A genome screen of 35 bipolar affective disorder pedigrees provides significant evidence for a susceptibility locus on chromosome 15q25-26

Abstract

Bipolar affective disorder is a heritable, relatively common, severe mood disorder with lifetime prevalence up to 4%. We report the results of a genome-wide linkage analysis conducted on a cohort of 35 Australian bipolar disorder families which identified evidence of significant linkage on chromosome 15q25-26 and suggestive evidence of linkage on chromosomes 4q, 6q and 13q. Subsequent fine-mapping of the chromosome 15q markers, using allele frequencies calculated from our cohort, gave significant results with a maximum two-point LOD score of 3.38 and multipoint LOD score of 4.58 for marker D15S130. Haplotype analysis based on pedigree-specific, identical-by-descent allele sharing, supported the location of a bipolar susceptibility gene within the Z maxÀ1 linkage confidence interval of 17 cM, or 6.2 Mb, between markers D15S979 and D15S816. Non-parametric and affecteds-only linkage analysis further verified the linkage signal in this region. A maximum NPL score of 3.38 (P = 0.0008) obtained at 107.16 cM (near D15S130), and a maximum two-point LOD score of 2.97 obtained at marker D15S1004 (affecteds only), support the original genome-wide findings on chromosome 15q. These results are consistent with four independent positive linkage studies of mood and psychotic disorders, and raise the possibility that a common gene for susceptibility to bipolar disorder, and other psychiatric disorders may lie in this chromosome 15q25-26 region. Keywords: bipolar affective disorder; manic depressive illness; susceptibility locus; genetic linkage; chromosome 15q Bipolar (BP) affective disorder (MIM 125480) is a severe mood disorder characterised by alternating periods of mania and depression with reversion to normal behaviour in between these episodes. Bipolar disorder is a relatively common condition with a worldwide prevalence between 0.5 and 1.5% 1 and lifetime prevalence of up to 4%. 2 The disorder has a severe impact on sufferers, being ranked the sixth most debilitating disorder in the World Health Organisation Global Burden of Disease Report, 3 and results in suicide rates 15 times higher than the general population. 4 The aetiology of bipolar disorder remains unknown, with little knowledge of the underlying biological, anatomical or biochemical effects. However, family, twin and adoption studies have provided strong evidence that genetic factors contribute to the disorder with heritability estimates in the range of 60-85%. 5,6 The high heritability, increased relative risks within families, 7 and familial clustering of the disorder provide the opportunity to use genetic approaches to identify predisposing genes. The inheritance pattern of the disorder is complex with non-Mendelian inheritance suggesting the involvement of multiple genes and environmental factors.Many genetic studies have attempted to map BP susceptibility loci and have provided evidence for linkage to a number of chromosomal regions (reviewed by Baron 8 ). One meta-analysis of wholegenome linkage scans did not identify consistent loci across linkage studie...

Genome-wide association study reveals two new risk loci for bipolar disorder

“…Canadian and Spanish data were kindly provided by Catherine Laprise (UQAC, Saguenay, Canada) and Manolis Kogevinas (CREAL, Barcelona, Spain). Genotyping of the samples Australia, Germany II, Germany III, and PGC-BD were described in previous studies 7,8,[42][43][44] . We aimed to genotype the patient and controls from the same population on the same chip type.…”

Characterisation of Genetic Variation in ST8SIA2 and Its Interaction Region in NCAM1 in Patients with Bipolar Disorder

“…We and others have previously identified the 15q25–26 genomic region as harbouring a mental illness risk gene through linkage in family cohorts with bipolar spectrum disorder [16], bipolar disorder and schizophrenia [17], [18] or psychosis [19]. We subsequently found evidence of disease association with variants in ST8SIA2 in both bipolar disorder and schizophrenia [20].…”

“…Diagnosis was made by structured interview using the Diagnostic Interview for Genetic Studies (DIGS), using Research Diagnostic Criteria. To enrich for individuals who may have a genetic defect in ST8SIA2 , we selected one individual affected with bipolar disorder type 1 (BPI) or type 2 (BPII) (n = 39 and n = 3 respectively) from 42 families who showed evidence of linkage to chromosome 15q25–26 [16], and six additional unrelated BPI cases from our case-control cohort to ensure equivalent representation of major haplotypes to those observed in population samples [20]. A total of 45 BPI cases (94%) and three BPII cases (6%) formed the selected sample.…”

From molecules and cells to diseases: West meets East for medical research in Tianjin

“…Continuing the theme of specific genes and their association with neural diseases, Professor Peter Schofield, Director of the Prince of Wales Medical Research Institute reported a significant link of chromosome locus 15q25-26 and susceptibility to bipolar disorder in 35 Australian multi-generational families [10]. He and his team have so far genotyped 376 single nucleotide polymorphisms at 15-kb resolution across the high-priority region and 20-kb resolution across the remaining 6.2-Mb interval in an Australian casecontrol cohort.…”

“…He and his team have so far genotyped 376 single nucleotide polymorphisms at 15-kb resolution across the high-priority region and 20-kb resolution across the remaining 6.2-Mb interval in an Australian casecontrol cohort. The gene ST8SIA2, previously associated with schizophrenia in Japanese and Chinese patients, was identified as a putative bipolar susceptibility gene within the 15q25-26 linkage region [10].…”