GW Beecham’s research while affiliated with University of Miami and other places
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Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. // Methods: We performed the first genomewide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genomewide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. // Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; p value = 2.5E-08, beta = 1.27, SE = 0.23, risk allele: C) met genomewide significance for the penetrance model. Co-immunoprecipitation analyses of LRRK2 and CORO1C supported an interaction between these 2 proteins. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: p value = 1.1E-07; age-at-onset top variant: p value = 9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. // Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations.
Autopsy measures of Alzheimer’s disease neuropathology have been leveraged as endophenotypes in previous genome-wide association studies (GWAS). However, despite evidence of sex differences in Alzheimer’s disease risk, sex-stratified models have not been incorporated into previous GWAS analyses. We looked for sex-specific genetic associations with Alzheimer’s disease endophenotypes from six brain bank data repositories. The pooled dataset included 2701 males and 3275 females, the majority of whom were diagnosed with Alzheimer’s disease at autopsy (70%). Sex-stratified GWAS were performed within each dataset and then meta-analysed. Loci that reached genome-wide significance (P < 5 × 10−8) in stratified models were further assessed for sex interactions. Additional analyses were performed in independent datasets leveraging cognitive, neuroimaging and CSF endophenotypes, along with age-at-onset data. Outside of the APOE region, one locus on chromosome 7 (rs34331204) showed a sex-specific association with neurofibrillary tangles among males (P = 2.5 × 10−8) but not females (P = 0.85, sex-interaction P = 2.9 × 10−4). In follow-up analyses, rs34331204 was also associated with hippocampal volume, executive function, and age-at-onset only among males. These results implicate a novel locus that confers male-specific protection from tau pathology and highlight the value of assessing genetic associations in a sex-specific manner.
Background
Substantial progress has been made toward unraveling the genetic architecture of multiple sclerosis (MS) within populations of European ancestry, but few genetic studies have focused on Hispanic and African American populations within the United States.
Objective
We sought to test the relevance of common European MS risk variants outside of the major histocompatibility complex ( n = 200) within these populations.
Methods
Genotype data were available on 2652 Hispanics (1298 with MS, 1354 controls) and 2435 African Americans (1298 with MS, 1137 controls). We conducted single variant, pathway, and cumulative genetic risk score analyses.
Results
We found less replication than statistical power suggested, particularly among African Americans. This could be due to limited correlation between the tested and causal variants within the sample or alternatively could indicate allelic and locus heterogeneity. Differences were observed between pathways enriched among the replicating versus all 200 variants. Although these differences should be examined in larger samples, a potential role exists for gene–environment or gene–gene interactions which alter phenotype differentially across racial and ethnic groups. Cumulative genetic risk scores were associated with MS within each study sample but showed limited diagnostic capability.
Conclusion
These findings provide a framework for fine-mapping efforts in multi-ethnic populations of MS.
Transcriptome-wide association analysis is a powerful approach to studying the genetic architecture of complex traits. A key component of this approach is to build a model to impute gene expression levels from genotypes by using samples with matched genotypes and gene expression data in a given tissue. However, it is challenging to develop robust and accurate imputation models with a limited sample size for any single tissue. Here, we first introduce a multi-task learning method to jointly impute gene expression in 44 human tissues. Compared with single-tissue methods, our approach achieved an average of 39% improvement in imputation accuracy and generated effective imputation models for an average of 120% more genes. We describe a summary-statistic-based testing framework that combines multiple single-tissue associations into a powerful metric to quantify the overall gene–trait association. We applied our method, called UTMOST (unified test for molecular signatures), to multiple genome-wide-association results and demonstrate its advantages over single-tissue strategies.
Introduction
There is conflicting evidence whether high-density lipoprotein cholesterol (HDL-C) is a risk factor for Alzheimer's disease (AD) and dementia. Genetic variation in the cholesteryl ester transfer protein (CETP) locus is associated with altered HDL-C. We aimed to assess AD risk by genetically predicted HDL-C.
Methods
Ten single nucleotide polymorphisms within the CETP locus predicting HDL-C were applied to the International Genomics of Alzheimer's Project (IGAP) exome chip stage 1 results in up 16,097 late onset AD cases and 18,077 cognitively normal elderly controls. We performed instrumental variables analysis using inverse variance weighting, weighted median, and MR-Egger.
