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Initial Genome Scan of the NIMH Genetics Initiative Bipolar Pedigrees: Chromosomes 4, 7, 9, 18, 19, 20, and 21q
Abstract
An initial genome scan was performed on 540 individuals from 97 families segregating bipolar disorder, collected through the National Institutes of Mental Health Genetics Initiative. We report here affected-sib-pair (ASP) data on 126 marker loci (≈68,000 genotypes) mapping to chromosomes 4, 7, 9, 18, 19, 20, and 21q, under three affection status models. Modest increases in identical-by-descent (IBD) allele sharing were found at the following loci: D4S2397 and D4S391 (P < 0.05) on 4p, D4S1647 (P < 0.05) on 4q, D7S1802 and D7S1869 (low P = 0.01) on 7p, D9S302 (P = 0.004) on 9q, and D20S604 on 20p and D20S173 on 20q (P ≤ 0.05). In addition, five markers on 7q displayed increased IBD sharing (P = 0.046–0.002). Additional ASP analyses on chromosomes 18 and 21q marker data were performed using disease phenotype models defined previously. On chromosome 18, only D18S40 on 18p and D18S70 on 18q yielded a slight elevation in allele sharing (P = 0.02), implying that the reported linkages in these regions were not confirmed. On chromosome 21q, a cluster of markers within an ≈9 cM interval: D21S1254, D21S65, D21S1440, and D21S1255 exhibited excess allele sharing (P = 0.041–0.008). Multilocus data on overlapping marker quartets, from D21S1265 to D21S1255, which were consistent with increased IBD sharing (P < 0.01, with a low of 0.0009), overlapped a broad interval of excess allele sharing reported previously, increasing support for a susceptibility locus for bipolar disorder on 21q. Am. J. Med. Genet. 74:254–262, 1997. © 1997 Wiley-Liss, Inc.
... Inbred mouse strains demonstrate considerable strain variation in PPI of acoustic and tactile startle (BULLOCK et al. 1997; LOGUE et al. 1997; PAYLOR and CRAWLEY 1997; RALPH et Two PPI QTLs on mouse chromosome 16 Petryshen et al. 6 al. 2001; VARTY et al. 2001; WILLOTT et al. 2003), suggesting that the forebrain processes that regulate PPI vary across inbred strains and are genetically determined. The heritability of PPI of acoustic startle has been estimated to range from h 2 ...
... Our distal chromosome 16 PPI region is syntenic with human 21q21.1, where a locus for bipolar disorder has been reported (DETERA-WADLEIGH et al. 1996), although subsequent bipolar disorder studies have reported linkage peaks more telomeric (DETERA-WADLEIGH et al. 1997;KELSOE et al. 2001). Patient association studies of the human orthologs of candidate genes from each of the mouse PPI loci will be the focus of future studies by our group. ...
... In this study we analyzed 644 families ascertained by the National Institute of Mental Health Human (NIMH) genetics initiative. These families, currently the largest pedigree series, which are freely available to qualified researchers worldwide, are also known in the literature as 'waves 1, 2, 3, and 4 pedigrees' (Detera-Wadleigh et al., 1997;Edenberg et al., 1997;Dick et al., 2003;Kassem et al., 2006). The 644 pedigrees contain 1565 individuals with BPI disorder or schizoaffective (SA) disorder, bipolar type, 199 persons with bipolar II (BPII) disorder, 282 patients with recurrent major depressive disorder (MDD), and 876 unaffected persons with genotypes. ...
... Wave 1, 2, 3, and 4 families have been genotyped, at various intervals, with microsatellite loci spaced every approximately 10 cM or less across the genome. Linkage studies of these families have been performed in four 'waves' (McInnes et al., 1996;Detera-Wadleigh et al., 1997;Edenberg et al., 1997;Rice et al., 1997;Stine et al., 1997;Dick et al., 2003;McInnis et al., 2003;Kassem et al., 2006). Implicated regions include 1q, 5q, 6q, 7p, 10p, 16p, 16q, 17q, and 22q. ...
Our aim is to map chromosomal regions that harbor loci that increase susceptibility to bipolar disorder.
We analyzed 644 bipolar families ascertained by the National Institute of Mental Health Human Genetics Initiative for bipolar disorder. The families have been genotyped with microsatellite loci spaced every approximately 10 cM or less across the genome. Earlier analyses of these pedigrees have been limited to nonparametric (model-free) methods and thus, information from unaffected subjects with genotypes was not considered. In this study, we used parametric analyses assuming dominant and recessive transmission and specifying a maximum penetrance of 70%, so that information from unaffecteds could be weighed in the linkage analyses. As in previous linkage analyses of these pedigrees, we analyzed three diagnostic categories: model 1 included only bipolar I and schizoaffective, bipolar cases (1565 patients of whom approximately 4% were schizoaffective, bipolar); model 2 included all individuals in model 1 plus bipolar II patients (1764 total individuals); and model 3 included all individuals in model 2 with the addition of patients with recurrent major depressive disorder (2046 total persons).
Assuming dominant inheritance the highest genome-wide pair-wise logarithm of the odds (LOD) score was 3.2 with D16S749 using model 2 patients. Multipoint analyses of this region yielded a maximum LOD score of 4.91. Under recessive transmission a number of chromosome 20 markers were positive and multipoint analyses of the area gave a maximum LOD of 3.0 with model 2 cases.
The chromosome 16p and 20 regions have been implicated by some studies and the data reported herein provide additional suggestive evidence of bipolar susceptibility genes in these regions.
... Furthermore, the influence of genetic factors is supported as biological parents are more often affected than the adoptive parents of BPD adoptees (Mendlewicz and Rainer 1977). A multitude of linkage and association studies have been conducted during the past decade (DeLisi et al. 2000; Detera-Wadleigh et al. 1999; Detera-Wadleigh et al. 1997; Dick et al. 2002; Liu et al. 2003; Stober et al. 2000a; Stober et al. 2001; Stober et al. 2000b; Stober et al. 2002) and even more susceptibility genes for psychiatric disorders have been identified (Table 1.1 ). An extensive combination of linkageand association studies and other approaches have been performed to clarify the genetic mechanism of complex mental disorders. ...
In der vorliegenden Arbeit wurden die regulatorischen Regionen der Gene für den Kaliumchloridtransporter 3 (KCC3, SLC12A6) und den Glukokortikoidrezeptor (NR3C1) untersucht. Hierbei handelt es sich um Gene, die bereits mit psychiatrischen Erkrankungen assoziiert worden sind. Die Promotorregionen beider Gene wurden in Abhängigkeit von bereits in der Literatur beschriebenen DNA-Polymorphismen und unter besonderer Berücksichtigung epigenetischer DNA-Modifikationen mittels bisulfitspezifischer Sequenzierung und Luciferase-Assay funktionell charakterisiert.
Es konnte gezeigt werden, dass DNA-Polymorphismen und epigenetische Veränderungen der Erbinformation – letztere können in Abhängigkeit unterschiedlicher Lebenserfahrungen entstehen – funktionelle Relevanz für die Promotoraktivität der untersuchten Gene haben. Strukturelle und modifikatorische DNA-Variationen sowie Gen-Umwelt Wechselwirkungen beeinflussen somit die Genregulation und können unter bestimmten Bedingungen krankheitsrelevant werden.
... Chromosomal regions of interest include 4p16 (11)(12)(13), 4q35 (14), 10p (15), 10q25-q26 (16,17), 12q23-q24 (18)(19)(20)(21), 13q32 (13), 18p11.2-cen (22)(23)(24)(25), 18q21-q23 (23,24,(26)(27)(28)(29), 21q22 (30)(31)(32) and 22q (16). ...
... The PDLIM5 gene has been found to be linked to the occurrence of several mental disorders that include bipolar disorder (Detera-Wadleigh et al., 1997), schizophrenia (Mowry et al., 2000;Kato, 2007), and major depression (Camp et al., 2005) through several linkage studies. Previous gene expression studies showed that PDLIM5 mRNA expression was significantly upregulated in postmortem brain tissue of patients with bipolar disorder (Iwamoto et al., 2004b) and schizophrenia (Kato et al., 2005) compared with control individuals, while being significantly downregulated in peripheral blood leukocytes (Numata et al., 2007;Zain et al., 2012) and lymphoblastoid cell lines (Iwamoto et al., 2004a(Iwamoto et al., , 2004b. ...
Two single nucleotide polymorphisms of PDLIM5, rs7690296 and rs11097431, were genotyped using Mass-Array SNP genotyping by Sequenom technology in 244 bipolar disorder patients, 471 schizophrenia patients, and 601 control individuals who were Malay, Chinese, and Indian ethnic groups in the Malaysian population. A significant association was observed in allele frequency between the rs7690296 polymorphism and bipolar disorder in the Indian ethnic group [P=0.02, adjusted odds ratio (OR) 0.058, 95% confidence interval (CI) 0.36-0.93]. A significant association was also observed between the rs7690296 polymorphism and schizophrenia under the recessive model for both Malay (P=0.02, adjusted OR 1.86, 95% CI 1.12-3.10) and Indian (P=0.02, adjusted OR 1.92, 95% CI 1.10-3.37) ethnic groups. However, no association was detected between the rs11097431 polymorphism either with bipolar disorder or with schizophrenia. Therefore, it can be deduced that the nonsynonymous rs7690296 polymorphism could play an important role in the pathophysiology of both bipolar disorder and schizophrenia.
... McInnes [McInnes et al., 1996] analysed over 470 autosomal and X-linked markers in two BPAD pedigrees from a restricted gene pool in Costa Rica, and although positive for chromosome 18p, the peak score occurred within the chromosomal region 18q22-q23, consistent with the initial investigation of the same two pedigrees [Freimer et al., 1996]. Moreover, the analysis of other bipolar cohorts has demonstrated additional support for an 18 q locus [De bruyn et al., 1996; Detera-Wadleigh et al., 1997; McMahon et al., 1997], although not all studies agree [reviewed by Van Broeckhoven and Verheyen, 1999]. Notwithstanding conflicting results, the positive linkage results in some of the data sets suggest that BPAD predisposition genes and perhaps schizophrenia genes may lie within regions on 4p, 18p, and 18q. ...
