Maaser, Anna, Forstner, Andreas J., Strohmaier, Jana, Hecker, Julian, Ludwig, Kerstin U., Sivalingam, Sugirthan, Streit, Fabian, Degenhardt, Franziska, Witt, Stephanie H., Reinbold, Celine S., Koller, Anna C., Raff, Ruth, Heilmann-Heimbach, Stefanie, Fischer, Sascha B., Herms, Stefan ORCID: 0000-0002-2786-8200, Hoffmann, Per, Thiele, Holger, Nuernberg, Peter, Fier, Heide Loehlein, Orozco-Diaz, Guillermo, Carmenate-Naranjo, Deinys, Proenza-Barzaga, Niurka, Auburger, Georg W. J., Andlauer, Till F. M., Cichon, Sven, Marcheco-Teruel, Beatriz, Mors, Ole, Rietschel, Marcella and Noethen, Markus M. (2018). Exome sequencing in large, multiplex bipolar disorder families from Cuba. PLoS One, 13 (10). SAN FRANCISCO: PUBLIC LIBRARY SCIENCE. ISSN 1932-6203

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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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Maaser, AnnaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Forstner, Andreas J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Strohmaier, JanaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hecker, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ludwig, Kerstin U.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Sivalingam, SugirthanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Streit, FabianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Degenhardt, FranziskaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Witt, Stephanie H.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinbold, Celine S.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Koller, Anna C.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Raff, RuthUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Heilmann-Heimbach, StefanieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fischer, Sascha B.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Herms, StefanUNSPECIFIEDorcid.org/0000-0002-2786-8200UNSPECIFIED
Hoffmann, PerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Thiele, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Fier, Heide LoehleinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Orozco-Diaz, GuillermoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Carmenate-Naranjo, DeinysUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Proenza-Barzaga, NiurkaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Auburger, Georg W. J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Andlauer, Till F. M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Cichon, SvenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Marcheco-Teruel, BeatrizUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Mors, OleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rietschel, MarcellaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Noethen, Markus M.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-168856
DOI: 10.1371/journal.pone.0205895
Journal or Publication Title: PLoS One
Volume: 13
Number: 10
Date: 2018
Publisher: PUBLIC LIBRARY SCIENCE
Place of Publication: SAN FRANCISCO
ISSN: 1932-6203
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
GENOME-WIDE ASSOCIATION; VARIANTS; SCHIZOPHRENIA; IDENTIFICATION; MUTATIONS; DATABASE; CACNA1C; DBNSFP; GENES; PLINKMultiple languages
Multidisciplinary SciencesMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/16885

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