Artículo de revista
Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion
Fecha
2020Registro en:
Molecular Psychiatry, Feb 2020
10.1038/s41380-020-0654-3
Autor
Cleynen, Isabelle
Engchuan, Worrawat
Hestand, Matthew S.
Heung, Tracy
Holleman, Aarón M.
Johnston, H. Richard
Monfeuga, Thomas
McDonald McGinn, Donna M.
Gur, Raquel E.
Morrow, Bernice E.
Swillen, Ann
Vorstman, Jacob A. S.
Bearden, Carrie E.
Chow, Eva W. C.
van den Bree, Marianne
Emanuel, Beverly S.
Vermeesch, Joris R.
Warren, Stephen T.
Owen, Michael J.
Chopra, Pankaj
Cutler, David J.
Duncan, Richard
Kotlar, Alex V.
Mulle, Jennifer G.
Voss, Anna J.
Zwick, Michael E.
Diacou, Alexander
Golden, Aaron
Guo, Tingwei
Lin, Jhih Rong
Wang, Tao
Zhang, Zhengdong
Zhao, Yingjie
Marshall, Christian
Merico, Daniele
Jin, Andrea
Lilley, Brenna
Salmons, Harold I.
Oanh, Tran
Pardinas, Antonio
Walters, James T. R.
Demaerel, Wolfram
Boot, Erik
Butcher, Nancy J.
Costain, Gregory A.
Lowther, Chelsea
Evers, Rens
van Amelsvoort, Therese A. M. J.
van Duin, Esther
Vingerhoets, Claudia
Breckpot, Jeroen
Devriendt, Koen
Vergaelen, Elfi
Vogels, Annick
Crowley, T. Blaine
McGinn, Daniel E.
Moss, Edward M.
Sharkus, Robert J.
Unolt, Marta
Zackai, Elaine H.
Calkins, Mónica E.
Gallagher, Robert S.
Gur, Rubén C.
Tang, Sunny X.
Fritsch Montero, Rosemarie
Ornstein Letelier, Claudia
Repetto, Gabriela M.
Breetvelt, Elemi
Duijff, Sasja N.
Fiksinski, Ania
Moss, Hayley
Niarchou, Maria
Murphy, Kieran C.
Prasad, Sarah E.
Daly, Eileen M.
Gudbrandsen, María
Murphy, Clodagh M.
Murphy, Declan G.
Buzzanca, Antonio
Di Fabio, Fabio
Digilio, María C.
Pontillo, María
Marino, Bruno
Vicari, Stefano
Coleman, Karlene
Cubells, Joseph F.
Ousley, Opal Y.
Carmel, Miri
Gothelf, Doron
Mekori Domachevsky, Ehud
Michaelovsky, Elena
Weinberger, Ronnie
Eliez, Stephan
Sandini, Corrado
Schneider, Maude
Bena, Frederique Sloan
Antshel, Kevin M.
Fremont, Wanda
Kates, Wendy R.
Belzeaux, Raoul
Busa, Tiffany
Schoch, Kelly
Shashi, Vandana
Simon, Tony J.
Tassone, Flora
Arango, Celso
Suner, Damia H.
Raventos Simic, Jasna
Epstein, Michael P.
Williams, Nigel M.
Bassett, Anne S.
Institución
Resumen
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 similar to 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 (p(adj) = 6.73 x 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.