... Moreover, at the cellular level, SP3 and SP4 expression mostly colocalize with abnormally phosphorylated tau protein in the neurofibrillary tangles (NFTs) in AD brains, suggesting that neurons overexpressing Sp members are those implicated in the disease [2]. On the other hand, the human SP4 gene has been mapped to chromosome 7p15, where a susceptibility locus for a broad spectrum of human psychiatric disorders was identified [3], including schizophrenia and bipolar disorder [4] . Indeed, a human genetic association study provided direct evidence for the human SP4 gene as a susceptibility gene for both these diseases [5]. ...
Transcription factor Sp4 (Specificity protein 4) levels are increased in the brain of patients with Alzheimer's disease (AD), and Sp4 colocalizes with neurofibrillary tangles. Moreover, SP4 is a susceptibility gene for bipolar disorder and schizophrenia, which share many clinical features with frontotemporal lobar degeneration (FTLD). The distribution of three tagging single nucleotide polymorphisms(SNPs)-rs9639379, rs10272006, and rs6461569-has been determined in a population of 352 patients diagnosed clinically with AD, 290 patients with FTLD, and 341 age-matched controls. Expression analysis of SP4 was performed in peripheral blood mononuclear cells (PBMC). No significant differences in either allelic or genotypic frequency of the three SNPs were found (p > 0.05), even stratifying according to gender and to the apolipoprotein E status. Significantly increased SP4 relative expression levels were observed in PBMC from patients with AD as compared with controls (7.132 ± 1.301 versus 3.396 ± 0.829, p < 0.050) and a similar trend was shown in patients with FTLD compared with controls (6.525 ± 1.500 versus 3.396 ± 0.829, p = 0.073). According to these results, SP4 gene does not act as a susceptibility factor either for AD or FTLD. However, Sp4 mRNA levels are upregulated in patients, possibly resulting in an aberrant expression of downstream target genes involved in the pathogenesis of both diseases.
... Confirmation has been recorded by the NIMH Genetics Initiative collaborative study of BP disorder. 111 Thus, there are three independent confirmatory studies of this BP susceptibility locus. Xq26, including the coagulation factor IX (F9) locus is a third region of interest regarding BP susceptibility loci. ...
Linkage studies have defined at least five bipolar (BP) disorder susceptibility loci that meet suggested guidelines for initial identification and subsequent confirmation. These loci, found on 18p11, 18q22, 21q21, 4p16, and Xq26, are targets for BP candidate gene investigations. Molecular dissection of expressed sequences for these regions is likely to yield specific BP susceptibility alleles in most cases, in all probability, these BP susceptibility alleles will be common in the general population, and, individually, will be neither necessary nor sufficient for manifestation syndrome. Additive or multiplicative oligogenic models involving several susceptibility loci appear most reasonable at present, it is hoped thai these BP susceptibility genes will increase understanding of many mysteries surrounding these disorders, including drug response, cycling patterns, age-of-onset, and modes of transmission.
... The PROKR2 gene is located on chromosome 20p12.3, which was shown to be linked to bipolar disorder in three studies (Wadleigh et al. 1997; Fanous et al. 2008; Ross et al. 2008). An association between PROKR2 gene variants and major depressive disorder and bipolar disorder was reported in a Japanese population (Kishi et al. 2009b); however, this study was small and confirmatory studies will be necessary to validate this finding. ...
Methamphetamine (METH) is a frequent drug of abuse in U.S. populations and commonly associated with psychosis. This may be a factor in frequent criminal justice referrals and lengthy treatment required by METH users. Persecutory delusions and auditory hallucinations are the most consistent symptoms of METH-associated psychosis (MAP). MAP has largely been studied in Asian populations and risk factors have varied across studies. Duration, frequency and amount of use as well as sexual abuse, family history, other substance use, and co-occurring personality and mood disorders are risk factors for MAP. MAP may be unique with its long duration of psychosis and recurrence without relapse to METH. Seven candidate genes have been identified that may be associated with MAP. Six of these genes are also associated with susceptibility, symptoms, or treatment of schizophrenia and most are linked to glutamatergic neurotransmission. Animal studies of pre-pulse inhibition, attenuation of social interaction, and stereotypy and alterations in locomotion are used to study MAP in rodents. Employing various models, rodent studies have identified neuroanatomical and neurochemical changes associated with METH use. Throughout this review, we identify key gaps in our understanding of MAP and suggest potential directions for future research.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Linkage studies have defined at least five bipolar (BP) disorder susceptibility loci that meet suggested guidelines for initial identification and subsequent confirmation. These loci, found on 18p11, 18q22, 21q21, 4p16, and Xq26, are targets for BP candidate gene investigations. Molecular dissection of expressed sequences for these regions is likely to yield specific BP susceptibility alleles in most cases, in all probability, these BP susceptibility alleles will be common in the general population, and, individually, will be neither necessary nor sufficient for manifestation syndrome. Additive or multiplicative oligogenic models involving several susceptibility loci appear most reasonable at present, it is hoped thai these BP susceptibility genes will increase understanding of many mysteries surrounding these disorders, including drug response, cycling patterns, age-of-onset, and modes of transmission.
Mosaic trisomy 20 is a genetic condition in which three chromosomes 20 are found in some cells. Its clinical phenotype seems to be highly variable, with most features not reported across all individuals and not considered pathognomonic of the condition. Limited and recent evidence indicates that neuropsychiatric manifestations may be more present in the context of trisomy 20 than was once thought. Here, we present a case of a 14-year-old female adolescent of White/Caucasian ethnicity with mosaic trisomy 20, who was admitted twice to an inpatient Child and Adolescent Neuropsychiatry Unit for persisting self-injury and suicidal ideation. A severe and complex neuropsychiatric presentation emerged at the cognitive, emotional, and behavioral levels, including mild neurodevelopmental issues, isolation, socio-relational difficulties, depressed mood, temper outbursts, irritability, low self-esteem, lack of interest, social anxiety, panic attacks, self-cutting, and low-average-range and heterogeneous intelligence quotient profile. Particularly, the patient was considered at high risk of causing harm, mainly to self, and appeared to be only partially responsive to medication, even when polypharmacy was attempted to improve clinical response. Except for school bullying, no other severe environmental risk factors were present in the patient’s history. The patient received a diagnosis of disruptive mood dysregulation disorder.
Glutamatergic dysregulation is implicated in the neuropathology of bipolar disorder (BD). There is increasing interest in investigating the role of metabotropic glutamate receptors (mGluRs) in BD and as a target for treatment intervention. Bipolar mGluR studies (published January 1992 – April 2016) were identified via PubMed, Embase, Web of Science, and Scopus. Full-text screening, data extraction, and quality appraisal were conducted in duplicate, with strict inclusion and exclusion criteria. The initial literature search for mGluRs in BD, including non-bipolar mood disorders and primary psychotic disorders, identified 1544 articles. 61 abstracts were selected for relevance, 16 articles met full inclusion criteria, and three additional articles were found via citations. Despite limited literature, studies demonstrated: single nucleotide polymorphisms (SNPs) associated with BD, including a GRM3 SNP associated with greater likelihood of psychosis (rs6465084), mRNA binding protein Fragile X Mental Retardation Protein associated with altered mGluR1/5 activity in BD populations, and lithium decreasing mGluR5 expression and mGluR-mediated intracellular calcium signaling. Limited research has been performed on the role of mGluRs in BD, but results highlight the importance of ongoing study. Future directions for research of mGluRs in BD include GRM polymorphisms, epigenetic regulation, intracellular proteins, and pharmacologic interactions.
Bipolar disorder type 1 (BPD) is a chronic psychiatric illness and is associated with oxidative stress. Superoxide dismutase-1 (SOD1; OMIM: 147450) metabolizes highly reactive and more dangerous superoxide radicals into less reactive molecules. A functional 50-bp insertion/deletion (Ins/Del) polymorphism in the promoter region of the gene has been reported. The primary aim of the current case–control study was to explore whether the SOD1 Ins/Del polymorphism associated with the risk of BPD. A secondary aim was to investigate the association between the study polymorphism and age of onset of BPD. The present case–control study was performed in Shiraz (southern Iran) on 228 BPD and 224 healthy blood donor controls. The genotypes of the SOD1 Ins/Del polymorphism were determined by polymerase chain reaction. There was no significant association between the genotypes of Ins/Del polymorphism and the risk of BPD. Using Cox proportional hazards regression model, after adjustment for family history of BPD, revealed a significant association between the SOD1 Ins/Del polymorphism and age of onset. The age of onset was significantly lower for the Del/Del genotype than the ‘Ins/Ins + Ins/Del’ genotypes (hazard ratio = 2.33, 95%CI: 1.08–5.02, p = .030). Our present findings revealed that although the SOD1 Ins/Del polymorphism was not associated with the risk of BPD, it was significantly associated with age of onset of BPD.
Psychiatrische Erkrankungen sind Störungen des Erlebens und des Verhaltens. Ihre klinische Symptomatik manifestiert sich v.a. in den psychischen Funktionen der Emotionen, der Affekte und des Willens, der Wahrnehmung und des Denkens, der Verhaltenskontrolle und des Sozialverhaltens sowie in vegetativen Funktionen wie Appetit und Schlaf. Dabei sind die schwersten bzw. am häufigsten auftretenden psychiatrischen Erkrankungen des Erwachsenenalters Psychosen (v.a. Schizophrenien), affektive und Angststörungen, Demenzen (v.a. vom Alzheimer-Typ) und Abhängigkeitserkrankungen.
The causation of the affective disorders is the subject of much speculation, but little secure knowledge. The most reliable and replicable findings on this topic to date are the following:
Affective disorders occur with increased frequency in patients’ relatives as compared with the population at large, which implies that familial factors play a role in their causation.
Concordance rates for affective disorders are higher in monozygotic than in dizygotic twins, which implies that these familial factors are at least partly genetic.
