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Article Dans Une Revue Molecular Psychiatry Année : 2020

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

Isabelle Cleynen (1) , Worrawat Engchuan (2) , Matthew Hestand (1) , Tracy Heung (2) , Aaron Holleman (3) , H. Richard Johnston (3) , Thomas Monfeuga (4) , Donna Mcdonald-Mcginn (5) , Raquel Gur (5) , Bernice Morrow (6) , Ann Swillen (7) , Jacob Vorstman (8, 9) , Carrie Bearden (10) , Eva Chow (8) , Marianne van den Bree (4) , Beverly Emanuel (11) , Joris Vermeesch (1) , Stephen Warren (12) , Michael Owen (4) , Pankaj Chopra (12) , David Cutler (12) , Richard Duncan (12) , Alex Kotlar (12) , Jennifer Mulle (12) , Anna Voss (12) , Michael Zwick (12) , Alexander Diacou (6) , Aaron Golden (6) , Tingwei Guo (6) , Jhih-Rong Lin (6) , Tao Wang (6) , Zhengdong Zhang (6) , Yingjie Zhao (6) , Christian Marshall (8) , Daniele Merico (2) , Andrea Jin (11) , Brenna Lilley (11) , Harold Salmons (11) , Oanh Tran (11) , Peter Holmans (4) , Antonio Pardinas (4) , James Walters (4) , Wolfram Demaerel (1) , Erik Boot (13) , Nancy Butcher (14) , Gregory Costain (14) , Chelsea Lowther (14) , Rens Evers (15) , Therese van Amelsvoort (15) , Esther van Duin (15) , Claudia Vingerhoets (15) , Jeroen Breckpot (7) , Koen Devriendt (7) , Elfi Vergaelen (7) , Annick Vogels (7) , T. Blaine Crowley (11) , Daniel Mcginn (11) , Edward Moss (11) , Robert Sharkus (11) , Marta Unolt (11) , Elaine Zackai (11) , Monica Calkins (5) , Robert Gallagher (5) , Ruben Gur (5) , Sunny Tang (5) , Rosemarie Fritsch (16) , Claudia Ornstein (16) , Gabriela Repetto (17) , Elemi Breetvelt (8) , Sasja Duijff (9) , Ania Fiksinski (9) , Hayley Moss (4) , Maria Niarchou (4) , Kieran Murphy (18) , Sarah Prasad (18) , Eileen Daly (19) , Maria Gudbrandsen (19) , Clodagh Murphy (19) , Declan Murphy (19) , Antonio Buzzanca (20) , Fabio Di Fabio (20) , Maria Digilio (21) , Maria Pontillo (21) , Bruno Marino (20) , Stefano Vicari (21) , Karlene Coleman (12) , Joseph Cubells (12) , Opal Ousley (12) , Miri Carmel (22) , Doron Gothelf (22) , Ehud Mekori-Domachevsky (22) , Elena Michaelovsky (22) , Ronnie Weinberger (23) , Abraham Weizman (22) , Leila Kushan (10) , Maria Jalbrzikowski (24) , Marco Armando (25) , Stéphan Eliez (25) , Corrado Sandini (25) , Maude Schneider (25) , Frédérique Sloan Béna (26) , Kevin Antshel (27) , Wanda Fremont (28) , Wendy Kates (28) , Raoul Belzeaux (29) , Tiffany Busa (30) , Nicole Philip (31) , Linda Campbell (32) , Kathryn Mccabe (32) , Stephen Hooper (33) , Kelly Schoch (33) , Vandana Shashi (34) , Tony Simon (35) , Flora Tassone (35) , Celso Arango (36) , David Fraguas (36) , Sixto García-Miñaúr (37) , Jaume Morey-Canyelles (38) , Jordi Rosell (38) , Damià Suñer (38) , Jasna Raventos-Simic (38) , Michael Epstein (12) , Nigel Williams (4) , Anne Bassett (8)
1 KU Leuven - Catholic University of Leuven = Katholieke Universiteit Leuven
2 SickKids - The Hospital for sick children [Toronto]
3 Emory University [Atlanta, GA]
4 Cardiff University
5 University of Pennsylvania
6 Albert Einstein College of Medicine [New York]
7 University Hospitals Leuven [Leuven]
8 University of Toronto
9 University Medical Center [Utrecht]
10 UC - University of California
11 CHOP - Children’s Hospital of Philadelphia
12 Emory University School of Medicine
13 University Health Network [Toronto, ON, Canada]
14 CAMH - Centre for Addiction and Mental Health [Toronto]
15 Maastricht University [Maastricht]
16 UCHILE - Universidad de Chile = University of Chile [Santiago]
17 Clínica Alemana & Universidad del Desarrollo
18 RCSI - Royal College of Surgeons in Ireland
19 King‘s College London
20 UNIROMA - Università degli Studi di Roma "La Sapienza" = Sapienza University [Rome]
21 IRCCS Ospedale Pediatrico Bambino Gesù = Bambino Gesù Children’s Hospital
22 TAU - Tel Aviv University
23 The Edmond and Lily Safra Children's Hospital [Tel-Hahsomer, Israel]
24 University of Pittsburgh School of Medicine
25 UNIGE - Université de Genève = University of Geneva
26 Geneva University Hospitals and Geneva University
27 Syracuse University
28 SUNY Upstate Medical University
29 Hôpitaux Sud - Hôpital Sainte-Marguerite [CHU - APHM]
30 Service de pédiatrie multidisciplinaire [Hôpital de la Timone Enfants - APHM]
31 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
32 UoN - University of Newcastle [Callaghan, Australia]
33 UNC - University of North Carolina [Chapel Hill]
34 Duke University School of Medicine
35 UC Davis - University of California [Davis]
36 UCM - Universidad Complutense de Madrid = Complutense University of Madrid [Madrid]
37 La Paz University Hospital
38 Hospital Universitario Son Espases
Carrie Bearden
Eva Chow
  • Fonction : Auteur
Marianne van den Bree
Michael Owen
Peter Holmans
  • Fonction : Auteur
James Walters
  • Fonction : Auteur
Jeroen Breckpot
Hayley Moss
  • Fonction : Auteur
Miri Carmel
  • Fonction : Auteur
Raoul Belzeaux

Résumé

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.

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Dates et versions

hal-03216078 , version 1 (28-09-2023)

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Isabelle Cleynen, Worrawat Engchuan, Matthew Hestand, Tracy Heung, Aaron Holleman, et al.. Genetic contributors to risk of schizophrenia in the presence of a 22q11.2 deletion. Molecular Psychiatry, 2020, ⟨10.1038/s41380-020-0654-3⟩. ⟨hal-03216078⟩
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