1. Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion
- Author
-
Richard Duncan, Tao Wang, Carrie E. Bearden, David J. Cutler, Stephen T. Warren, Maria Pontillo, Robert Sean Gallagher, Elemi J. Breetvelt, Tingwei Guo, Nancy J. Butcher, Jennifer G. Mulle, Claudia Ornstein, Claudia Vingerhoets, Clodagh M. Murphy, Ehud Mekori-Domachevsky, Wendy R. Kates, Jacob A. S. Vorstman, Tracy Heung, Joris Vermeesch, Maria Gudbrandsen, Ann Swillen, H. Richard Johnston, Oanh Tran, Marco Armando, Joseph F. Cubells, Raoul Belzeaux, Jeroen Breckpot, Bruno Marino, Tony J. Simon, Harold I. Salmons, Maria Jalbrzikowski, Wanda Fremont, Anna J. Voss, Worrawat Engchuan, Opal Y. Ousley, Stefano Vicari, Jordi Rosell, Sixto García-Miñaur, Declan G. Murphy, Alexander Diacou, Ania Fiksinski, Abraham Weizman, Edward Moss, Stephan Eliez, Miri Carmel, Vandana Shashi, Anne S. Bassett, Ronnie Weinberger, Hayley Moss, Marianne Bernadette van den Bree, Kelly Schoch, Maude Schneider, Linda E. Campbell, Sasja N. Duijff, Eileen Daly, Annick Vogels, Stephen R. Hooper, David Fraguas, Sarah E. Prasad, Chelsea Lowther, Michael John Owen, Frédérique Béna, Gabriela M. Repetto, Eva W.C. Chow, Bernice E. Morrow, Robert J. Sharkus, Celso Arango, Christian R. Marshall, Jasna Raventos-Simic, Jaume Morey-Canyelles, Tiffany Busa, Andrea Jin, James T.R. Walters, Leila Kushan, Wolfram Demaerel, Monica E. Calkins, Jhih Rong Lin, Elaine H. Zackai, Esther D.A. van Duin, Antonio Buzzanca, Corrado Sandini, Kieran C. Murphy, Beverly S. Emanuel, Erik Boot, Maria Niarchou, Nigel Williams, Elfi Vergaelen, Maria Cristina Digilio, Daniele Merico, Karlene Coleman, Gregory A. Costain, Matthew S. Hestand, Peter Holmans, Michael E. Zwick, Michael P. Epstein, Damià H. Suñer, Yingjie Zhao, Marta Unolt, Kathryn McCabe, Aaron M. Holleman, Zhengdong Zhang, Rosemarie Fritsch, Alex V. Kotlar, Elena Michaelovsky, T. Blaine Crowley, Brenna Lilley, Sunny X. Tang, Rens Evers, Ruben C. Gur, Isabelle Cleynen, Flora Tassone, Nicole Philip, Kevin M. Antshel, Koen Devriendt, Antonio F. Pardiñas, Pankaj Chopra, Thomas Monfeuga, Fabio Di Fabio, Therese van Amelsvoort, Aaron Golden, Doron Gothelf, Donna M. McDonald-McGinn, Raquel E. Gur, Daniel E. McGinn, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), The Hospital for sick children [Toronto] (SickKids), Emory University [Atlanta, GA], Cardiff University, University of Pennsylvania [Philadelphia], Albert Einstein College of Medicine [New York], University Hospitals Leuven [Leuven], University of Toronto, University Medical Center [Utrecht], University of California, Children’s Hospital of Philadelphia (CHOP ), Emory University School of Medicine, University Health Network, Centre for Addiction and Mental Health [Toronto] (CAMH), Maastricht University [Maastricht], Universidad de Chile, Clínica Alemana & Universidad del Desarrollo, Royal College of Surgeons in Ireland (RCSI), King‘s College London, Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome], Children's Hospital Bambino Gesù [Rome, Italie], Tel Aviv University [Tel Aviv], The Edmond and Lily Safra Children's Hospital [Tel-Hahsomer, Israel], University of Pittsburgh School of Medicine, Pennsylvania Commonwealth System of Higher Education (PCSHE), University of Geneva [Switzerland], Geneva University Hospitals and Geneva University, Syracuse University, SUNY Upstate Medical University, State University of New York (SUNY), Hôpital Sainte-Marguerite [CHU - APHM] (Hôpitaux Sud ), Hôpital d'Enfants de la Timone [Marseille], Assistance Publique - Hôpitaux de Marseille (APHM), Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Newcastle [Australia] (UoN), University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Duke University School of Medicine, University of California [Davis] (UC Davis), Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), La Paz University Hospital, Hospital Universitario Son Espases, University of Pennsylvania, University of California (UC), Universidad de Chile = University of Chile [Santiago] (UCHILE), Università degli Studi di Roma 'La Sapienza' = Sapienza University [Rome] (UNIROMA), Tel Aviv University (TAU), Université de Genève = University of Geneva (UNIGE), University of Newcastle [Callaghan, Australia] (UoN), Caugant, Julien, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, and MUMC+: MA Med Staf Spec Psychiatrie (9)
- Subjects
0301 basic medicine ,[SDV]Life Sciences [q-bio] ,VARIANTS ,Cohort Studies ,0302 clinical medicine ,Medicine ,Copy-number variation ,BRAIN ,ddc:616 ,Genetics ,education.field_of_study ,PSYCHIATRIC-DISORDERS ,ASSOCIATION ,3. Good health ,[SDV] Life Sciences [q-bio] ,Psychiatry and Mental health ,Schizophrenia ,Cohort ,BEHAVIOR ,Adult ,DATABASE ,Population ,COPY-NUMBER VARIATION ,Article ,03 medical and health sciences ,Cellular and Molecular Neuroscience ,Settore MED/39 - NEUROPSICHIATRIA INFANTILE ,mental disorders ,DiGeorge Syndrome ,Humans ,genetics ,22q11deletion syndrome ,schizophrenia ,education ,Molecular Biology ,Gene ,Microarray analysis techniques ,business.industry ,MUTATIONS ,CONSORTIUM ,medicine.disease ,Institutional repository ,INDIVIDUALS ,030104 developmental biology ,Psychotic Disorders ,Case-Control Studies ,22q11.2 deletion syndrome ,genetic factors ,Polygenic risk score ,business ,030217 neurology & neurosurgery ,International 22q11.2DS Brain and Behavior Consortium - Abstract
Schizophrenia occurs in about one in four individuals with 22q11.2 deletion syndrome (22q11.2DS). The aim of this International Brain and Behavior 22q11.2DS Consortium (IBBC) study was to identify genetic factors that contribute to schizophrenia, in addition to the ~20-fold increased risk conveyed by the 22q11.2 deletion. Using whole-genome sequencing data from 519 unrelated individuals with 22q11.2DS, we conducted genome-wide comparisons of common and rare variants between those with schizophrenia and those with no psychotic disorder at age ≥25 years. Available microarray data enabled direct comparison of polygenic risk for schizophrenia between 22q11.2DS and independent population samples with no 22q11.2 deletion, with and without schizophrenia (total n = 35,182). Polygenic risk for schizophrenia within 22q11.2DS was significantly greater for those with schizophrenia (padj = 6.73 × 10−6). Novel reciprocal case–control comparisons between the 22q11.2DS and population-based cohorts showed that polygenic risk score was significantly greater in individuals with psychotic illness, regardless of the presence of the 22q11.2 deletion. Within the 22q11.2DS cohort, results of gene-set analyses showed some support for rare variants affecting synaptic genes. No common or rare variants within the 22q11.2 deletion region were significantly associated with schizophrenia. These findings suggest that in addition to the deletion conferring a greatly increased risk to schizophrenia, the risk is higher when the 22q11.2 deletion and common polygenic risk factors that contribute to schizophrenia in the general population are both present. ispartof: Molecular Psychiatry vol:26 issue:8 pages:1-15 ispartof: location:England status: published
- Published
- 2020