Genetic Linkage for Bipolar Disorder to the Distal Region of Chromosome 19q: A Large Family Whole Genome Sequencing Study

ABSTRACT Background Bipolar disorder (BD) is among the most heritable psychiatric disorders, with a genetic architecture likely consisting of both common genetic variants with small effects and rare variants with strong effects in certain families or populations. Genome‐wide association studies (GWAS) with increasingly large sample sizes have identified many susceptibility genes, but common variants in these genes do not have a clear pathophysiological pathway to BD. Genetic linkage studies have the potential to identify rare causal variants in certain families. Aims We sought to determine the chromosomal regions linked with BD in a specific family that has many members affected by the lithium‐responsive subtype of BD. Materials and Methods We performed genome‐wide genetic linkage analysis of a family identified through a lithium‐responsive BD index patient with many relatives also affected with lithium‐responsive BD‐related mood disorders: three with BD I, four with BD II, and one with a major depressive episode. Results WGS (whole genome sequence) data were obtained for 12 members of the lithium‐responsive BD pedigree including the eight affected subjects. Both parametric and nonparametric linkage analyses with the narrow BD phenotype and the broader phenotype including all eight with mood disorders provided evidence of linkage to the same region of chromosome 19. The maximum nonparametric linkage score was 3.89 for the broad phenotype, which exceeds typical thresholds for genome‐wide significance. Discussion We identified a region of chromosome 19 that has not previously been linked to BD. Nor have significant GWAS variants been found in this region. It is possible that this family has different genetic origins for lithium‐responsive BD than other patients studied previously. The family we analyzed is part of a larger cohort of BD patients and their family members, and genetic linkage analysis of additional families could be informative. Conclusion These results provide a starting point for investigating genes in this chromosomal region that may be involved in the pathophysiology of the lithium‐responsive subtype of BD.