susceptibility gene for AD and to follow up the regions of interest on chromosomes 4, 6, and 20.
Prior to performance of linkage analysis, elimination of all Mendelian inconsistencies in the pedigree data is essential. Often, identification of erroneous genotypes by visual inspection can be very difficult and time consuming. In fact, sometimes the errors are not recognized until the stage of running linkage-analysis software. The effort then required to find the erroneous genotypes and to cross-reference pedigree and marker data that may have been recoded and renumbered can be not only tedious but also quite daunting, in the case of very large pedigrees. We have implemented four error-checking algorithms in a new computer program, PedCheck, which will assist researchers in identifying all Mendelian inconsistencies in pedigree data and will provide them with useful and detailed diagnostic information to help resolve the errors. Our program, which uses many of the algorithms implemented in VITESSE, handles large data sets quickly and efficiently, accepts a variety of input formats, and offers various error-checking algorithms that match the subtlety of the pedigree error. These algorithms range from simple parent-offspring-compatibility checks to a single-locus likelihood-based statistic that identifies and ranks the individuals most likely to be in error. We use various real data sets to illustrate the power and effectiveness of our program.
We completed a systematic survey of the human genome, conducted at an average resolution of 10 cM, for the identification of simple sequence tandem repeat polymorphisms (SSTRPs) that target new risk genes for Alzheimer disease (AD) by virtue of linkage disequilibrium. The efficiency of our association study was enhanced by genotyping pools of DNA from autopsy-confirmed cases with AD and matched controls. Allelic associations with AD were observed for 6 of the 391 SSTRPs in the CHLC Human Screening Set/Weber Version 6 (Research Genetics, Inc., Huntsville, AL): D1S518, D1S547, D10S1423, D12S1045, D19S178, and DXS1047. These allelic associations were replicated in an independent sample of autopsied AD cases and controls recruited from a geographically disparate site. The association of the large D19S178 alleles with AD appeared to arise from linkage disequilibrium with the APOE epsilon 4 allele, whose effect on increasing the risk of AD has been established. None of the remaining SSTRPs was in close proximity to loci previously reported to influence the risk of developing AD. Instead, they may identify five novel AD susceptibility loci.
Alzheimer's disease is the most common form of dementia that occurs in later years. The diagnosis is confirmed by the pathological findings of betaA4-amyloid-containing neuritic plaques and neurofibrillary tangles, the former being present in sufficient quantity commensurate with age. Other forms of dementia are more difficult to diagnose clinically; their pathology is noted for the lack of plaques and tangles. A patient with a family history of dementia presented with the clinical signs of Alzheimer's disease which lasted for 13 years. At autopsy the brain tissue had betaA4-amyloid-containing neuritic plaques, but no neurofibrillary tangles (i.e., the tissue was negative for staining with the tau antibody). Genetic analysis of DNA from family members revealed no linkage with chromosome 17 markers, indicating that this was not frontotemporal dementia. However, there was linkage with chromosome 3 markers. Thus, this form of Alzheimer's disease with a pathology of plaques only is linked with markers on chromosome 3.
To investigate the relative proportion of genetic and environmental contributions to verbal memory in community-dwelling World War II veteran twins.
The California Verbal Learning Test (CVLT) was administered to 94 monozygotic (MZ) and 89 dizygotic (DZ) elderly male twin pair participants in the fourth examination of the National Heart, Lung, and Blood Institute Twin Study.
Subjects voluntarily participated on an outpatient basis at a research or medical center facility in 1 of 4 sites in the United States.
Subjects had a mean age of 71.8 years (SD, 2.9 years), a mean educational level of 13.6 years (SD, 2.8 years), and no history of stroke and/or a Mini-Mental State Examination score of 23 or greater.
Twin pair similarity in performance on 4 factor analytically derived components of the CVLT measuring verbal learning and memory, response discrimination, learning strategy, and recognition memory.
The MZ intraclass correlation was significantly larger than the DZ correlation for verbal learning and memory (I<.001) but not for the other 3 components of memory. Using maximum likelihood methods, the best-fitting genetic model indicated that verbal learning and memory has a substantial genetic component (56% of total variance), whereas response discrimination has a much smaller, although still detectable, genetic component (24% of total variance). There is no evidence of genetic influence on learning strategy or recognition memory.
Differential contribution of genetic and environmental influences to specific components of memory suggest that, in this group of elderly male twin pairs, some components may be more amenable to intervention than others.
