Whole-exome sequencing in an Afrikaner family with bipolar disorder.

Background: Bipolar disorder (BD) has considerable heritability, with genome-wide association studies indicating that multiple common genetic variants contribute to risk. Less work has been undertaken to assess the contribution of rare variation in the development of this complex disorder, particularly in isolated populations. Using whole-exome sequencing (WES), the aim of this study was to identify rare, potentially damaging variants contributing to risk for BD in the Afrikaner population.

Methods: WES was performed on eight Afrikaner family members, five affected and three unaffected. The analyses focused on i) the identification of rare, damaging variation, and ii) the molecular pathways in which these rare variants play a role using in silico prediction tools such as wANNOVAR and KOBAS 3.0.

Results: Two rare and potentially damaging missense variants in FAM71B and SLC26A9 were shared by affected family members but were absent in unaffected members. In addition, variants in genes that play a role in pathways involved in signal transduction and synaptic transmission were shared by the five affected individuals.

Limitations: Two main limitations affect this study: the limited number of cases and controls, and the fact that whole-exome sequencing can only capture a small fragment of the genome which may harbor mutations.

Conclusion: This is the first WES study of BD in an Afrikaner family, and findings suggest that novel candidate genes may contribute to risk for BD in this population. Future work in larger samples of this population as well as in other populations is needed to fully investigate the role of the candidate genes found here.