Combined Analysis from Eleven Linkage Studies of Bipolar Disorder Provides Strong Evidence of Susceptibility Loci on Chromosomes 6q and 8q

Abstract

Several independent studies and meta-analyses aimed at identifying genomic regions linked to bipolar disorder (BP) have failed to find clear and consistent evidence of linkage regions. Our hypothesis is that combining the original genotype data provides benefits of increased power and control over sources of heterogeneity that outweigh the difficulty and potential pitfalls of the implementation. We conducted a combined analysis using the original genotype data from 11 BP genomewide linkage scans comprising 5,179 individuals from 1,067 families. Heterogeneity among studies was minimized in our analyses by using uniform methods of analysis and a common, standardized marker map and was assessed using novel methods developed for meta-analysis of genome scans. To date, this collaboration is the largest and most comprehensive analysis of linkage samples involving a psychiatric disorder. We demonstrate that combining original genome-scan data is a powerful approach for the elucidation of linkage regions underlying complex disease. Our results establish genomewide significant linkage to BP on chromosomes 6q and 8q, which provides solid information to guide future gene-finding efforts that rely on fine-mapping and association approaches.

AHI1, a pivotal neurodevelopmental gene, and C6orf217 are associated with susceptibility to schizophrenia

“…Furthermore, several groups have reported evidence for linkage of bipolar disorder on chromosome 6q 22 -24 with additional support from a recent meta-analysis. 25 Given the extensive genomic distance spanned by these reports, it is feasible that the incriminated chromosome 6q region harbors more than one gene implicated in the pathogenesis of schizophrenia, bipolar disorder and possibly other neuropsychiatric phenotypes. 21 Based on an autosomal scan of Arab-Israeli families, we previously reported linkage of schizophrenia to chromosome 6q23.…”

Genome-wide association in bipolar

“…The 16p12 region does not appear positive in the major meta-analyses of BD linkage. [11][12][13] Lack of persuasive linkage evidence does not invalidate an association finding, of course.…”

Whole-genome association study of bipolar disorder

“…Linkage data have largely identified areas with modest evidence of linkage to BP disorder that are not well localized, even when the data are pooled. 5,6 Candidate gene studies while implicating several genes, 7 have only been able to focus on a minority of genes in the genome, and the interpretation of replication of individual findings has been difficult. Furthermore, strong support for applying a whole genome approach to BP disorder comes from the success in finding novel, strong and consistent susceptibility loci in type 2 diabetes, [8][9][10] prostate cancer, 11 Crohn's disease, 12 breast cancer 13 and coronary artery disease 14 using similar whole genome approaches.…”