The growing number of reports on candidate genes an genomic regions of interest in bipolar disorder reveals a tremendously active field of study. As with other complex psychiatric syndromes, these early findings will require a great deal of effort to replicate and clarify. This review serves both as an update and an introduction to some of the issues confronting investigators. Potential strategies in study design, population selection, and molecular methods are explored as well.
Über Ursachen affektiver Störungen liegen sehr viele Spekulationen, aber wenig gesichertes Wissen vor. Die am besten replizierbaren Aussagen über deren Usachen sind:
Affektive Erkrankungen treten familiär gehäuft auf, weshalb familiaäre Ursachenfaktoren relevant sind
Höhere Konkordanzraten bei monozygoten Zwillingen als bei dizygoten belegen, daß ein Teil der familiären Ursachenfaktoren genetischer Natur ist
Bipolar affective disorder (BAD) has a lifetime prevalence of 1-2%, and strong heritability is highly suggestive of a genetic component. A 15 cM genome-wide screen of microsatellite markers on 35 individuals from a large and informative Australian pedigree has identified a potential susceptibility locus on chromosome 4q35 (1). Analysis of five markers at 4q35 in a total of 545 individuals (including 158 affecteds) from 41 pedigrees results in a maximum two-point LOD score of 2.56 for D4S1652. A disease haplotype has been found in six of these pedigrees and recombinations within these families narrow the susceptibility region to approximately 4 Mb near the telomeric end of chromosome 4q35. Analysis of the 97 pedigree NIMH cohort (2) also showed six pedigrees with suggestive linkage to chromosome 4q35 and carrying a potential disease haplotype. Using the known EST and STS markers in the region, a YAC/BAC contig has been constructed in order to facilitate the examination of candidate genes. BACs have been identified for 31 markers and 24 ESTs and genes in this region. Candidate genes located within the probable critical region include melatonin receptor 1A (MTNR1A), adenine nucleotide translocator 1 (ANT1) and FSHD region 1 (FRG1), amongst others. Direct sequence analysis of these candidate genes is being used to identify SNP variation. The SNPs are being examined over a population cohort to determine their importance as potential susceptibility alleles.
Since the development of genetic linkage maps that have permitted the mapping of single-locus Mendelian disorders, like Duchenne Muscular dystrophy and Huntington's disease, these gene mapping strategies have been used in more complex disorders, such as behavioural phenotypes that result through the combined effects of multiple gene and environmental factors. However, the delination of behavioral phenotypes is still at an early stage. This paper presents some recent findings regarding behavioural phenotypes pertaining to intelligence, personality and psychopatology. It is concludede that there are still many difficulties and questions that need to be answered in order to understand the biological basis of specific human behavioural petterns.
Traditional methods used to asses genetic effects, such as twins, adoption and family studies, have demonstrated the role genetic vulnerability factors in the etiology of major psychiatric diseases such as affective disorders and schizophrenia. It remains however impossible, using these methods, to specify the genetic variables involved and the exact mode of transmission of these diseases. New genetic approaches in psychiatry include the use of DNA markers in sophisticated strategies to examine families and populations. Genetic linkage (in families) and allelic association (in unrelated subjects) are the most frequent techniques applied searching for genes in psychiatric diseases. Advances in these methods have permitted their application to complex diseases in which the mode of genetic transmission is unknown. Affective disorders and, in particular, bipolar affective disorder (BPAD) have been examined in many molecular genetic studies which have covered a large part of the genome, specific hypotheses such as mutations have also, been studied. Most recent studies indicate that several chromosomal regions may be involved in the aetiology of affective disorders. Large multi-centre and multi-disciplinary projects are currently underway in Europe and in the US and hopefully will improve our understanding of the genetic factors involved in affective disorders. In parallel to these new developments in molecular genetics, the classical genetic epidemiology, represented by twin, adoption and family studies, have been improved, providing validated models to test the gene-environment interactions.
Bipolar disorder (also known as manic depressive illness) is a complex genetic disorder in which the core feature is pathological disturbance in mood (affect) ranging from extreme elation, or mania, to severe depression usually accompanied by disturbances in thinking and behaviour. The lifetime prevalence of 1% is similar in males and females and family, twin, and adoption studies provide robust evidence for a major genetic contribution to risk. There are methodological impediments to precise quantification, but the approximate lifetime risk of bipolar disorder in relatives of a bipolar proband are: monozygotic co-twin 40-70%; first degree relative 5-10%; unrelated person 0.5-1.5%. Occasional families may exist in which a single gene plays the major role in determining susceptibility, but the majority of bipolar disorder involves the interaction of multiple genes (epistasis) or more complex genetic mechanisms (such as dynamic mutation or imprinting). Molecular genetic positional and candidate gene approaches are being used for the genetic dissection of bipolar disorder. No gene has yet been identified but promising findings are emerging. Regions of interest identified in linkage studies include 4p16, 12q23-q24, 16p13, 21q22, and Xq24-q26. Chromosome 18 is also of interest but the findings are confusing with up to three possible regions implicated. To date most candidate gene studies have focused on neurotransmitter systems influenced by medication used in clinical management of the disorder but no robust positive findings have yet emerged. It is, however, almost certain that over the next few years bipolar susceptibility genes will be identified. This will have a major impact on our understanding of disease pathophysiology and will provide important opportunities to investigate the interaction between genetic and environmental factors involved in pathogenesis. This is likely to lead to major improvements in treatment and patient care but will also raise important ethical issues that will need to be addressed.
A genome-wide scan for genetic linkage can suggest fresh insights into disease aetiology. However, in the case of complex disorders such as bipolar affective disorder (BPAD), the results of genome-wide scans must be interpreted with caution. We review 10 published and 10 in-progress genome scans of BPAD, encompassing 3536 affected individuals in 1119 pedigrees. We find that ascertainment methods vary widely, with no two studies using identical methods. Sample sizes and marker densities have generally been well below what is now considered adequate, but several in-progress studies are using larger samples and more closely spaced markers. Few findings reach the 'suggestive' threshold, and fewer still reach the 'significant' threshold at genome-wide levels of significance. Strategies for pooling samples or subjecting findings in different samples to meta-analysis are being developed, but differences in ascertainment methods may have a large impact on the uniformity of different samples and hamper efforts at combining data or findings. There is also a need for methods that help define more genetically homogeneous phenotypes, take into account interactions between multiple susceptibility loci, and accommodate additional complexity (eg parent-of-origin effects) in the search for linkage.
Factors of genetic vulnerability in bipolar mood disorders
A study of the factors of genetic vulnerability in bipolar mood disorders has met and is still meeting with numerous methodological difficulties such as a lack of knowledge on the genetic model of the illness, etiological and clinical heterogeneity, the absence of external validity criteria to define pathologies and the absence of biological or genetic validity of the diagnostic classifications of psychiatric pathologies. This overview illustrates the strategies set up in order to overcome these difficulties and puts the accent on identifying more valid phenotypical indicators, with the aim of facilitating analysis of the underlying genetic component. One analysis concentrates on the patients and aims to break down their heterogeneity in order to identify more homogeneous sub groups, more relevant to analysis of the genetic component (with the hope of reducing the underlying etiological heterogeneity). The other attempts to identify the phenotypical markers of genetic vulnerability in patients’ relatives who, though unaffected, can be at risk.
This chapter presents the current perspective of psychiatric genetics. The chapter illustrates that psychiatric disorders is a major focus of genetic investigation. They are among the most common disorders for which predominantly genetic etiologies have been suggested by family and twin studies, they are causes of severe morbidity and mortality, and there are essentially no other specific pathophysiological clues, so that genetic linkage studies have seemed justified despite the many obstacles to the detection of loci underlying genetically complex disorders. The most intensively-studied of these disorders are schizophrenia and bipolar (manic-depressive) disorder, with panic disorder, autism and alcoholism also receiving substantial attention. Published estimates of lifetime risk in the general population, risk to siblings of probands, MZ concordance and heritability for some of these disorders are highlight in chapter. The discussion focuses primarily on schizophrenia and bipolar disorder to illustrate the issues currently facing this field of research.
Identifying genes for schizophrenia through clas- sical genetic approaches has proven arduous. Here, we present a comprehensive convergent analysis that translationally integrates brain gene expression data from a relevant pharmaco- genomic mouse model (involving treatments with a psychomimetic agent—phencyclidine (PCP), and an anti-psychotic—clozapine), with human genetic linkage data and human postmortem brain data, as a Bayesian strategy of cross validat- ing findings. Topping the list of candidate genes, we have three genes involved in GABA neuro-
Bipolar disorder is a severe mental illness characterized by mood swings of elation and depression. Family, twin, and adoption
studies suggest a complex genetic etiology that may involve multiple susceptibility genes and an environmental component.
To identify chromosomal loci contributing to vulnerability, we have conducted a genome-wide scan on ≈396 individuals from
22 multiplex pedigrees by using 607 microsatellite markers. Multipoint nonparametric analysis detected the strongest evidence
for linkage at 13q32 with a maximal logarithm of odds (lod) score of 3.5 (P = 0.000028) under a phenotype model that included bipolar I, bipolar II with major depression, schizoaffective disorder,
and recurrent unipolar disorder. Suggestive linkage was found on 1q31-q32 (lod = 2.67; P = 0.00022) and 18p11.2 (lod = 2.32; P = 0.00054). Recent reports have linked schizophrenia to 13q32 and 18p11.2. Our genome scan identified other interesting regions,
7q31 (lod = 2.08; P = 0.00099) and 22q11-q13 (lod = 2.1; P = 0.00094), and also confirmed reported linkages on 4p16, 12q23-q24, and 21q22. By comprehensive screening of the entire
genome, we detected unreported loci for bipolar disorder, found support for proposed linkages, and gained evidence for the
overlap of susceptibility regions for bipolar disorder and schizophrenia.