Results
Based on 10 single nucleotide polymorphisms distinctly predicting HDL-C in the CETP locus, we found that HDL-C was not associated with risk of AD (P > .7).
Discussion
Our study does not support the role of HDL-C on risk of AD through HDL-C altered by CETP. This study does not rule out other mechanisms by which HDL-C affects risk of AD.
Neurology
April 10, 2018; 90 (15 Supplement) APRIL 23, 2018
African Haplotypic Background Mitigates the Effect of APOE e4 Risk Allele in Alzheimer Disease (P2.195)
Farid Rajabli, Briseida Feliciano-Astacio, Katrina Celis, Kara L. Hamilton-Nelson, Patrice Whitehead, Larry D. Adams, Parker L. Bussies, Jacob McCauley, Heriberto Acosta, Angel Chinea, Alejandra Rodriguez Betancourt, Goldie S. Byrd, Eden Martin, Christiane Reitz, Lindsay Farrer, Gerard Schellenberg, Richard Mayeux, Jeffery M. Vance, Michael L. Cuccaro, Jonathan L. Haines, Badri N. Vardarajan, Gary W. Beecham, Margaret A. Pericak-Vance
First published April 9, 2018,
Abstract
Objective: Our objective is to evaluate the role of race/ethnicity and genetic ancestry at APOE gene in African American (AA) and Caribbean Hispanic (CHI) populations.
Background: Alzheimer disease (AD) is a progressive neurodegenerative disease and occurs in all ethnic and racial groups. The APOE gene’s ɛ4 allele (ApoE4) is a major risk factor for AD whose effect shows strong racial/ethnic differences. The underlying reasons for differential ApoE4 effects across the populations are not clear. The differences may be due to the ancestry-specific genetic factors or due to environmental/cultural factors. One way to explore these is using local ancestry (LA) methods. LA refers to the ancestral background of a particular chromosomal region and may be correlated with ancestry-specific genetic factors that are located in or near the genomic region in question. Thus, our goal to assess the relevance of the LA to the differential effect of the ApoE4 in AA and CHI.
Design/Methods: ApoE4 and genome-wide genotyping were performed in 2,229 AA (811 cases, 1,418 controls) and 267 Puerto Rican (PR) CHI samples (169 cases, 98 controls). LA was calculated using SHAPEIT and RFMix. Association between affection status and ApoE4 genotype in the presence of the LA was analyzed using genotype-based and haplotype-based logistic regression models.
Results: The genotype-based models showed that ApoExLA interaction term significantly associated with AD in the PR (p=0.048) and AA (p=0.008). The haplotype-based model showed that PR and AA individuals with European LA (PR:OR=4.18(1.79–9.78); AA:OR=2.83(1.99–4.02)) have a stronger ApoE4 effect than those with AF LA(PR:OR=2.54(0.59–10.98); AA:OR=2.18(1.85–2.58)).
Conclusions: Given the discordance between the previous racial disparities in ApoE4 risk, we showed that the LA at APOE has a larger effect rather than environmental or ethnic interaction. This highly suggests that the APOE region from AF populations may harbor protective factors that help mitigate the effect of the ApoE4.
Study Supported by: This investigation was supported by grant “Genomic Characterization of Alzheimer’s Disease Risk in the Puerto Rican Population” (1RF1AG054074), and “Alzheimer’s Disease Genetics Consortium”, (U01AG032984) from the National Institutes on Aging of NIH.
Disclosure: Dr. Rajabli has nothing to disclose. Dr. Feliciano-Astacio has nothing to disclose. Dr. Celis has nothing to disclose. Dr. Hamilton has nothing to disclose. Dr. Whitehead has nothing to disclose. Dr. Adams has nothing to disclose. Dr. Bussies has nothing to disclose. Dr. McCauley has nothing to disclose. Dr. Acosta has nothing to disclose. Dr. Chinea has nothing to disclose. Dr. Betancourt has nothing to disclose. Dr. Byrd has nothing to disclose. Dr. Martin has nothing to disclose. Dr. Reitz has nothing to disclose. Dr. Farrer has nothing to disclose. Dr. Schellenberg has nothing to disclose. Dr. Mayeux has nothing to disclose. Dr Vance has nothing to disclose. Dr. Cuccaro has nothing to disclose. Dr. Haines has nothing to disclose. Dr. Vardarajan has nothing to disclose. Dr. Beecham has nothing to disclose. Dr. Pericak-Vance has nothing to disclose.
