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Whole-exome sequencing of 81 individuals from 27 multiply affected bipolar disorder families.


ABSTRACT: Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of depression and mania. Research suggests that the cumulative impact of common alleles explains 25-38% of phenotypic variance, and that rare variants may contribute to BD susceptibility. To identify rare, high-penetrance susceptibility variants for BD, whole-exome sequencing (WES) was performed in three affected individuals from each of 27 multiply affected families from Spain and Germany. WES identified 378 rare, non-synonymous, and potentially functional variants. These spanned 368 genes, and were carried by all three affected members in at least one family. Eight of the 368 genes harbored rare variants that were implicated in at least two independent families. In an extended segregation analysis involving additional family members, five of these eight genes harbored variants showing full or nearly full cosegregation with BD. These included the brain-expressed genes RGS12 and NCKAP5, which were considered the most promising BD candidates on the basis of independent evidence. Gene enrichment analysis for all 368 genes revealed significant enrichment for four pathways, including genes reported in de novo studies of autism (padj?

SUBMITTER: Forstner AJ 

PROVIDER: S-EPMC7026119 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Whole-exome sequencing of 81 individuals from 27 multiply affected bipolar disorder families.

Forstner Andreas J AJ   Fischer Sascha B SB   Schenk Lorena M LM   Strohmaier Jana J   Maaser-Hecker Anna A   Reinbold Céline S CS   Sivalingam Sugirthan S   Hecker Julian J   Streit Fabian F   Degenhardt Franziska F   Witt Stephanie H SH   Schumacher Johannes J   Thiele Holger H   Nürnberg Peter P   Guzman-Parra José J   Orozco Diaz Guillermo G   Auburger Georg G   Albus Margot M   Borrmann-Hassenbach Margitta M   González Maria José MJ   Gil Flores Susana S   Cabaleiro Fabeiro Francisco J FJ   Del Río Noriega Francisco F   Perez Perez Fermin F   Haro González Jesus J   Rivas Fabio F   Mayoral Fermin F   Bauer Michael M   Pfennig Andrea A   Reif Andreas A   Herms Stefan S   Hoffmann Per P   Pirooznia Mehdi M   Goes Fernando S FS   Rietschel Marcella M   Nöthen Markus M MM   Cichon Sven S  

Translational psychiatry 20200204 1


Bipolar disorder (BD) is a highly heritable neuropsychiatric disease characterized by recurrent episodes of depression and mania. Research suggests that the cumulative impact of common alleles explains 25-38% of phenotypic variance, and that rare variants may contribute to BD susceptibility. To identify rare, high-penetrance susceptibility variants for BD, whole-exome sequencing (WES) was performed in three affected individuals from each of 27 multiply affected families from Spain and Germany. W  ...[more]

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