Contribution of Rare Copy Number Variants to Bipolar Disorder Risk Is Limited to Schizoaffective Cases

• Type of Material: Article
• Authors: Alexander W. Charney, Icahn School of Medicine at Mount Sinai; Eli A. Stahl, Icahn School of Medicine at Mount Sinai; Elaine K. Green, University of Plymouth; Chia-Yen Chen, Broad Institute of MIT and Harvard; Jennifer L. Moran, Massachusetts General Hospital; Kimberley Chambert, Broad Institute of MIT and Harvard; Richard A. Belliveau, Broad Institute of MIT and Harvard; Liz Forty, Cardiff University; Katherine Gordon-Smith, University of Birmingham; Phil H. Lee, Broad Institute of MIT and Harvard; Evelyn J. Bromet, SUNY Stony Brook; Peter F. Buckley, Virginia Commonwealth University; Michael A. Escamilla, Texas Tech University; Ayman H. Fanous, Suny Downstate Medical Center; Laura J. Fochtmann, SUNY Stony Brook; Douglas S. Lehrer, Wright State University; Dolores Malaspina, Icahn School of Medicine at Mount Sinai; Stephen R. Marder, University of California Los Angeles; Christopher P. Morley, SUNY Upstate Medical University; Humberto Nicolini, Universidad Autonoma Ciudad Mexico; Diana O. Perkins, University of North Carolina Chapel Hill; Jeffrey Rakofsky, Emory University; Mark Rapaport, Emory University; Helena Medeiros, Suny Downstate Medical Center; Janet L. Sobell, University of Southern California; Lena Backlund, Karolinska Institutet; Sarah E. Bergen, Karolinska Institutet; Anders Jureus, Karolinska Institutet; Martin Schalling, Karolinska Institutet; Paul Lichtenstein, Karolinska Institutet; James A. Knowles, Suny Downstate Medical Center; Katherine E. Burdick, Icahn School of Medicine at Mount Sinai; Ian Jones, Cardiff University; Lisa A. Jones, University of Birmingham; Christina M. Hultman, Icahn School of Medicine at Mount Sinai; Roy Perlis, Massachusetts General Hospital; Shaun M. Purcell, Harvard Medical School; Steven A. McCarroll, Broad Institute of MIT and Harvard; Carlos N. Pato, Suny Downstate Medical Center; Michele T. Pato, Suny Downstate Medical Center; Ariana Di Florio, University of North Carolina Chapel Hill; Nick Craddock, Cardiff University; Mikael Landen, Karolinska Institutet; Jordan W. Smoller, Broad Institute of MIT and Harvard; Douglas M. Ruderfer, Vanderbilt University; Pamela Sklar, Icahn School of Medicine at Mount Sinai
• Language: English
• Date: 2019-07-15
• Publisher: Elsevier Science Inc.
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2018 Society of Biological Psychiatry.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.biopsych.2018.12.009
• Title of Journal or Parent Work: Biological Psychiatry
• Volume: 86
• Issue: 2
• Start Page: 110
• End Page: 119
• Grant/Funding Information: Work at the Icahn School of Medicine at Mount Sinai was also supported by the Institute for Genomics and Multiscale Biology and the the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai.; European Commission-Marie Curie Fellowship (AD), Wellcome Trust (IJ, KG, LAJ, LF, NC).; Stanley Medical Research Institute (JLM, KC, RAB, SAM), philanthropic gifts from Kent and Elizabeth Dauten and Ted and Vada Stanley (JLM, KC, RAB, SAM), the Swedish Research Council 2013–3196 (CMH); We acknowledge funding support from by National Institutes of Health (NIH)/National Institute of Mental Health (NIMH) grant R01MH085542 (AWC, JWS and PS), NIH/NIMH grant R01 MH106547 (JWS, PS, SAM), NIH/NIMH grant R01MH085548 (AHF, CNP, CPM, DM, DOP, DSL, ELB, HM, HN, JAK, JJR, JLS, LJF, MAE, MHR, MTP, PFB, SRM), NIH/NIMH grant K99MH101367 (PHL); Swedish Medical Research Council grants K2014–62X-14647–12-51 and K2010–61P-21568–01-4 (ML), the Swedish foundation for Strategic Research grant KF10–0039 (ML), the Swedish Federal Government under the LUA/ALF agreement grants ALF 20130032 and ALFGbG-142041 (ML); JwS is an MGH Tepper Family Research Scholar.
• Keywords: Neurosciences; Copy number variant; Life Sciences & Biomedicine; Duplications; De-novo NCS; Neurosciences & Neurology; Science & Technology; Genetics; Increase risk; Genome wide association; Polygenic risk score; Bipolar disorder; Psychiatry; Rare variant burden; Schizophrenia; Deletions
• Research Categories: Psychology, Behavioral; Psychology, Clinical; Biology, Neuroscience; Biology, Genetics

Abstract

Background. Genetic risk for bipolar disorder (BD) is conferred through many common alleles, while a role for rare copy number variants (CNVs) is less clear. BD subtypes schizoaffective disorder bipolar type (SAB), bipolar I disorder (BD I) and bipolar II disorder (BD II) differ according to the prominence and timing of psychosis, mania and depression. The factors contributing to the combination of symptoms within a given patient are poorly understood. Methods. Rare, large CNVs were analyzed in 6353 BD cases (3833 BD I [2676 with psychosis, 850 without psychosis], 1436 BD II, 579 SAB) and 8656 controls. Measures of CNV burden were integrated with polygenic risk scores (PRS) for schizophrenia (SCZ) to evaluate the relative contributions of rare and common variants to psychosis risk. Results. CNV burden did not differ relative to controls in BD when treated as a single diagnostic entity. Burden in SAB was increased relative to controls (p-value = 0.001), BD I (p-value = 0.0003) and BD II (p-value = 0.0007). Burden and SCZ PRS were increased in SAB compared to BD I with psychosis (CNV p-value = 0.0007, PRS p-value = 0.004) and BD I without psychosis (CNV p-value = 0.0004, PRS p-value = 3.9 × 10−5). Within BD I, psychosis was associated with increased SCZ PRS (p-value = 0.005) but not CNV burden. Conclusions. CNV burden in BD is limited to SAB. Rare and common genetic variants may contribute differently to risk for psychosis and perhaps other classes of psychiatric symptoms.