1. Investigating rare pathogenic/likely pathogenic exonic variation in bipolar disorder
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Arianna DiFlorio, Patrick F. Sullivan, Sebastian Zöllner, Margarita Rivera, Richard M. Myers, Stanley J. Watson, Jun Li, Anders Juréus, Sarah E. Bergen, Gonçalo R. Abecasis, Jordan W. Smoller, Michael Conlon O'Donovan, Neil Risch, Hoang T. Nguyen, Chen Jiang, Xiaoming Jia, Mehdi Pirooznia, Danielle Posthuma, Adam E. Locke, Peter P. Zandi, John B. Vincent, Niamh Mullins, Duncan Palmer, Shaun Purcell, Gerome Breen, Christina M. Hultman, Andreas Reif, Khanh K. Thai, Virginia L. Willour, Pui-Yan Kwok, Laura J. Scott, Anne U. Jackson, Michael John Owen, Fernando S. Goes, Steven A. McCarroll, James B. Potash, Mikael Landén, Jennifer L. Moran, Michele T. Pato, Hyun Min Kang, Marco P. Boks, Sinéad B. Chapman, W. Richard McCombie, Janet L. Sobell, Matthew Zawistowski, Rolf Adolfsson, Yongwen Zhuang, Michael Boehnke, René S. Kahn, Huda Akil, James T.R. Walters, Margit Burmeister, Douglas Blackwood, Cathryn M. Lewis, Eli A. Stahl, Mark N. Kvale, Melissa DelaBastide, Catherine Schaefer, Benjamin M. Neale, Giulio Genovese, Carlos N. Pato, Nicholas John Craddock, Andrew McQuillin, Shawn Levy, Aiden Corvin, Pamela Sklar, Weiqing Wang, Andrew M. McIntosh, Ling Shen, Eric T. Monson, Derek W. Morris, Douglas M. Ruderfer, Roel A. Ophoff, Peter McGuffin, Sarah Cohen-Woods, Willem H. Ouwehand, Complex Trait Genetics, Amsterdam Neuroscience - Complex Trait Genetics, Goes, Fernando S [0000-0001-6262-8264], Locke, Adam E [0000-0001-6227-198X], Palmer, Duncan [0000-0002-0824-0047], Wang, Weiqing [0000-0003-1565-0148], Genovese, Giulio [0000-0003-3066-5575], Jackson, Anne U [0000-0002-9672-2547], Nguyen, Hoang [0000-0001-6910-7269], Pirooznia, Mehdi [0000-0002-4210-6458], Zawistowski, Matthew [0000-0002-3005-083X], Abecasis, Gonçalo [0000-0003-1509-1825], Bergen, Sarah [0000-0002-5888-0034], Burmeister, Margit [0000-0002-1914-2434], Kwok, Pui-Yan [0000-0002-5087-3059], Li, Jun Z [0000-0001-6727-0812], Levy, Shawn E [0000-0002-1369-5740], Watson, Stanley [0000-0003-4980-5523], Blackwood, Douglas [0000-0002-4076-9346], Boehnke, Michael [0000-0002-6442-7754], Breen, Gerome [0000-0003-2053-1792], Landen, Mikael [0000-0002-4496-6451], Lewis, Cathryn [0000-0002-8249-8476], McCarroll, Steven A [0000-0002-6954-8184], McIntosh, Andrew [0000-0002-0198-4588], McQuillin, Andrew [0000-0003-1567-2240], Morris, Derek [0000-0002-3413-570X], O'Donovan, Michael [0000-0001-7073-2379], Boks, Marco [0000-0001-6163-7484], Kahn, Rene [0000-0001-5909-8004], Ouwehand, Willem [0000-0002-7744-1790], Owen, Michael [0000-0003-4798-0862], Potash, James B [0000-0002-5802-8079], Reif, Andreas [0000-0002-0992-634X], Vincent, John [0000-0003-0692-2519], Neale, Benjamin [0000-0003-1513-6077], Purcell, Shaun [0000-0002-7402-5812], Schaefer, Catherine [0000-0003-2644-055X], Stahl, Eli A [0000-0002-1192-0561], Zandi, Peter P [0000-0001-8423-2623], Scott, Laura J [0000-0002-4886-5084], Apollo - University of Cambridge Repository, Human genetics, Amsterdam Neuroscience - Compulsivity, Impulsivity & Attention, Amsterdam Reproduction & Development (AR&D), Psychiatry, APH - Mental Health, Amsterdam Neuroscience - Mood, Anxiety, Psychosis, Stress & Sleep, and APH - Digital Health
