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

International 22q11.2DS Brain and Behavior Consortium, Rosemarie Fritsch

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72 Scopus citations


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)4496-4510
Number of pages15
JournalMolecular Psychiatry
Issue number8
StatePublished - Aug 2021

Bibliographical note

Funding Information:
to DG, U01 MH087626 to MEC, RSG, RCG, and REG, U54HD090260 to AD, TG, BEM, and YZ, UO1-MH191719 and R01 MH087636-01A1 to TBC, BSE, AJ, BL, DMM-M, DEM, EMM, HIS, RJS, OT, MU, and EHZ, Van de Werf fund for cardiovascular research to JB, IWT 131625 to WD, Wellcome Trust grant 102428/Z/13/Z to TM and NMW, and Canadian Institutes of Health Research grants MOP-79518, MOP-89066, MOP-97800 and MOP-111238, a McLaughlin Centre Accelerator grant, the Canada Research Chairs program, and Dalglish Chair to ASB. The authors thank all individuals with 22q11.2 deletion syndrome and their families for their generous contributions to this and related research studies, and are grateful to support charities including Max Appeal, The 22Crew and Unique. This work included participants of the NCMH study, a collaboration between Cardiff, Swansea and Bangor Universities. We thank the following members of the Division of Psychological Medicine and Clinical Neurosciences at the Cardiff School of Medicine for technical assistance: S. Chawner, A. Cunningham, C. Eaton, A. Evans, S. Morrison, H. Moulding, P. Birch, M. Tong, S. Bowen, L. Benger, M. Thomas, L. Reed, C.T. Carmichael, L. Bates, B. Lugonja, J. Morgan, N. Vinh, A. Evans, L. Hopkins, L. Tram, S. Jacques, S. Lewis.

Funding Information:
Acknowledgements The IBBC is supported by the National Institute of Mental Health grants U01MH101719, U01MH0101720, U01MH0101723, U01MH101722, and U01MH101724. Other grant support includes: Brain and Behavior Foundation Young Researcher grant (formerly NARSAD, grant no. 21278) to MA, Fondecyt-Chile Grant 1171014 to RF, CO, and GMR, grant FWO G.0E11.17N to JRV, MRC Centre grant MR/L010305/1, National Institute of Mental Health grant U01MH101724, and Welsh Government funded Research Centre 514032 to MJO, NARSAD (Brain and Behavior Research Foundation) to OYO, National Institute of Mental Health grant MH064824 to KMA, WF, WRK, and TJS, NIH grant R01GM117946 to MPE, RD and AJV, NIH grant U54NS091859 to PC, PE, HRJ, and STW, NIH grant R01MH100917 to DJC, PE, AVK, JGM, and MEZ, NIMH K01 MH112774 to MJ, NIMH R01 MH085953 and NIH U54 EB020403 to CEB and LK, NIMH U01MH101724 to MvdB, P01HD070454 to TBC, AD, BSE, TG, AJ, BL, DMM-M, DEM, EMM, BEM, HIS, RJS, OT, MU, EHZ, and YZ, P50MH09689 and R01-MH-1072351 to REG, P50MH096891 to MEC and RCG, National Institute of Mental Health R01 MH085953 to CMM and DGM, R01-MH-107235 to RCG, Canadian Institutes of Health Research grant MOP-74631 to EWCC, Swiss National Science Foundation (Grant number 324730_144260) and National Center of Competence in Research (NCCR) “Synapsy-The Synaptic Bases of Mental Diseases” (Grant number 51NF40-185897) to SE, T32 MH019112 to SXT, the Binational Science Foundation, grant 2017370

Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.


  • Adult
  • Case-Control Studies
  • Cohort Studies
  • DiGeorge Syndrome
  • Humans
  • Psychotic Disorders
  • Schizophrenia


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