Disputes & Debates: Rapid online correspondence
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http://n.neurology.org/content/90/15_Supplement/P2.195
Objective
Alzheimer’s disease (AD) is a neurodegenerative disorder for which more than 20 genetic loci have been implicated to date. However, studies demonstrate not all genetic factors have been identified. Therefore, in this study we seek to identify additional rare variants and novel genes potentially contributing to AD.
Methods
Whole exome sequencing was performed on 23 multi-generational families with an average of eight affected subjects. Exome sequencing was filtered for rare, nonsynonymous and loss-of-function variants. Alterations predicted to have a functional consequence and located within either a previously reported AD gene, a linkage peak (LOD>2), or clustering in the same gene across multiple families, were prioritized.
Results
Rare variants were found in known AD risk genes including AKAP9, CD33, CR1, EPHA1, INPP5D, NME8, PSEN1, SORL1, TREM2 and UNC5C. Three families had five variants of interest in linkage regions with LOD>2. Genes with segregating alterations in these peaks include CD163L1 and CLECL1, two genes that have both been implicated in immunity, CTNNA1, which encodes a catenin in the cerebral cortex and MIEF1, a gene that may induce mitochondrial dysfunction and has the potential to damage neurons. Four genes were identified with alterations in more than one family include PLEKHG5, a gene that causes Charcot-Marie-Tooth disease and THBS2, which promotes synaptogenesis.
Conclusion
Utilizing large families with a heavy burden of disease allowed for the identification of rare variants co-segregating with disease. Variants were identified in both known AD risk genes and in novel genes.
INTRODUCTION: Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood. METHODS: We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset. RESULTS: Genome-wide significant (GWS) associations in single-nucleotide polymorphism (SNP)–based tests (P < 5 × 10−8) were identified for SNPs in PFDN1/HBEGF, USP6NL/ECHDC3, and BZRAP1-AS1 and for the interaction of the (apolipoprotein E) APOE ε4 allele with NFIC SNP. We also obtained GWS evidence (P < 2.7 × 10−6) for gene-based association in the total sample with a novel locus, TPBG (P = 1.8 × 10−6). DISCUSSION: Our findings highlight the value of transethnic studies for identifying novel AD susceptibility loci.
Several variants in the gene ABCA7 have been identified as potential causal variants for late-onset Alzheimer’s disease (LOAD). In order to replicate these findings, and search for novel causal variants, we performed targeted sequencing of this gene in cohorts of non-Hispanic White (NHW) and African-American (AA) LOAD cases and controls. We sequenced the gene ABCA7 in 291 NHW LOAD cases and 103 controls. Variants were prioritized for rare, damaging variants and previously reported variants associated with LOAD, and were follow-up genotyped in 4,076 NHW and 1,157 AA cases and controls. We confirm three previously associated ABCA7 risk variants and extend two of these associations to other populations, an intronic variant in NHW (P = 3.0 × 10⁻³) (originally reported in a Belgian population), and a splice variant originally associated in the Icelandic population, which was significantly associated in the NHW cohort (P = 1.2 × 10⁻⁶) and nominally associated in the AA cohort (P = 0.017). We also identify a 3′-UTR splice variant that segregates in four siblings of one family and is nominally associated with LOAD (P = 0.040). Multiple variants in ABCA7 contribute to LOAD risk.
Citations (12)
... Therefore, dedicated studies are needed to evaluate the role of pathogenic LRRK2 variants in the development of atypical parkinsonian features. Finally, modifiers of disease penetrance and AAO are areas of major interest but were beyond the scope of this review; for these issues, readers are referred to published works that have examined the effects of other gene�c (including polygenic) 90,91 , is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint ...