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Bipolar Disorder ,Genome-wide association study ,Biology ,Medical and Health Sciences ,Polymorphism, Single Nucleotide ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,0302 clinical medicine ,SDG 3 - Good Health and Well-being ,Clinical Research ,Genetic variation ,medicine ,Genetics ,2.1 Biological and endogenous factors ,Humans ,Exome ,Genetic Predisposition to Disease ,Bipolar disorder ,Polymorphism ,Molecular Biology ,Gene ,030304 developmental biology ,Medicinsk genetik ,Psychiatry ,0303 health sciences ,Prevention ,Human Genome ,Psychology and Cognitive Sciences ,Genetic Variation ,Single Nucleotide ,Heritability ,Biological Sciences ,medicine.disease ,Serious Mental Illness ,Phenotype ,3. Good health ,Brain Disorders ,Psychiatry and Mental health ,Mental Health ,Schizophrenia ,Medical Genetics ,030217 neurology & neurosurgery ,Genome-Wide Association Study - Abstract
Bipolar disorder (BD) is a serious mental illness with substantial common variant heritability. However, the role of rare coding variation in BD is not well established. We examined the protein-coding (exonic) sequences of 3,987 unrelated individuals with BD and 5,322 controls of predominantly European ancestry across four cohorts from the Bipolar Sequencing Consortium (BSC). We assessed the burden of rare, protein-altering, single nucleotide variants classified as pathogenic or likely pathogenic (P-LP) both exome-wide and within several groups of genes with phenotypic or biologic plausibility in BD. While we observed an increased burden of rare coding P-LP variants within 165 genes identified as BD GWAS regions in 3,987 BD cases (meta-analysis OR = 1.9, 95% CI = 1.3–2.8, one-sided p = 6.0 × 10−4), this enrichment did not replicate in an additional 9,929 BD cases and 14,018 controls (OR = 0.9, one-side p = 0.70). Although BD shares common variant heritability with schizophrenia, in the BSC sample we did not observe a significant enrichment of P-LP variants in SCZ GWAS genes, in two classes of neuronal synaptic genes (RBFOX2 and FMRP) associated with SCZ or in loss-of-function intolerant genes. In this study, the largest analysis of exonic variation in BD, individuals with BD do not carry a replicable enrichment of rare P-LP variants across the exome or in any of several groups of genes with biologic plausibility. Moreover, despite a strong shared susceptibility between BD and SCZ through common genetic variation, we do not observe an association between BD risk and rare P-LP coding variants in genes known to modulate risk for SCZ., International Bipolar Sequencing Consortium (NIMH) R01 MH 110437, Whole Genome Sequencing for Schizophrenia and Biopolar Disorder in the GPS (NIMH) UO1 MH105653, Whole Genome and Exome Sequencing for Bipolar Disorder (NIMH) R01 MH 094145, Multi-ethnic GWAS of Bipolar I Disorder (NIH) R01 MH 085543, Genetic Epidemiology Research in Adult Health and Aging (GERA) RC2 AG036607, Kaiser Permanente Research Program on Genes, Environment, and Health, Rare Bipolar Loci Identification Through Synaptome Sequencing (NIMH) R01 MH 087979 MH 087992, 2/2 Large Scale Genetic Studies of Schizophrenia in Sweden R01MH095034, 1/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder R01MH106531, 1/2 Large Scale Genetic Studies of Schizophrenia in Sweden R01MH077139, 2/3 Genetic Analysis of the International Cohort Collection for Bipolar Disorder R01MH106527, Dalio Foundation
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- 2021
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