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.
Highlights
Bipolar disorder (BD) is a severe neuropsychiatric disorder with an estimated heritability of around 70% [1]
After correction for multiple testing, polygenic risk score (PRS) based on BD-associated genetic variants were not significantly higher in BD cases than in family members with no lifetime history of psychiatric illness (S2 Fig)
When PRS calculation was restricted to BD variants with genome-wide significance (p-value threshold 5×10−8), the PRS of BD cases from the two Cuban families showed a nominally significant increase compared to the PRS of family members with no psychiatric disorder or a non-BD psychiatric phenotype
Summary
Bipolar disorder (BD) is a severe neuropsychiatric disorder with an estimated heritability of around 70% [1]. Molecular genetic research indicates that BD is a multifactorial disorder, in which both genetic and environmental factors impact disease susceptibility [5]. Research has shown that the cumulative impact of common alleles with small effects explains only around 25–38% of the phenotypic variance for BD [12, 13]. A plausible hypothesis is that rare, high penetrance variants may contribute to BD susceptibility. One approach to the evaluation of this hypothesis is the investigation of large, multigenerational pedigrees with a high prevalence of BD. In such pedigrees, the existence of a genetic variant of strong effect—as inherited from a common ancestor—may be more likely [14]
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