... Previous studies have shown that gene expression differs by sex throughout the genome(9, 10), and several genome-wide association studies (GWAS) have identified genetic variants that show sex-specific effects in human disease (11)(12)(13)(14). However, while previous studies have identified genes with sex-biased expression (sb-Genes)(10, 15,16), how well sb-Genes replicate 15 across diverse datasets and the underlying molecular mechanisms of why individual genes display sex-biased expression are not well characterized. ...
... proposed to implement TWAS with individual-level or summary-level GWAS data, such as PrediXcan [6], Fusion [7], TIGAR [8], S-PrediXcan [9] , T-GEN [10], and UTMOST [11]. ...
... An inheritable genetic factor is recognized to comprise at least one-third of the complex MS etiological make-up, identified as the HLA-DRB1 * 15:01 [6]. The current theory explaining the world-wide dissemination of this disease, including the Americas, the Middle and Far East, is the European genetic risk factor, passed on throughout history though military invasions, migration and other historical and socio-political phenomena [7,8]. While the causality of MS is multifactorial, autoimmunity is the main driver behind its mechanisms [9]; it is involved in the initiation of the characteristic, erroneous, autoimmune cascade, a response of the innate immune system to an antigen, followed by the participation of the adaptive immune system. ...
... We did not consider local ancestry of the APOE haplotype in this analysis, and if years of education is associated with local African ancestry in our cohort, the moderation of schooling on the effect of APOE 4 could be due to confounding. Prior research indicates that within admixed groups, such as Hispanics and African Americans, those who inherit a genetic region around the APOE allele of African ancestry are at lower risk for AD than those who inherit a European APOE region [67,68]. Marden et al. [69] demonstrated a relationship between global African genetic ancestry and social factors such as years of education. ...
... p = 3.61E-07). 60 The strength of the association between e2 and e4 and AD risk or AAO varies with ancestry. 50,e2,e3 While e4 is associated with increased AD risk across populations, albeit to different degrees, the protective effect of e2 seems attenuated or inverted in non-European cohorts. ...
... Rare variants in known AD risk genes, such as AKAP9, CD33, and CR1, were also identified, pointing to links between AD, immunity, neuronal structure, and mitochondrial function. The discovery of genetic links across multiple families suggests potential significance in other neurological pathologies, such as Charcot-Marie-Tooth and other synapse dysfunctions [45]. ...
... Many of these identified changes appear likely to result in loss of function mutations and have been found to be enriched in AD individuals. 4,20,21,[36][37][38][39][40][41][42] Consistent with this finding, results of expression studies that indicate that AD brains with low levels of ABCA7 develop AD at a younger age than those with higher expression of ABCA7, while individuals who expressed ABCA7 at similar levels to healthy controls developed AD at a very late age. 43,44 To date, only one protective low frequency coding missense variant has been identified (rs72973581, p.G215S) and has been hypothesized to induce a small gain of function or increase in ABCA7 expression, although this has not yet been confirmed. ...
... This may in part contribute to the persistence of CV health disparities [6]. Candidate SNPs for diabetes, obesity, hypertension (HTN), and dyslipidemia in subjects of European and Asian descent vary widely from those associated with CV risk factors in AAs and H/Ls [7][8][9][10] The disruption of circadian rhythmicity is increasingly being recognized as a major contributor to development of CV risk factors [11]. The master circadian clock is a complex structure located in the suprachiasmatic nucleus of the hypothalamus and generates a near 24-hour endogenous rhythm via transcriptionaltranslational feedback loops involving the expression of key circadian clock associated genes such as the Circadian Locomotor Output Cycles Kaput gene (Clock), the Brain muscle arnt-like gene (isoforms Bmal 1 and Bmal 2), the Period gene (isoforms Per1, Per2 and Per3) and the Cryptochrome gene (isoforms Cry1 and Cry2). ...
... While the databases discussed in Section 2 focus on the biophysical aspects of amyloid aggregation, other resources address different aspects of this issue. Databases such as ALZGENE [52], PDGENE [53], or ALSGENE [54] explore the genetic patterns influencing the pathological amyloid accumulation in AD, PD, and ALS, respectively, reporting genetic association of gene variants or non-synonymous single nucleotide polymorphisms (SNPs) to these disorders. By covering meta-analyses from multiple Genome-Wide Association Studies (GWAS) or association studies, novel genes with roles in these amyloidosis (other than the aggregating amyloid protein) can be established. ...