IntroductionGenetic epidemiology of bipolar disordersLinkage studies of bipolar disordersCandidate gene studies of bipolar disorderGenome-wide association studiesConclusions and future directionsReferences
Four sites collaborated with the NIMH to develop a resource for the genetic study of bipolar (BP) illness. Common methods of ascertainment and assessment were developed in 1989. A series of families with a bipolar I (BPI) proband and at least one BPI or schizoaffective, bipolar type (SA/BP) first-degree relative has been studied. We now report initial data from a genomic survey with an average intermarker interval of 10 cM on 540 subjects from 97 families. This is the largest commonly ascertained and assessed linkage sample for bipolar illness reported to date; it includes 232 subjects with BPI, 32 SA/BP, 72 bipolar II (BPII), and 88 unipolar, recurrent (UPR). Nonparametric methods of analysis were employed, with all sites using affected sib pair analysis. The strongest findings thus far appear to be on chromosomes 1, 6, 7, 10, 16, and 22. Support has also been found for some previously reported linkages, including 21q and possibly Xq26. All these areas (as well as others) will be followed up with additional markers and further analyses. No locus tested thus far meets stringent criteria for an initial finding of significant linkage. Am. J. Med. Genet. 74:227–237, 1997. © 1997 Wiley-Liss, Inc.
We report on an initial genome screen of 540 individuals from 97 families collected as part of the NIMH Genetics Initiative Bipolar Group. Among the individuals studied, 232 were diagnosed with bipolar (BP) I, 72 with BPII, 88 with major depressive disorder-recurrent type (UPR), and 32 with schizoaffective disorder, bipolar type (SA/BP). A total of 53 markers on chromosomes 2, 11, 13, 14, and X (average spacing: 11.5 cM) were studied at Johns Hopkins University. Tests for linkage were performed using nonparametric affected sib-pair and whole pedigree methods with three definitions of affected status. Three regions of interest were identified (13q14–32, Xp22, and Xq26–28). On chromosomes 2, 11, and 14, a disease locus with relative risk λi = 1.5 could be excluded in <10% of the genetic distance studied, while a locus conferring λi = 3 or greater could be excluded across at least 96%. The autosomal region that could not be excluded even with λi = 5 was near 13q14–32. In this region, two-point affected sib-pair analyses revealed a pair of consecutive loci with excess sharing (P < 0.05) and a multipoint affected sib-pair LOD score of 1.12. On the X chromosome, nonparametric multipoint affected sib-pair analyses revealed peak total LOD scores of 0.94 on Xp22 and 1.34 on Xq26–28. A locus linked to the markers in Xp22 would have λi = 3.6 in affected brother-brother pairs, while a locus linked to the markers in Xq26–28 would have λi ≥ 1.9 in affected sister-sister pairs. The results on 13q14–32, Xp22, and Xq26–28 suggest areas of interest for further studies. Am. J. Med. Genet. 74:263–269, 1997. © 1997 Wiley-Liss, Inc.
Objectives : To review the methodologies and findings in the genetics of bipolar disorder (BPD), and to suggest future directions for research.
Methods : Reports of family, twin, adoption, linkage, association, cytogenetic, and animal model studies, and segregation analyses in English, were identified from multiple MEDLINE searches. Hand searches were carried out in bibliographies from review articles.
Results : Family, twin, and adoption studies have provided strong evidence for a genetic etiology in BPD. Early reports of linkage of BPD to DNA markers at several chromosomal sites have not proven robust, perhaps because of the complex nature of BPD inheritance. However, linkage findings in the 1990s, on chromosomes 18, 21q, 12q, and 4p, have provided leads that are being pursued through both genetic and physical mapping. No gene has yet been definitively implicated in BPD.
Conclusions : Strategies for increasing the power to detect BPD genes include: (1) dividing the phenotype into genetically meaningful subtypes to decrease heterogeneity; and (2) ascertaining a very large family sample – a multicenter study now in progress will collect 700 bipolar I sibling pairs. BPD may result from several genes acting in concert so that new multilocus statistical methods could enhance the capacity to detect loci involved. Family‐based association studies using a very large number of newly identified single nucleotide polymorphisms (SNPs) may allow for more efficient screening of the genome. As the Human Genome Project approaches its goal of isolating all genes by 2003, the data generated is likely to speed identification of candidate BPD genes.
As part of a four-center NIMH Genetics Initiative on Bipolar Disorder, a genome screen using 365 markers was performed on 540 DNAs from 97 families, enriched for affected relative pairs. This is the largest uniformly ascertained and assessed linkage sample for this disease, and includes 232 subjects diagnosed with bipolar I (BPI), 32 with schizo-affective, bipolar type (SABP), 72 with bipolar II (BPII), and 88 with unipolar recurrent depression (UPR). A hierarchical set of definitions of affected status was examined. Under Model I, affected individuals were those with a diagnosis of BPI or SABP, Model II included as affected those fitting Model I plus BPII, and Model III included those fitting Model II plus UPR. This data set was previously analyzed using primarily affected sib pair methods. We report the results of nonparametric linkage analyses of the extended pedigree structure using the program Genehunter Plus. The strongest finding was a lod score of 2.5 obtained on chromosome 10 near the marker D10S1423 with diagnosis as defined under Model II. This region has been previously implicated in genome-wide studies of schizophrenia and bipolar disorder. Other chromosomal regions with lod scores over 1.50 for at least one Model Included chromosomes 8 (Model III), 16 (Model III), and 20 (Model I). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:18–23, 2000 © 2000 Wiley-Liss, Inc.
The familial aggregation and genetic transmission of bipolar disorder has been consistently demonstrated through family, twin, and adoption studies. These studies show that early onset of the disorder confers a greater familial risk to relatives, but relatively little is known about genetic transmission in families having juvenile-onset cases. Although there are few genetic epidemiologic studies of juvenile-onset bipolar disorder, the evidence from extant studies is clear: this form of bipolar disorder aggregates in families and appears to be highly heritable. It is not yet known if this aggregation is due to genetic or environmental sources as twin studies of juvenile-onset bipolar disorder are lacking; however, twin and adoption studies of broad-spectrum bipolar disorder clearly demonstrate the high heritability of the disorder, with a minority of disease risk attributable to shared and unique environmental experiences. As a potentially more severe and more organic form of bipolar disorder, it is reasonable to suspect that pediatric-onset bipolar disorder is at least as heritable as bipolar disorder ascertained without regard to age of onset, although this remains to be established. Molecular genetic studies of early-onset bipolarity have failed to reveal reliably significant contributors to disease risk, but such efforts have only recently begun. As suggested by Todd et al. [1993], because it may be a more genetically influenced condition, early-onset bipolar disorder may be the most useful bipolar subtype in identifying genes that influence risk for all cases of the illness. The study of early-onset disease forms has proven extremely useful in identifying genetic contributors to various diseases, including Alzheimers disease [Levy-Lahad et al., 1995a,b] and diabetes mellitus [Davies et al., 1994]. Presumably, individuals with an early onset of disease will produce stronger genetic signals in linkage and association studies due to less genetic heterogeneity, greater penetrance of risk alleles, or both. Furthermore, such cases may have a higher genetic loading of risk alleles (i.e., they possess a greater number of the critical alleles of risk genes), thus facilitating the detection of any one or more risk genes out of the many that may exist. Although early-onset bipolar disorder may be a product of an accumulation or convergence of numerous environmental and, especially, genetic risk factors in individual members of multiply-affected families, the early-onset form of the disorder may actually be due to altogether different genes than the more typical adult-onset form (i.e., early-onset bipolar disorder may be a phenocopy of the adult-onset form, or vice versa). The extent studies of pediatric bipolar disorder should be viewed in light of the fact that the phenotype is complex and comorbid with many other disorders, including CD, anxiety disorders, substance use disorders, and ADHD [Carlson, 1990; Carlson and Weintraub, 1993; Wozniak et al., 1995a, 2001, 2002; Geller and Luby, 1997; Geller et al., 2000, 2002; Carlson et al., 2002]. Thus, future genetic studies should address the breadth of the phenotype, its discrimination from other disorders, and its continuity with bipolar disorder in adulthood. As reviewed above, some evidence suggests that the early-onset bipolar disorder phenotype is associated with CD and ADHD. Thus the cooccurrence of these disorders may define a homogeneous subgroup of patients that may be useful for molecular genetic research.
Despite some progress, the overwhelming majority of susceptibility genes that likely play an important role in psychiatric disorders remain undiscovered. This may be due to the fact that the etiologies of psychiatric disorders are complex and involve multiple genes of small effect acting independently and interactively. We review promising new strategies that utilize clinical information to facilitate the search for these susceptibility genes. We discuss family studies methods that can be used to assess whether a clinical feature reflects the underlying genetic heterogeneity of psychiatric disorders. We then review approaches for incorporating clinical covariates into linkage and association analyses for gene mapping. Finally, we discuss some considerations for assessing the significance of findings that emerge from the exploration of clinical data. The strategy of using clinical information to resolve the genetic heterogeneity of complex disorders has been successfully used in the past. We believe the wider application of this strategy in the study of psychiatric disorders may yield considerable benefits in the future.
Family, twin, and adoption studies provide strong evidence for a genetic etiology in bipolar disorder (BPD). Early studies seeking to locate genes reported statistical evidence for linkage of BPD to DNA markers at several chromosomal sites. The earliest of these have not proven robust while several more powerful genome scans have had largely negative findings. Recurring, suggestively positive linkage findings on chromosomes 4p, 12q, 18p, 18q, and 21q have emerged as attractive candidate regions for further study. However, it is clear now that single gene forms of BPD, if they exist, must be uncommon. Clinical strategies for increasing the power of linkage and association studies include: (1) ascertaining very large family samples and (2) dividing the phenotypes and families into genetically meaningful subgroups to decrease heterogeneity. The Human Genome Project will soon provide the chromosomal location and DNA sequences for all genes. In doing so, it will make the identification of candidate genes for bipolar disorder a routine step in our studies. We summarize here the results of the current studies at Johns Hopkins to resolve the genetic causes of BPD related to the locus on 18q21–22. We have found that preferential transmission of paternal alleles to BPII offspring is the critical observation behind our linkage findings in this chromosomal region. Similar delineation of the individual and familial subtypes of BPD at the other candidate regions could lead to progress in isolation of the genes involved and to pathogenetic studies of the disease.
