Exome sequencing in large, multiplex bipolar disorder families from Cuba

Abstract

Bipolar disorder (BD) is a major psychiatric illness affecting around 1% of the global population. BD is characterized by recurrent manic and depressive episodes, and has an estimated heritability of around 70%. Research has identified the first BD susceptibility genes. However, the underlying pathways and regulatory networks remain largely unknown. Research suggests that the cumulative impact of common alleles with small effects explains only around 25-38% of the phenotypic variance for BD. A plausible hypothesis therefore is that rare, high penetrance variants may contribute to BD risk. The present study investigated the role of rare, nonsynonymous, and potentially functional variants via whole exome sequencing in 15 BD cases from two large, multiply affected families from Cuba. The high prevalence of BD in these pedigrees renders them promising in terms of the identification of genetic risk variants with large effect sizes. In addition, SNP array data were used to calculate polygenic risk scores for affected and unaffected family members. After correction for multiple testing, no significant increase in polygenic risk scores for common, BD-associated genetic variants was found in BD cases compared to healthy relatives. Exome sequencing identified a total of 17 rare and potentially damaging variants in 17 genes. The identified variants were shared by all investigated BD cases in the respective pedigree. The most promising variant was located in the gene SERPING1 (p.L349F), which has been reported previously as a genome-wide significant risk gene for schizophrenia. The present data suggest novel candidate genes for BD susceptibility, and may facilitate the discovery of disease-relevant pathways and regulatory networks.

Fig 1. Pedigrees of the two investigated Cuban families.

DNA was available for all numbered individuals depicted by a diamond with a central dot. Exome sequencing was performed on subjects framed with a red circle. Orange indicates a diagnosis of BD I, BD II, or BD NOS. Blue indicates other psychiatric phenotypes, comprising recurrent MDD, MDD single episode, and alcohol abuse. Unaffected individuals are indicated by white diamonds. To preserve the anonymity and confidentiality of the families, no information is shown concerning sex or mortality. (A) Pedigree of family 1, including four cases selected for exome sequencing. (B) Family 2 was divided in pedigrees 2, 3, and 4. A total of 11 cases from family 2 were selected for exome sequencing.