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

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

Research output: Contribution to journalArticlepeer-review

4 Scopus citations


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 < 0.006) and schizophrenia (padj = 0.015). These results suggest a possible genetic overlap with BD for autism and schizophrenia at the rare-sequence-variant level. The present study implicates novel candidate genes for BD development, and may contribute to an improved understanding of the biological basis of this common and often devastating disease.

Original languageEnglish (US)
Article number57
JournalTranslational psychiatry
Issue number1
StatePublished - Dec 1 2020

ASJC Scopus subject areas

  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience
  • Biological Psychiatry


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