To review studies that have reported on the prevalence of memory complaints and the relationship between memory complaints and impairment or decline (dementia) in elderly individuals.
All publications in the English language relating to memory complaints, memory impairment, cognitive disorder and dementia in MEDLINE, PSYCHLIT and EMBASE computerized databases, together with a search of relevant citations.
The prevalence of memory complaints, defined as everyday memory problems, shows a large variation of approximately 25 - 50%. A high age, female gender and a low level of education are generally associated with a high prevalence of memory complaints. In community-based samples of elderly subjects an association has been found between memory complaints and memory impairment, after adjustment for depressive symptomatology. Memory complaints predict dementia after a follow-up of at least 2 years, in particular in those with mild cognitive impairment, defined as Mini Mental State Examination (MMSE) > 23. Memory complaints in highly educated elderly subjects may be predictive of dementia even when there is no indication of cognitive impairment on short cognitive screen tests. The shift in methodology which is noticeable in the recently published major studies is discussed as a possible explanation for the established association between memory complaints and decline in memory (or dementia) in elderly subjects. Three methodological factors, in particular, are responsible for the results: community-based sampling, longitudinal design and the treatment of variables such as depression, cognitive impairment and level of education.
Memory complaints in elderly people should no longer be considered merely as an innocent age-related phenomenon or a symptom of depression. Instead, these complaints deserve to be taken seriously, at least as a possible early sign of dementia.
Four genes affecting Alzheimer's Disease (AD)(AP, PS1, PS2, and APOE) have been identified and a fifth potential gene localized to chromosome 12. Collectively, these genes explain at most half of the genetic effect in AD. Understanding the genetics of AD is critical to developing new treatments. The quest to find the remaining AD genes led us to undertake a large genomic screen using over 466 families (730 affected sibpairs) in late-onset AD. In conjunction with this increase in power, we initiated several novel approaches to identify potential AD-related genes. This included stratification of the data into an autopsy-confirmed subset of 199 AD families. Each of these targeted analyses resulted in the identification of novel regions containing potential AD genetic risk factors. Our most significant finding was on chromosome 9 in the autopsy-confirmed subset where we obtained an MLS of 4.31. These approaches, together with new methodologies such as conditional linkage analysis, generalized family-based association tests (PDT), and a new generation of genetic markers (SNPs), opens the door for additional AD gene discovery. Such strategies are necessary if we are to understand the subtle and complex threads that, woven together, create the intricate tapestry of AD.
The apolipoprotein E (APOE) gene is the only genetic risk factor that has so far been linked to risk for late-onset Alzheimer's disease (LOAD). However,
50 percent of Alzheimer's disease cases do not carry an APOE4 allele, suggesting that other risk factors must exist. We performed a two-stage genome-wide screen in sibling pairs with
LOAD to detect other susceptibility loci. Here we report evidence for an Alzheimer's disease locus on chromosome 10. Our stage
one multipoint lod score (logarithm of the odds ratio for linkage/no linkage) of 2.48 (266 sibling pairs) increased to 3.83
in stage 2 (429 sibling pairs) close to D10S1225 (79 centimorgans). This locus modifies risk for Alzheimer's disease independent
ofAPOE genotype.
Although the role of genetic factors in the origin of Parkinson disease has long been disputed, several genes involved in autosomal dominant and recessive forms of the disease have been localized. Mutations associated with early-onset autosomal recessive parkinsonism have been identified in the Parkin gene, and recently a second gene, PARK6, involved in early-onset recessive parkinsonism was localized on chromosome 1p35-36. We identified a family segregating early-onset parkinsonism with multiple consanguinity loops in a genetically isolated population. Homozygosity mapping resulted in significant evidence for linkage on chromosome 1p36. Multipoint linkage analysis using MAPMAKER-HOMOZ generated a maximum LOD-score of 4.3, with nine markers spanning a disease haplotype of 16 cM. On the basis of several recombination events, the region defining the disease haplotype can be clearly separated, by > or =25 cM, from the more centromeric PARK6 locus on chromosome 1p35-36. Therefore, we conclude that we have identified on chromosome 1 a second locus, PARK7, involved in autosomal recessive, early-onset parkinsonism.
