The contribution of rare variants to risk of schizophrenia in individuals with and without intellectual disability
Year: 2017
Type: article
Abstract: By meta-analyzing rare coding variants in whole-exome sequences of 4,133 schizophrenia cases and 9,274 controls, de novo mutations in 1,077 trios, and copy number variants from 6,882 cases and 11,255 controls, we show that individuals with schizophrenia carry a significant burden of rare damaging variants in 3,488 genes previously identified as having a near-complete depletion of loss-of-function variants. In schizophrenia patients who also have intellectual disability, this burden is concentrated in risk genes associated with neurodevelopmental disorders. After excluding known neurodevelopmental disorder risk genes, a significant rare variant burden persists in other loss-of-function intolerant genes, and while this effect is notably stronger in schizophrenia patients with intellectual disability, it is also seen in patients who do not have intellectual disability. Together, our results show that rare damaging variants contribute to the risk of schizophrenia both with and without intellectual disability, and support an overlap of genetic risk between schizophrenia and other neurodevelopmental disorders.
DOI: 10.17615/bh38-wy20
Authors: Tarjinder Singh, James Walters, Mandy Johnstone, David Curtis, Jaana Suvisaari, Minna Torniainen, Elliott Rees, Conrad Iyegbe, Douglas Blackwood, Andrew M. McIntosh, George Kirov, Daniel H. Geschwind, Robin M. Murray, Marta Di Forti, Elvira Bramon, Michael J. Gandal, Christina M. Hultman, Pamela Sklar, Aarno Palotie, Patrick F. Sullivan, Michael O’Donovan, Michael J. Owen, Jeffrey C. Barrett
Institutions: Wellcome Trust, Cardiff University, University of Edinburgh, Queen Mary University of London, University College London, King's College London, University of California, Los Angeles, Karolinska Institutet, Icahn School of Medicine at Mount Sinai, Broad Institute, University of Helsinki, Institute for Molecular Medicine Finland, University of North Carolina at Chapel Hill
Language: English
Subfield: Psychiatry and Mental health
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: Williams College, University of Pennsylvania, Johns Hopkins University, NHS Blood and Transplant, Wellcome Trust, Broad Institute, National Institute for Health and Care Research, British Heart Foundation, Cardiff University, Vetenskapsrådet, National Institutes of Health, Stanley Center for Psychiatric Research, Broad Institute, NIHR BioResource, Medical Research Council, NIHR Cambridge Biomedical Research Centre, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, National Cancer Institute
Awards: WTCCC2 core activities., G1572361985, G1606511277, 1/2 A Large-Scale Schizophrenia Association Study in Sweden, G2146332128, WTCCC2 core activities, Statistical Methods for Gene Environment Interactions In Lung Cancer, G385907487, G4321129689, G4375501919, The Collaborative Genetic Study of Nicotine Dependence, Genome Wide Association Coordinating Center, G4584873075, G4612446324, G5318416024, G564567861, G567453067, G6132732, G6345711408, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G7093047072, WTCCC2 core activities., Tobacco Dependence: Treatment and Outcomes, G8163728846, G8218456548, G8408547947, G8491121283, G88852782, Understanding the genetic basis of common human diseases: core funding for the Wellcome Trust Centre for Human Genetics., G8975541179, G9000176579
OpenAlex ID: W3023275109