Journal Article

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

Fremont Wanda, Tassone Flora, Weizman, Abraham, Walters, James T, Morrow, Bernice E, Zhao, Yingjie, van Amelsvoort Therese A M J, Arango Celso, Jalbrzikowski, Maria, Hooper, Stephen R, Chow, Eva W, Diacou Alexander, Duncan, Richard, Cleynen Isabelle, Duijff Sasja N, Cubells, Joseph F, Philip, Nicole, Campbell, Linda E, Sharkus, Robert J, Eliez Stéphan, Béna, Frédérique Sloan, Elemi, Breetvelt, Calkins, Monica E, Buzzanca, Antonio, Boot, Erik, Morey-Canyelles Jaume, Pardinas Antonio, Monfeuga, Thomas, Vorstman Jacob A S, Lin Jhih-Rong, Zackai, Elaine H, Fabio Fabio Di, Kotlar Alex V, Guo Tingwei, Murphy, Declan G, Bearden, Carrie E, García-Miñaúr Sixto, Vogels Annick, Ornstein, Claudia, Raventos-Simic Jasna, Miri, Carmel, Salmons, Harold I, Vermeesch, Joris R, Murphy, Kieran C, Owen, Michael J, Richard, Johnston H, Voss, Anna J, Golden, Aaron, Williams, Nigel M, Breckpot Jeroen, Mekori-Domachevsky Ehud, Costain, Gregory A, Busa Tiffany, Weinberger, Ronnie, Murphy, Clodagh M, Kates, Wendy R, Merico Daniele, Tran Oanh, Devriendt Koen, Evers Rens, Zwick, Michael E, Armando, Marco, McDonald-McGinn, Donna M, Chopra

2021

Overview

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.

• Publisher: Nature Publishing Group
• Subject: DNA microarrays / Gene deletion / Genetic factors / Genomes / Mental disorders / Psychosis / Risk factors / Schizophrenia / Whole genome sequencing