Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion

Stefano Vicari, Yu Yang Zhao, Isabelle Cleynen, Worrawat Engchuan, Matthew S. Hestand, Tracy Heung, Aaron M. Holleman, H. Richard Johnston, Thomas Monfeuga, Donna M. Mcdonald-Mcginn, Raquel E. Gur, Bernice E. Morrow, Ann Swillen, Jacob A. S. Vorstman, Carrie E. Bearden, Eva W. C. Chow, Marianne Van Den Bree, Beverly S. Emanuel, Joris R. Vermeesch, Stephen T. WarrenMichael J. Owen, Pankaj Chopra, David J. Cutler, Richard Duncan, Alex V. Kotlar, Jennifer G. Mulle, Anna J. Voss, Michael E. Zwick, Alexander Diacou, Aaron Golden, Tingwei Guo, Jhih-Rong Lin, Tao Wang, Zhengdong Zhang, Yingjie Zhao, Christian Marshall, Daniele Merico, Andrea Jin, Brenna Lilley, Harold I. Salmons, Oanh Tran, Peter Holmans, Antonio Pardinas, James T. R. Walters, Wolfram Demaerel, Erik Boot, Nancy J. Butcher, Gregory A. Costain, Chelsea Lowther, Rens Evers, Therese A. M. J. Van Amelsvoort, Esther Van Duin, Claudia Vingerhoets, Jeroen Breckpot, Koen Devriendt, Elfi Vergaelen, Annick Vogels, T. Blaine Crowley, Daniel E. Mcginn, Edward M. Moss, Robert J. Sharkus, Marta Unolt, Elaine H. Zackai, Monica E. Calkins, Robert S. Gallagher, Ruben C. Gur, Sunny X. Tang, Rosemarie Fritsch, Claudia Ornstein, Gabriela M. Repetto, Elemi Breetvelt, Sasja N. Duijff, Ania Fiksinski, Hayley Moss, Maria Niarchou, Kieran C. Murphy, Sarah E. Prasad, Eileen M. Daly, Maria Gudbrandsen, Clodagh M. Murphy, Declan G. Murphy, Antonio Buzzanca, Fabio Di Fabio, Maria Pontillo, Karlene Coleman, Joseph F. Cubells, Opal Y. Ousley, Miri Carmel, Doron Gothelf, Ehud Mekori-Domachevsky, Elena Michaelovsky, Ronnie Weinberger, Abraham Weizman, Leila Kushan, Maria Jalbrzikowski, Marco Armando, Stéphan Eliez, Corrado Sandini, Maude Schneider, Frédérique Sloan Béna, Kevin M. Antshel, Wanda Fremont, Wendy R. Kates, Raoul Belzeaux, Tiffany Busa, Nicole Philip, Linda E. Campbell, Kathryn L. Mccabe, Stephen R. Hooper, Kelly Schoch, Vandana Shashi, Tony J. Simon, Flora Tassone, Celso Arango, David Fraguas, Sixto García-Miñaúr, Jaume Morey-Canyelles, Jordi Rosell, Damià H. Suñer, Jasna Raventos-Simic, Michael P. Epstein, Nigel M. Williams, Anne S. Bassett

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24 Citations (Scopus)


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.
Original languageEnglish
Pages (from-to)N/A-N/A
JournalMolecular Psychiatry
Publication statusPublished - 2020


  • 22q11.2 deletion syndrome
  • Schizophrenia
  • genetic factors


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