Of late-onset Alzheimer's disease patients 50% do not carry an apolipoprotein E epsilon 4 allele, indicating that there must be other genetic or environmental risk factors for the disease. During the past few years, both genetic linkage and candidate gene studies have been undertaken in order to identify novel genetic risk factors for late-onset Alzheimer's disease. Previous genome screens implicated a region of chromosome 12 that contains the genes that encode both alpha(2)-macroglobulin and the low-density lipoprotein receptor-related protein. However, candidate gene studies have produced mixed results with respect to both of these genes. New linkage studies now provide strong evidence for Alzheimer's disease susceptibility loci on chromosomes 9 and 10. The locus on chromosome 10 very probably modifies risk for Alzheimer's disease by modulating beta-amyloid-42 levels.
Alzheimer's disease (AD) is a genetically complex disorder that accounts for the majority of dementia in the elderly population. Over 100 rare, highly penetrant mutations have been described in three genes (APP, PSEN1, PSEN2) for early-onset familial AD. In the more common late-onset form, a polymorphism in the apolipoprotein E gene has been associated with increased susceptibility. However, recent studies suggest that these four genes account for less than 30% of the genetic variance for AD and that more genetic factors remain to be identified. In this review, we present a brief history of AD genetics and preview some of the next frontiers in Alzheimer gene discovery primarily focusing on chromosomes 12, 10, and 9.
AD is a complex neurodegenerative disorder comprising several disease-associated chromosome loci. To find novel susceptibility genes for late-onset AD, a population-based genome-wide search using linkage disequilibrium (LD) mapping approach has been performed.
Forty-seven patients with late-onset AD and 51 age-matched control subjects were carefully chosen from the same geographic area in eastern Finland, where the population is descended mainly from a small group of original founders. These subjects were initially genotyped with 366 polymorphic microsatellite markers, and a follow-up analysis was performed with additional microsatellite markers for those chromosome loci found to be associated with AD.
Initial genome-wide screening revealed 21 chromosomal loci significantly associated with AD in addition to the 13q12 locus described previously. Subsequent comparison of single-allele frequencies of the microsatellite markers in the AD and control groups indicated the presence both of possible risk alleles (odds ratio [OR] > 1) and of possible protective alleles (OR < 1). Screening of the LD regions with additional microsatellite markers revealed seven chromosomal loci where more than one microsatellite marker was associated with AD (1p36.12, 2p22.2, 3q28, 4p13, 10p13, 18q12.1, and 19p13.3) in addition to the 13q12 locus.
These genome-wide LD screening data suggest that several AD-associated chromosomal loci exist, which may encompass novel susceptibility genes for late-onset AD. Therefore, extensive screening of the genes located in the vicinity of these LD regions is necessary to elucidate their role in AD.
A number of methods have previously been described which carry out linkage analysis considering information for two or more loci simultaneously. Apart from some ad hoc methods such as analysing subsamples, these methods use information regarding linkage at all loci under consideration. However, if the actual genotype-specific effects are known for some loci then it would be preferable to consider the genotypes of these loci directly, rather than the amount of allele-sharing they demonstrate. Here we present an extension to our likelihood-based method of model-free linkage analysis as implemented in the MFLINK program. This allows the incorporation of liability classes. The genotypes of a locus known to affect risk can be used to assign subjects to liability classes prior to carrying out linkage tests at other loci. An example application is presented for genome scan data on Alzheimer's disease with analysis conditional on Apoliprotein E (APOE) genotypes. The results provide support for the existence of additional susceptibility loci linked to D10S1211 and to D12S358.
Working memory (WM) encompasses both short-term memory (storage) and executive functions that play an essential role in all forms of cognition. In this study, the genetic structure of storage and executive functions engaged in both a spatial and verbal WM span task is investigated using a twin sample. The sample consists of 143 monozygotic (MZ) and 93 dizygotic (DZ) Japanese twin pairs, ages 16 to 29 years. In 155 (87 MZ, 62 DZ) of these pairs, cognitive ability scores from the Kyodai Japanese IQ test are also obtained. The phenotypic relationship between WM and cognitive ability is confirmed (r = 0.26-0.44). Individual differences in WM storage and executive functions are found to be significantly influenced by genes, with heritability estimates all moderately high (43%-49%), and estimates for cognitive ability comparable to previous studies (65%). A large part of the genetic variance in storage and executive functions in both spatial and verbal modalities is due to a common genetic factor that accounts for 11% to 43% of the variance. In the reduced sample, this common genetic factor accounts for 64% and 26% of the variance in spatial and verbal cognitive ability, respectively. Additional genetic variance in WM (7%-30%) is due to modality specific factors (spatial and verbal) and a storage specific factor that may be particularly important for the verbal modality. None of the variance in cognitive ability is accounted for by the modality and storage genetic factors, suggesting these may be specific to WM.