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oai:repisalud.isciii.es:20.500.12105/179982024-11-28T15:48:12Zcom_20.500.12105_15322com_20.500.12105_2051col_20.500.12105_16927

00925njm 22002777a 4500 dc Forstner, Andreas J. author Fischer, Sascha B. author Schenk, Lorena M. author Strohmaier, Jana author Maaser-Hecker, Anna author Reinbold, Céline S. author Sivalingam, Sugirthan author Hecker, Julian author Streit, Fabian author Degenhardt, Franziska author Witt, Stephanie H. author Schumacher, Johannes author Thiele, Holger author Nürnberg, Peter author Guzman-Parra, José author Orozco Diaz, Guillermo author Auburger, Georg author Albus, Margot author Borrmann-Hassenbach, Margitta author González, Maria José author Gil Flores, Susana author Cabaleiro Fabeiro, Francisco J. author del Río Noriega, Francisco author Perez Perez, Fermin author Haro González, Jesus author Rivas, Fabio author Mayoral, Fermin author Bauer, Michael author Pfennig, Andrea author Reif, Andreas author Herms, Stefan author Hoffmann, Per author Pirooznia, Mehdi author Goes, Fernando S. author Rietschel, Marcella author Nöthen, Markus M. author Cichon, Sven author 2020-02-04 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. http://hdl.handle.net/10668/3860 http://hdl.handle.net/20.500.12105/17998 32066727 10.1038/s41398-020-0732-y 2158-3188 Translational Psychiatry Whole exome sequencing Bipolar disorder Neuropsychiatry Genetic predisposition to disease Secuenciación del exoma completo Trastorno bipolar Neuropsiquiatría Predisposición genética a la enfermedad Whole-exome sequencing of 81 individuals from 27 multiply affected bipolar disorder families