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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
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.
Keywords : Genetics Schizophrenia
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Submitted on : Monday, May 3, 2021 - 5:09:26 PM
Last modification on : Monday, May 10, 2021 - 10:03:12 AM

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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, Nature Publishing Group, 2020, ⟨10.1038/s41380-020-0654-3⟩. ⟨hal-03216078⟩

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