Prior genomewide scans of schizophrenia support evidence of linkage to regions of chromosome 20. However, association analyses have yet to provide support for any etiologically relevant variants.
We analyzed 2988 LD-tagging single nucleotide polymorphisms (SNPs) in 327 genes on chromosome 20, to test for association with schizophrenia in 270 Irish high-density families (ISHDSF, N = 270 families, 1408 subjects). These SNPs were genotyped using an Illumina iSelect genotyping array which employs the Infinium assay. Given a previous report of novel linkage with chromosome 20p using latent classes of psychotic illness in this sample, association analysis was also conducted for each of five factor-derived scores based on the Operational Criteria Checklist for Psychotic Illness (delusions, hallucinations, mania, depression, and negative symptoms). Tests of association were conducted using the PDTPHASE and QPDTPHASE packages of UNPHASED. Empirical estimates of gene-wise significance were obtained by adaptive permutation of a) the smallest observed P-value and b) the threshold-truncated product of P-values for each locus.
While no single variant was significant after LD-corrected Bonferroni-correction, our gene-dropping analyses identified loci which exceeded empirical significance criteria for both gene-based tests. Namely, R3HDML and C20orf39 are significantly associated with depressive symptoms of schizophrenia (P(emp)<2×10⁻⁵) based on the minimum P-value and truncated-product methods, respectively.
Using a gene-based approach to family-based association, R3HDML and C20orf39 were found to be significantly associated with clinical dimensions of schizophrenia. These findings demonstrate the efficacy of gene-based analysis and support previous evidence that chromosome 20 may harbor schizophrenia susceptibility or modifier loci.
Considerable advances have been made in identifying specific genetic components of bipolar manic depressive illness (BP) and schizophrenia (SZ), despite their complex inheritance. Meta-analysis of all published whole-genome linkage scans reveals overall support for illness genes in several chromosomal regions. In two of these regions, on the lonq arm of chromosome 13 and on the long arm of chromosome 22, the combined studies of BP and SZ are consistent with a common susceptibility locus for the two disorders. This lends some plausibility to the hypothesis of some shared genetic predispositions for BP and SZ. Other linkages are supported by multiple studies of specific chromosomal regions, most notably two regions on chromosome 6 in SZ. The velocardiofacial syndrome is associated with deletions very close to the linkage region on chromosome 22, and with psychiatric manifestations of both BP and SZ. Endophenotypes of SZ, previously demonstrated to be heritable, have been found to have chromosomal linkage in at least one study. These include eye-tracking abnormalities linked to the short arm of chromosome 6, and abnormality of the P50 cortical evoked potential linked to chromosome 15. Variants in specific genes have been associated with susceptibility to illness, and other genes have been associated with susceptibility to side effects of pharmacological treatment. These genetic findings may eventually be part of an integrated genetic, environmental, and interactive-factor epidemiology of the major mental illnesses.
Schizophrenia and bipolar disorder (BPD) are common neurodevelopmental disorders, characterized by various life-crippling symptoms and high suicide rates. Multiple studies support a strong genetic involvement in the etiology of these disorders, although patterns of inheritance are variable and complex. Adenosine-to-inosine RNA editing is a cellular mechanism, which has been implicated in mental disorders and suicide. To examine the involvement of altered RNA editing in these disorders, we: (i) quantified the mRNA levels of the adenosine deaminase acting on RNA (ADAR) editing enzymes by real-time quantitative polymerase chain reaction, and (ii) measured the editing levels in transcripts of several neuroreceptors using 454 high-throughput sequencing, in dorsolateral-prefrontal cortices of schizophrenics, BPD patients and controls. Increased expression of specific ADAR2 variants with diminished catalytic activity was observed in schizophrenia. Our results also indicate that the I/V editing site in the glutamate receptor, ionotropic kainate 2 (GRIK2) transcript is under-edited in BPD (type I) patients (45.8 versus 53.9%, P= 0.023). GRIK2 has been implicated in mood disorders, and editing of its I/V site can modulate Ca(+2) permeability of the channel, consistent with numerous observations of elevated intracellular Ca(+2) levels in BPD patients. Our findings may therefore, at least partly, explain a molecular mechanism underlying the disorder. In addition, an intriguing correlation was found between editing events on separate exons of GRIK2. Finally, multiple novel editing sites were detected near previously known sites, albeit most with very low editing rates. This supports the hypothesis raised previously regarding the existence of wide-spread low-level 'background' editing as a mechanism that enhances adaptation and evolvability.
An analytical study is conducted of the properties of statistical tests to detect linkage between a disease locus and a very polymorphic marker locus when data on sib pairs are available. In most instances the most powerful test is the test based on the mean number of marker alleles shared identical by descent by the two members of a sib pair, and the most efficient sampling strategy is almost always to sample only pairs with both sibs affected. We show it is valid to use the information from all possible sib pairs as though they came from separate families when data on sibships of size three or larger are available, though more power may be obtained if different weights are given to the different sibship sizes.
Radiation hybrid (RH) mapping, a somatic cell genetic technique, was developed as a general approach for constructing long-range
maps of mammalian chromosomes. This statistical method depends on x-ray breakage of chromosomes to determine the distances
between DNA markers, as well as their order on the chromosome. In addition, the method allows the relative likelihoods of
alternative marker orders to be determined. The RH procedure was used to map 14 DNA probes from a region of human chromosome
21 spanning 20 megabase pairs. The map was confirmed by pulsed-field gel electrophoretic analysis. The results demonstrate
the effectiveness of RH mapping for constructing high-resolution, contiguous maps of mammalian chromosomes.
In 1992, we described a second-generation genetic linkage map of the human genome. Using 1,267 new microsatellite markers, we now present a new genetic linkage map containing a total of 2,066 (AC)n short tandem repeats, 60% of which show a heterozygosity of over 0.7. Statistical linkage analysis based on the genotyping of eight large CEPH families placed these markers in the 23 linkage groups. The map includes 1,266 intervals and spans a total distance of 3690 centiMorgans (cM). A total of 1,041 markers could be ordered with odds ratios greater than 1000:1. About 56% of this map is at a distance of 1 cM or less from one of its markers.
The influence of genetic factors in schizophrenia has been convincingly demonstrated by family, twin and adoption studies, but the mode of transmission remains uncertain. The reported pattern of recurrence risks suggests a set of interacting loci. Based on prior evidence for linkage on chromosome 6p (K. Kendler, pers. comm.), we have scanned the short arm of chromosome 6 in 54 families for loci predisposing to schizophrenia, using 25 microsatellite markers spanning 60 centiMorgans (cM). Allele sharing identity by descent was examined in affected sib-pairs from these families, followed by multipoint sib-pair linkage analysis. Positive lod scores were obtained over a wide region (D6S470 to D6S271), with a maximum lod score of 2.2 occurring near D6S274, located in 6p22. However, we obtained a lod score of -2 at D6S296, the locus found by others to provide the greatest linkage evidence. At D6S274, we report a positive lod score as do Straub et al. (individually non-significant). A combined total lod of 3.6-4.0 suggests the possibility of a susceptibility locus in this region. However, methodological differences between our studies makes a firm conclusion difficult.
In the course of a systematic genomic survey, 22 manic-depressive (bipolar) families were examined for linkage to 11 chromosome 18 pericentromeric marker loci, under dominant and recessive models. Overall logarithm of odds score analysis for the pedigree series was not significant under either model, but several families yielded logarithm of odds scores consistent with linkage under dominant or recessive models. Affected sibling pair analysis of these data yielded evidence for linkage (P < 0.001) at D18S21. Affected pedigree member analysis also suggests linkage, with multilocus results for five loci giving P < 0.0001 and P = 0.0007 for weighting functions f(p) = 1 and 1/square root p, respectively, where p is the allele frequency. These results imply a susceptibility gene in the pericentromeric region of chromosome 18, with a complex mode of inheritance. Two plausible candidate genes, a corticotropin receptor and the alpha subunit of a GTP binding protein, have been localized to this region.
Twenty-one multiplex bipolar (BP) families, suitable for linkage studies, are described. The families include 365 informative persons (whose genotypes can be determined from available DNA samples), 154 of whom have BP, schizoaffective or recurrent unipolar diagnoses. The power of such a series to detect linkage is estimated through simulations under assumptions concerning the inheritance of BP illness, the genetic distances between the illness locus and markers, and marker heterozygosity. It is concluded that this series has greater than 50% power to detect linkage when only 25% of the families are linked to the locus under study. This paper is intended to serve as an introduction to a systematic genomic search for genes causing vulnerability to BP disease among these families.
In the last few years there have been rapid advances in developing genetic maps for humans, greatly enhancing our ability
to localize and identify genes for inherited disorders. Through the collaborative efforts of three large groups generating
microsatellite markers and the efforts of the 110 CEPH collaborators, a comprehensive human linkage map is presented here.
It consists of 5840 loci, of which 970 are uniquely ordered, covering 4000 centimorgans on the sex-averaged map. Of these
loci, 3617 are polymerase chain reaction-formatted short tandem repeat polymorphisms, and another 427 are genes. The map has
markers at an average density of 0.7 centimorgan, providing a resource for ready transference to physical maps and achieving
one of the first goals of the Human Genome Project--a comprehensive, high-density genetic map.
A genetic linkage map of the human genome was constructed that consists of 1416 loci, including 279 genes and expressed sequences. The loci are represented by 1676 polymorphic systems genotyped with the CEPH reference pedigree resource. A total of 339 microsatellite repeat markers assayed by PCR are contained within the map, and of the 351 markers with heterozygosities of at least 70%, 205 are microsatellites. Seven telomere loci define physical and genetic endpoints for 2q, 4p, 7q, 8p, 14q, 16p, and 16q, and in other cases distal markers on the maps have been localized to terminal cytogenetic bands. Therefore, at least 92% of the autosomal length of the genome and 95% of the X chromosome is estimated to be spanned by the map. Since the maps have relatively high marker density and numerous highly informative loci, they can be used to map disease phenotypes, even for those with limited pedigree resources. The baseline map provides a foundation for achieving continuity of clone-based physical maps and for the development of a truly integrated physical, genetic, and cytogenetic map of the human.
