Exome sequencing in large, multiplex bipolar disorder families from Cuba

  • 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.
Author:Anna MaaserORCiDGND, Andreas Josef Forstner, Jana Strohmaier, Julian Hecker, Kerstin Urte Ludwig, Sugirthan Sivalingam, Fabian StreitORCiDGND, Franziska Degenhardt, Stephanie WittORCiDGND, Céline S. ReinboldORCiDGND, Anna C. Koller, Ruth Raff, Stefanie Heilmann-Heimbach, Sascha B. FischerORCiD, Stefan HermsORCiD, Per HoffmannORCiDGND, Holger Thiele, Peter Nürnberg, Heide Fier, Guillermo Orozco-Díaz, Deinys Carmenate-Naranjo, Niurka Proenza-Barzaga, Georg AuburgerORCiDGND, Till Felix Malte Andlauer, Sven Cichon, Beatriz Marcheco-Teruel, Ole Mors, Marcella RietschelORCiDGND, Markus Maria Nöthen
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/30379966
Parent Title (English):PLoS one
Place of publication:Lawrence, Kan.
Contributor(s):Klaus Brusgaard
Document Type:Article
Year of Completion:2018
Date of first Publication:2018/10/31
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Contributing Corporation:Bipolar Disorder Working Group of the Psychiatric Genomics Consortium
Release Date:2018/11/06
Tag:Alleles; Bipolar disorder; Consortia; Depression; Etiology; Genome-wide association studies; Molecular genetics; Schizophrenia
Issue:(10): e0205895
Page Number:17
First Page:1
Last Page:17
Copyright: © 2018 Maaser et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0