In 265 Irish pedigrees, with linkage analysis we find evidence for a vulnerability locus for schizophrenia in region 6p24-22. The greatest lod score, assuming locus heterogeneity, is 3.51 (P = 0.0002) with D6S296. Another test, the C test, also supported linkage, the strongest results being obtained with D6S296 (P = 0.00001), D6S274 (P = 0.004) and D6S285 (P = 0.006). Non-parametric analysis yielded suggestive, but substantially weaker, findings. This locus appears to influence the vulnerability to schizophrenia in roughly 15 to 30% of our pedigrees. Evidence for linkage was maximal using an intermediate phenotypic definition and declined when this definition was narrowed or was broadened to include other psychiatric disorders.
We have recently described a family in which there is cosegregation of major affective disorder with Darier`s disease and have mapped this autosomal dominant skin disorder to 12q23-q24.1. This has provided an interesting candidate region for genetic studies of bipolar disorder. We have studied the segregation of seven markers spanning the Darier`s disease locus in 45 bipolar disorder pedigrees and found modest evidence in support of linkage under heterogeneity for 5 of these markers. Nonparametric analyses were suggestive of linkage with a marker at the gene encoding a secretory form of phospholipase A2. Our sample has relatively low power to detect linkage under heterogeneity and independent researchers should examine markers from this region in further samples of bipolar pedigrees. 41 refs., 1 fig., 7 tabs.
Manic-depressive illness, or bipolar disorder (BP), is characterized by episodes of elevated mood (mania) and depression1. We designed a multistage study in the genetically isolated population of the Central Valley of Costa Rica2,3 to identify genes that promote susceptibility to severe BP (termed BPI), and screened the genome of two Costa Rican BPI pedigrees (Mclnnes et al., submitted). We considered only individuals who full-filled very stringent diagnostic criteria for BPI to be affected. The strongest evidence for a BPI locus was observed in 18q22-q23. We tested 16 additional markers in this region and seven yielded peak lod scores over 1.0. These suggestive lod scores were obtained over a far greater chromosomal length (about 40 cM) than in any other genome region. This localization is supported by marker haplotypes shared by 23 of 26 BPI affected individuals studied. Additionally, marker allele frequencies over portions of this region are significantly different in the patient sample from those of the general Costa Rican population. Finally, we performed an analysis which made use of both the evidence for linkage and for association in 18q23, and we observed significant lod scores for two markers in this region.
Expanded analyses of the NIMH Collaborative Study family data on bipolar disorder showed that an earlier suggestion of non-Mendelian transmission was dependent on the definition of the liability indicator. When an appropriate liability indicator was used. polygenic and generalised single major locus models were almost equally compatible with the data.
(C) Lippincott-Raven Publishers.
Twenty-one multiplex bipolar (BP) families, suitable for linkage studies, are described. The families include 365 informative persons (whose genotypes can be determined from available DNA samples), 154 of whom have BP, schizoaffective or recurrent unipolar diagnoses. The power of such a series to detect linkage is estimated through simulations under assumptions concerning the inheritance of BP illness, the genetic distances between the illness locus and markers, and marker heterozygosity. It is concluded that this series has greater than 50% power to detect linkage when only 25% of the families are linked to the locus under study. This paper is intended to serve as an introduction to a systematic genomic search for genes causing vulnerability to BP disease among these families.
(C) Lippincott-Raven Publishers.
Four sites collaborated with the NIMH to develop a resource for the genetic study of bipolar (BP) illness. Common methods of ascertainment and assessment were developed in 1989. A series of families with a bipolar I (BPI) proband and at least one BPI or schizoaffective, bipolar type (SA/BP) first-degree relative has been studied. We now report initial data from a genomic survey with an average intermarker interval of 10 cM on 540 subjects from 97 families. This is the largest commonly ascertained and assessed linkage sample for bipolar illness reported to date; it includes 232 subjects with BPI, 32 SA/BP, 72 bipolar II (BPII), and 88 unipolar, recurrent (UPR). Nonparametric methods of analysis were employed, with all sites using affected sib pair analysis. The strongest findings thus far appear to be on chromosomes 1, 6, 7, 10, 16, and 22. Support has also been found for some previously reported linkages, including 21q and possibly Xq26. All these areas (as well as others) will be followed up with additional markers and further analyses. No locus tested thus far meets stringent criteria for an initial finding of significant linkage. Am. J. Med. Genet. 74:227–237, 1997. © 1997 Wiley-Liss, Inc.
We are conducting a genome search for a predisposing locus to bipolar (manicdepressive) illness by genotyping 21 moderate-sized pedigrees. We report linkage data derived from screening marker loci on chromosomes 2, 3, 4, 7, 9, 10p, 11p, 22, and the pseudoautosomal region at Xpter. To analyze for linkage, two-point marker to illness lod scores were calculated under a dominant model with either 85% or 50% maximum penetrance and a recessive model with 85% maximum penetrance, and two affection status models. Under the dominant high penetrance model the cumulative lod scores in the pedigree series were less than −2 at Θ = 0.01 in 134 of 142 loci examined, indicating that if the disease is genetically homogeneous linkage could be excluded in these marker regions. Similar results were obtained using the other genetic models. Heterogeneity analysis was conducted when indicated, but no evidence for linkage was found. In the course of mapping we found a positive total lod score greater than +3 at the D7S78 locus at Θ = 0.01 under a dominant, 50% penetrance model. The lod scores for additional markers within the D7S78 region failed to support the initial finding, implying that this was a spurious positive. Analysis with affected pedigree member method for COL1A2 and D7S78 showed no significance for linkage but for PLANH1, at the weighting functions f(p) = 1 and f(p) = 1/sqrt(p) borderline P values of 0.036 and 0.047 were obtained. We also detected new polymorphisms at the mineralocorticoid receptor (MLR) and calmodulin II (CALMII) genes. These genes were genetically mapped and under affection status model 2 and a dominant, high penetrance mode of transmission the lod scores of < −2 at Θ = 0.01 were found. © 1994 Wiley-Liss, Inc.
A report on an initial genome screen on 540 individuals in 97 families was collected as part of the NIMH Genetics Initiative on Bipolar Disorder. Families were ascertained to be informative for genetic linkage and underwent a common ascertainment and assessment protocol at four clinical sites. The sample was genotyped for 65 highly polymorphic markers from chromosomes 1, 6, 8, 10, and 12. The average intermarker interval was 16 cM. Genotypic data was analyzed using affected sib pair, multipoint affected sib pair, and pedigree analysis methods.
Multipoint methods gave lod scores of approximately two on chromosomes 1, 6, and 10. The peak lod score on chromosome 6 occurred at the end of the q-arm, at some distance from the 6p24-22 area previously implicated for schizophrenia. We are currently genotyping additional markers to reduce the intermarker interval around the signals.
The interpretation of results from a genome screen of a complex disorder and the problem of achieving a balance between detecting false positive results and the ability to detect genes of modest effect are discussed. Am. J. Med. Genet. 74:247–253, 1997.
We report on an initial genome screen of 540 individuals from 97 families collected as part of the NIMH Genetics Initiative Bipolar Group. Among the individuals studied, 232 were diagnosed with bipolar (BP) I, 72 with BPII, 88 with major depressive disorder-recurrent type (UPR), and 32 with schizoaffective disorder, bipolar type (SA/BP). A total of 53 markers on chromosomes 2, 11, 13, 14, and X (average spacing: 11.5 cM) were studied at Johns Hopkins University. Tests for linkage were performed using nonparametric affected sib-pair and whole pedigree methods with three definitions of affected status. Three regions of interest were identified (13q14–32, Xp22, and Xq26–28). On chromosomes 2, 11, and 14, a disease locus with relative risk λi = 1.5 could be excluded in <10% of the genetic distance studied, while a locus conferring λi = 3 or greater could be excluded across at least 96%. The autosomal region that could not be excluded even with λi = 5 was near 13q14–32. In this region, two-point affected sib-pair analyses revealed a pair of consecutive loci with excess sharing (P < 0.05) and a multipoint affected sib-pair LOD score of 1.12. On the X chromosome, nonparametric multipoint affected sib-pair analyses revealed peak total LOD scores of 0.94 on Xp22 and 1.34 on Xq26–28. A locus linked to the markers in Xp22 would have λi = 3.6 in affected brother-brother pairs, while a locus linked to the markers in Xq26–28 would have λi ≥ 1.9 in affected sister-sister pairs. The results on 13q14–32, Xp22, and Xq26–28 suggest areas of interest for further studies. Am. J. Med. Genet. 74:263–269, 1997. © 1997 Wiley-Liss, Inc.
A susceptibility gene on chromosome 18 and a parent-of-origin effect have been suggested for bipolar affective disorder (BPAD). We have studied 28 nuclear families selected for apparent unilineal transmission of the BPAD phenotype, by using 31 polymorphic markers spanning chromosome 18. Evidence for linkage was tested with affected-sib-pair and LOD score methods under two definitions of the affected phenotype. The affected-sib-pair analyses indicated excess allele sharing for markers on 18p within the region reported previously. The greatest sharing was at D18S37: 64% in bipolar and recurrent unipolar (RUP) sib pairs (P = .0006). In addition, excess sharing of the paternally, but not maternally, transmitted alleles was observed at three markers on 18q: at D18S41, 51 bipolar and RUP sib pairs were concordant for paternally transmitted alleles, and 21 pairs were discordant (P = .0004). The evidence for linkage to loci on both 18p and 18q was strongest in the 11 paternal pedigrees, i.e., those in which the father or one of the father's sibs is affected. In these pedigrees, the greatest allele sharing (81%; P = .00002) and the highest LOD score (3.51; θ = 0.0) were observed at D18S41. Our results provide further support for linkage of BPAD to chromosome 18 and the first molecular evidence for a parent-of-origin effect operating in this disorder. The number of loci involved, and their precise location, require further study.
We previously developed a method of partitioning genetic variance of a quantitative trait to loci in specific chromosomal regions. In this paper, we compare this method--multipoint IBD (identical by descent) method (MIM)--with parametric multipoint linkage analysis (MLINK). A simulation study was performed comparing the methods for the major-locus, mixed, and two-locus models. The criterion for comparisons between MIM and MLINK was the average lod score from multiple replicates of simulated data sets. The effect of gene frequency, dominance, model misspecification, marker spacing, and informativeness are also considered in a smaller set of simulations. Within the context of the models examined, the MIM approach was found to be comparable in power with parametric multipoint linkage analysis when (a) parental data are unknown, (b) the effect of the major locus is small and there is additional genetic variation, or (c) the parameters of the major-locus model are misspecified. The performance of the MIM method relative to MLINK was markedly lower when the allele frequency at the trait locus was .2 versus .5, particularly for the case when parental data were assumed to be known. Dominance at the trait major locus, as well as marker spacing and heterozygosity, did not appear to have a large effect on the ELOD comparisons.
Given genetic marker data on unrelated individuals, maximum-likelihood allele-frequency estimates and their standard errors are easily calculated from sample proportions. When marker phenotypes are observed on relatives, this method cannot be used without either discarding a subset of the data or incorrectly assuming that all individuals are unrelated. Here, I describe a method for allele frequency estimation for data on relatives that is based on standard methods of pedigree analysis. This method makes use of all available marker information while correctly taking into account the dependence between relatives. I illustrate use of the method with family data for a VNTR polymorphism near the apolipoprotein B locus.
We present a rapid and efficient method for the isolation of minisatellite loci from human DNA. The method combines cloning a size-selected fraction of human MboI DNA fragments in a charomid vector with hybridization screening of the library in ordered array. Size-selection of large MboI fragments enriches for the longer, more variable minisatellites and reduces the size of the library required. The library was screened with a series of multi-locus probes known to detect a large number of hypervariable loci in human DNA. The gridded library allowed both the rapid processing of positive clones and the comparative evaluation of the different multi-locus probes used, in terms of both the relative success in detecting hypervariable loci and the degree of overlap between the sets of loci detected. We report 23 new human minisatellite loci isolated by this method, which map to 14 autosomes and the sex chromosomes.
A unique method of partitioning human quantitative genetic variation into effects due to specific chromosomal regions is presented. This method is based on estimating the proportion of genetic material, R, shared identical by descent (IBD) by sibling pairs in a specified chromosomal region, on the basis of their marker genotypes at a set of marker loci spanning the region. The mean and variance of the distribution of R conditional on IBD status and recombination pattern between two marker loci are derived as a function of the distance between the two loci. The distribution of the estimates of R is exemplified using data on 22 loci on chromosome 7. A method of using the estimated R values and observed values of a quantitative trait in a set of sibships to estimate the proportion of total genetic variance explained by loci in the region of interest is presented. Monte Carlo simulation techniques are used to show that this method is more powerful than existing methods of quantitative linkage analysis based on sib pairs. It is also shown through simulation studies that the proposed method is sensitive to genetic variation arising from both a single locus of large effect as well as from several loosely linked loci of moderate phenotypic effect.
This article summarizes discussion, conclusions, and recommendations of participants in a National Institute of Mental Health-sponsored workshop dealing with major issues in family and genetic studies of affective disorders. Key up-to-date findings in the field are reviewed with emphasis on areas of agreement. Remaining controversies and problems are identified, and a set of overall conclusions and recommendations for future research activities in the field is presented.
The relationship between increased risk in relatives over population prevalence (lambda R = KR/K) and probability of sharing zero marker alleles identical by descent (ibd) at a linked locus (such as HLA) by an affected relative pair is examined. For a model assuming a single disease-susceptibility locus or group of loci tightly linked to a marker locus, the relationship is remarkably simple and general. Namely, if phi R is the prior probability for the relative pair to share zero marker alleles identical by descent, then P (sharing 0 markers/both relatives are affected) is just phi R/lambda R. Alternatively, lambda AR, the increased risk over population prevalence to a relative R due to a disease locus tightly linked to marker locus A, equals the prior probability that the relative pair share zero A alleles ibd divided by the posterior probability that they share zero alleles ibd, given that they are both affected. For example, for affected sib pairs, P (sharing 0 markers/both sibs are affected) = .25/lambda S. This formula holds true for any number of alleles at the disease locus and for their frequencies, penetrances, and population prevalence. Similar formulas are derived for sharing one and two markers. Application of these formulas to several well-studied HLA-associated diseases yields the following results: For multiple sclerosis, insulin-dependent diabetes mellitus, and coeliac disease, a single-locus model of disease susceptibility is rejected, implying the existence of additional unlinked familial determinants. For all three diseases, the effect of the HLA-linked locus on familiality is minor: for multiple sclerosis, it accounts for only a 2.5-fold increased risk to sibs over the population prevalence, compared to an observed value of 20; for coeliac disease, it accounts for approximately a 5.25-fold increased risk to sibs, while the observed value is on the order of 60; for insulin-dependent diabetes mellitus, it accounts for a 3.42-fold increased risk in sibs, while the observed value is 15. In all cases, the secondary determinants must be outside the HLA region. For tuberculoid leprosy, an unlinked familial determinant is also implicated (increased risk to sibs due to HLA = 1.49; observed value = 2.38). For hemochromatosis and Hodgkin's disease, there is little evidence for HLA-unlinked familial determinants. With this formula, it is also possible to examine the hypothesis of pleiotropy versus linkage dis-equilibrium by comparing lambda AS with the increased risk to sibs due to the associated allele(s).(ABSTRACT TRUNCATED AT 400 WORDS)
The lod score method is widely used to test linkage and to estimate the recombination fraction between a disease locus and a marker locus. The parameters (gene frequency, penetrance, and degree of dominance) are assumed to be known at each locus. This condition may not be fulfilled at the disease locus. In this paper, we evaluate the errors due to the use of wrong parameters. The power of the linkage test is sensitive to the degree of dominance, and slightly to the penetrance, but not to the gene frequency. In contrast, the estimation of the recombination fraction may be strongly affected by an error on any genetic parameter.
A method is described for segregation analysis that incorporates linkage markers. The model allows for segregation (penetrance), linkage (recombination fraction), and association (linkage disequilibrium) parameters. A single-locus-multiple-allele model underlying the trait phenotype is assumed. When families have been ascertained in a systematic fashion, a joint (markers, phenotypes) likelihood with ascertainment is advocated. When ascertainment correction is not feasible, a conditional (markers given phenotypes) approach is recommended, which is also valid in the presence of reduced fertility and assortative mating. This approach, oriented toward determining mode of inheritance, differs from conventional linkage analysis, which is oriented toward detection of linkage. Therefore, it is more appropriately considered an extension of the affected sib-pair method to arbitrary pedigrees, including association information and allowing for multiple alleles. Incorporation of coupling parameters allows for discrimination between pleiotropy and linkage disequilibrium. The method is demonstrated through a reanalysis of four recently published family studies on type 1 diabetes and HLA. Recessive inheritance is rejected in all four data sets. For three of them, dominant inheritance is not rejected, while in the fourth, all two-allele models are rejected in favor of three alleles. Although association with the DR3 and DR4 alleles is quite strong, pleiotropy with regard to these alleles is unlikely. The results also suggest an additional familial factor(s) (e.g., locus).
The objective of this paper is to study the association between chromosomal fragile sites and type I bipolar disorder. This case-control study compares bipolar patients with normal controls. Ten cases of type I bipolar disorder diagnosed according to DSM-III-R criteria and the Composite International Diagnostic Interview (CIDI) were selected from the Escola Paulista affective disorders outpatient clinic and 10 healthy controls (CIDI negative for psychiatric diagnoses) matched for sex and age were drawn from the otorhinolaryngologic outpatient clinic of the same hospital. The cytogenetic analysis was carried out with blood lymphocytes, which were cultured in a folic acid-free medium. A total of 100 mitoses per subject were blindly analyzed to the psychiatric diagnostic assignment, and fragile sites were identified according to a minimum expected frequency of events per band in conformity with a Poisson distribution. A higher frequency of chromosomal lesions for cases than controls was found for the following bands: 1q32, 5q31, and 11q23, the 1q32 being considered a fragile site. Although no evident neuropsychiatric etiological component has been mapped to the 1q32 region so far, this finding may lead to further investigation of a possible linkage between genetic markers of this region and bipolar disorder.
Genetic studies are under way for many complex traits, spurred by the recent feasibility of whole genome scans. Clear guidelines for the interpretation of linkage results are needed to avoid a flood of false positive claims. At the same time, an overly cautious approach runs the risk of causing true hints of linkage to be missed. We address this problem by proposing specific standards designed to maintain rigor while also promoting communication.
We have performed linkage analysis in 186 multiplex families to search for genes that predispose to schizophrenia. Under a model with partially dominant inheritance, moderately broad disease definition and assuming locus homogeneity, a lod score of 3.2 was obtained for D6S260 on chromosome 6p23. A multipoint lod score of 3.9 (P = 2.3 x 10(-5)) was achieved when the F13A1 and D6S260 loci were analysed, allowing for locus heterogeneity. Adjusted for testing of multiple models, the multipoint lod score of 3.9 under heterogeneity has a genome wide significance of between 5-8%. The nonparametric affected pedigree member test provided results (P = 3 x 10(-4)) also supporting this finding. Our findings provide supportive evidence for a susceptibility locus for schizophrenia on distal chromosome 6p, and support a model of locus heterogeneity.
Co-segregation between Darier's disease and manic depressive illness has been reported. A gene causing Darier's disease has recently been mapped to chromosome 12q23-q24.1, and this region may thus be considered a candidate region potentially containing a gene involved in the aetiology of manic depressive illness. At least one possible candidate gene for manic depressive illness, pro-melanin-concentrating hormone, is located on chromosome 12q23-q24. The present study investigated linkage between manic depressive illness and this region on chromosome 12q, using three microsatellite polymorphisms as genetic markers which flank the gene causing Darier's disease. For all dominant models close linkage was excluded. For broader phenotypic models linkage was excluded in the interval between markers, even in one large family alone.
The mode of inheritance of bipolar affective disorder (BPAD) appears complex, and non-Mendelian models of inheritance have been postulated. Two non-Mendelian phenomena, genomic imprinting and mitochondrial inheritance, may contribute to the complex inheritance pattern seen in BPAD. Both imprinting and mitochondrial inheritance share the feature of differential expression of the phenotype, depending on the parent of origin. In this study we tested the hypothesis of a parent-of-origin effect on the transmission of BPAD. We examined the frequency and risk of affective disorder among relatives in a sample of 31 families ascertained through treated probands with BPAD and selected for the presence of affected phenotypes in only one parental lineage. Three specific comparisons were performed: (1) the observed frequency of transmitting mothers versus transmitting fathers; (2) the observed frequency and lifetime risk of BPAD among the maternal versus the paternal relatives of probands; and (3) the observed frequency and lifetime risk of BPAD for the offspring of affected mothers compared with the offspring of affected fathers. We observed a higher than expected frequency of affected mothers (P < .04), a 2.3-2.8-fold increased risk of illness for maternal relatives (P < .006), and a 1.3- 2.5-fold increased risk of illness for the offspring of affected mothers (P < .017). In seven enlarged pedigrees, fathers repeatedly failed to transmit the affected phenotype to daughters or sons. Taken together, these findings indicate a maternal effect in the transmission of BPAD susceptibility and suggest that molecular studies of mtDNA and imprinted DNA are warranted in patients with BPAD.
In a preliminary genome scan of 47 bipolar disorder families, we detected in one family a lod score of 3.41 at the PFKL locus on chromosome 21q22.3. The lod score is robust to marker allele frequencies, phenocopy rates and age-dependent penetrance, and remains strongly positive with changes in affection status. Fourteen other markers in 21q22.3 were tested on this family, with largely positive lod scores. Five of the other 46 families also show positive, but modest lod scores with PFKL. When all 47 families are analysed together, there is little support for linkage to PFKL under homogeneity or heterogeneity using lod score analysis, but the model-free affected-pedigree-member method yields statistically significant results (p < 0.0003). Our results are consistent with the presence of a gene in 21q22.3 predisposing at least one family to bipolar disorder.
In the last few years there have been rapid advances in developing genetic maps for humans, greatly enhancing our ability to localize and identify genes for inherited disorders. Through the collaborative efforts of three large groups generating microsatellite markers and the efforts of the 110 CEPH collaborators, a comprehensive human linkage map is presented here. It consists of 5840 loci, of which 970 are uniquely ordered, covering 4000 centimorgans on the sex-averaged map. Of these loci, 3617 are polymerase chain reaction-formatted short tandem repeat polymorphisms, and another 427 are genes. The map has markers at an average density of 0.7 centimorgan, providing a resource for ready transference to physical maps and achieving one of the first goals of the Human Genome Project--a comprehensive, high-density genetic map.
Darier's disease is a rare autosomal dominantly inherited keratosis. This is an account of one family in which there is co-occurrence of major affective disorder and Darier's disease in five members and absence of both disorders in five members. The pedigree is consistent with genetic linkage between the Darier gene and a major autosomal dominant susceptibility locus for major affective disorder. When the Darier's disease gene has been mapped, its chromosomal location will be an interesting candidate locus for linkage studies of major affective disorder.
Affective (mood) disorders are common. There are several methodological impediments to genetic studies of affective disorders, including uncertainties about the best definition of disease phenotype, difficulties in the assessment of lifetime diagnosis and variable age of onset of illness. Despite these difficulties, family, twin and adoption studies provide compelling evidence for the existence of important genetic factors in determining susceptibility to affective disorders. However, the mode of inheritance is unknown. Simple mendelian inheritance may occur in some families but cannot explain the majority of cases. With the advent of polymorphic DNA markers, linkage and association studies have become more useful methods for the genetic analysis of complex disorders such as affective illness. No consistent finding has yet emerged, although chromosomal region 11p15 (and to a lesser extent Xq28) are of continuing interest. In addition to further study of these regions it will also be necessary to look for susceptibility loci in other parts of the genome. Large samples will almost certainly be required. If susceptibility loci of major effect exist then linkage approaches will find them. However, if there are only loci of small effect, then association approaches will be necessary. At present, it seems prudent to pursue both linkage and association approaches together.
Most investigators presume that schizophrenia and affective disorder are separate diseases. Others have proposed alternatives to this Kraepelinian view. These alternatives were addressed by preliminary analyses of data from a family study of psychopathology.
The authors identified 1,895 first-degree relatives of 166 patients with DSM-III schizophrenia, 71 patients with affective disorder, and 85 medical comparison probands; 949 relatives were blindly diagnosed.
The risks for schizophrenia and affective disorder (unipolar melancholia and bipolar disorder combined) were significantly higher in the relatives of the schizophrenic probands and the relatives of the probands with affective disorder than in the relatives of the comparison probands. The morbid risk for nonmelancholic depressions was not significantly higher. Among the relatives of the schizophrenic probands, the risk for affective disorder was highest among the relatives of the patients with "core" schizophrenia, who were younger at illness onset, had chronic illness, had severe emotional blunting, and showed few affective features.
Despite limitations, these preliminary analyses, consistent with other studies, suggest some familial relationship between schizophrenia and severe forms of affective disorder.
The multipoint identity-by-descent method was developed to detect linkage to a specific chromosomal region through partitioning the genetic variance. This method has previously been applied to quantitative traits, and here is extended to a qualitative trait, where a dichotomous affected/unaffected status variable is transformed to a quantitative variable by incorporating covariates. This method is applied to the Alzheimer's disease data sets from Genetic Analysis Workshop 8, to investigate putative linkage to chromosomes 19 and 21. The multipoint identity-by-descent method is used to test for linkage through the qualitative trait, and for excess sharing of the chromosomal region among affected sibs. Results are compared to those of the affected-pedigree-member method and classical linkage analysis. None of these methods gave results showing clear linkage, with the only marginally significant results occurring for the Boston data set on chromosome 19 and the Duke data set for chromosome 21 using the multipoint identity-by-descent method.
The main clinical feature of bipolar affective disorder is a change of mood to depression or elation. Unipolar disorder, also termed major depressive disorder, describes the occurrence of depression alone without episodes of elevated mood. Little is understood about the underlying causes of these common and severe illnesses which have estimated lifetime prevalences in the region of 0.8% for bipolar and 6% for unipolar disorder. Strong support for a genetic aetiology is found in the familial nature of the condition, the increased concordance of monozygotic over dizygotic twins and adoption studies showing increased rates of illness in children of affected parents. However, linkage studies have met with mixed success. An initial report of linkage on the short arm of chromosome 11 (ref. 4) was revised and remains unreplicated. Reports proposing cosegregation of genes found on the X chromosome with bipolar illness have not been supported by others. More recently bipolar disorder has been reported to be linked with markers on chromosomes 18, 21, 16 and a region on the X chromosome different from those previously suggested. We have carried out a linkage study in twelve bipolar families. In a single family a genome search employing 193 markers indicated linkage on chromosome 4p where the marker D4S394 generated a two-point lod score of 4.1 under a dominant model of inheritance. Three point analyses with neighbouring markers gave a maximum lod score of 4.8. Eleven other bipolar families were typed using D4S394 and in all families combined there was evidence of linkage with heterogeneity with a maximum two-point lod score of 4.1 (theta = 0, alpha = 0.35).
In 22 multiplex pedigrees screened for linkage to bipolar disorder, by use of 18 markers on chromosome 21q, single-locus affected-sib-pair (ASP) analysis detected a high proportion (57%-62%) of alleles shared identical by descent (IBD), with P values of .049-.0008 on nine marker loci. Multilocus ASP analyses revealed locus trios in the distal region between D21S270 and D21S171, with excess allele sharing (nominal P values <.01) under two affection-status models, ASM I (bipolars and schizoaffectives) and ASM II (ASM I plus recurrent unipolars). In addition, under ASM I, the proximal interval spanned by D21S1436 and D21S65 showed locus trios with excess allele sharing (nominal P values of .03-.0003). These findings support prior evidence that a susceptibility locus for bipolar disorder is on 21q.
We have replicated the observation of McMahon et al. [1995] that there is excess maternal transmission of illness in a series of previously described unilineal Bipolar manic-depressive illness extended pedigrees [Berrettini et al., 1991]. ("Transmission" is defined for any ill person in a pedigree when father or mother has a personal or immediate family history of major affective disorder.) We divided our pedigrees into exclusively maternal transmission (Mat) and mixed maternal-paternal transmission (in different pedigree branches) (Pat). Using affected sib-pair-analysis, linkage to a series of markers on chromosome 18p-cen was observed in the Pat but not the Mat pedigrees, with significantly greater identity by descent (IBD) at these markers in the Pat pedigrees. As compared with the pedigree series as a whole, the proportion of alleles IBD in the linkage region is much increased in the Pat pedigrees. As shown by Kruglyak and Lander [1995], as the sharing proportion of alleles in affected relative pairs increases, the number of such pairs needed to resolve the linkage region to a 1 cM interval becomes smaller. Genetic subdivision of an illness by clinical or pedigree configuration criteria may thus play an important role in discovery of disease susceptibility mutations.
A recent series of studies have attempted to replicate evidence for a vulnerability locus for schizophrenia on chromosome 6p initially detected in the Irish Study of High-Density Schizophrenia Families (ISHDSF). Here, we want to comment briefly on these findings and respond to some of the issues raised in the preceding article by Baron. We disclaim, however, any pretensions to a definitive interpretation of the available evidence. Our level of ignorance in the interpretation of linkage evidence for complex psychiatric syndromes is too profound. Rather, we seek to make educated guesses on the basis of our understanding of the principles of linkage analysis, on our knowledge of the problems of statistical inference and on our intuition of how genes might influence vulnerability to complex human behavioral traits. 27 refs.