Using common genetic variation to examine phenotypic expression and risk prediction in 22q11.2 deletion syndrome
Open accessAbstract
The 22q11.2 deletion syndrome (22q11DS) is associated with a 20-25% risk of schizophrenia. In a cohort of 962 individuals with 22q11DS, we examined the shared genetic basis between schizophrenia and schizophrenia-related early trajectory phenotypes: sub-threshold symptoms of psychosis, low baseline intellectual functioning and cognitive decline. We studied the association of these phenotypes with two polygenic scores, derived for schizophrenia and intelligence, and evaluated their use for individual risk prediction in 22q11DS. Polygenic scores were not only associated with schizophrenia and baseline intelligence quotient (IQ), respectively, but schizophrenia polygenic score was also significantly associated with cognitive (verbal IQ) decline and nominally associated with sub-threshold psychosis. Furthermore, in comparing the tail-end deciles of the schizophrenia and IQ polygenic score distributions, 33% versus 9% of individuals with 22q11DS had schizophrenia, and 63% versus 24% of individuals had intellectual disability. Collectively, these data show a shared genetic basis for schizophrenia and schizophrenia-related phenotypes and also highlight the future potential of polygenic scores for risk stratification among individuals with highly, but incompletely, penetrant genetic variants.
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ASD risk is attributable to a combination of rare and common variation.
“Even CNVs with large effect sizes (OR > 30) for ASD present with variable psychiatric traits4, and risk is attributable to a combination of rare and common variation5,6.”
From A phenotypic spectrum of autism is attributable to the combined effects of rare variants, polygenic risk and sex (2022) · cites this paper as [6]
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References 62 · Cited by 139
- Authors
- International 22q11.2 Brain and Behavior Consortium, Davies, R. W., Fiksinski, A. M., Breetvelt, E. J., Williams, N. M., Hooper, S. R., Monfeuga, T., Bassett, A. S., Owen, M. J., Gur, R. E., Morrow, B. E., McDonald-McGinn, D. M., Swillen, A., Chow, E. W. C., van den Bree, M., Emanuel, B. S., Vermeesch, J. R., van Amelsvoort, T., Arango, C., Armando, M., Campbell, L. E., Cubells, J. F., Eliez, S., Garcia-Minaur, S., Gothelf, D., Kates, W. R., Murphy, K. C., Murphy, C. M., Murphy, D. G., Philip, N., Repetto, G. M., Shashi, V., Simon, T. J., Suñer, D. H., Vicari, S., Scherer, S. W., Bearden, C. E., & Vorstman, J. A. S.
- Affiliations
- Hospital for Sick Children (CA)
- Centre for Addiction and Mental Health (CA)
- Cardiff University (GB)
- University of North Carolina at Chapel Hill (US)
- University Health Network (CA)
- Children's Hospital of Philadelphia (US)
- Albert Einstein College of Medicine (US)
- Universitair Ziekenhuis Leuven (BE)
- Universidad Complutense de Madrid (ES)
- University of Geneva (CH)
- University of Newcastle Australia (AU)
- Emory University (US)
- Tel Aviv University (IL)
- SUNY Upstate Medical University (US)
- Royal College of Surgeons in Ireland (IE)
- King's College London (GB)
- Inserm (FR)
- Clínica Alemana (CL)
- Duke University (US)
- University of California, Davis (US)
- Bambino Gesù Children's Hospital (IT)
- SickKids Foundation (CA)
- University of California, Los Angeles (US)
- University of Toronto (CA)
- Corresponding author
- Vorstman, Jacob A. S.
- ORCID
- Davies, Robert W.
- Fiksinski, Ania M.
- Breetvelt, Elemi J.
- Williams, Nigel M.
- Hooper, Stephen R.
- Monfeuga, Thomas
- Bassett, Anne S.
- Owen, Michael J.
- Gur, Raquel E.
- Morrow, Bernice E.
- McDonald-McGinn, Donna M.
- Swillen, Ann
- Chow, Eva W. C.
- Emanuel, Beverly S.
- Vermeesch, Joris R.
- Arango, Celso
- Armando, Marco
- Campbell, Linda E.
- Cubells, Joseph F.
- Gothelf, Doron
- Kates, Wendy R.
- Murphy, Kieran C.
- Murphy, Clodagh M.
- Murphy, Declan G.
- Repetto, Gabriela M.
- Shashi, Vandana
- Vicari, Stefano
- Scherer, Stephen W.
- Bearden, Carrie E.
- Vorstman, Jacob A. S.
- Venue
- Nature Medicine
- Published
- 2020-11-09
- Volume
- 26
- Issue
- 12
- Pages
- 1912-1918
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC7975627
- OpenAlex
- W3104731129
- Cited by
- 139
- References
- 62
- Citations by year
- 2026: 12 · 2025: 18 · 2024: 24 · 2023: 26 · 2022: 26 · 2021: 33
- FWCI
- 15.51
- Type
- journal article
- Language
- en
- Open access
- Licence
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by-nc-nd)
- Archive ouverte UNIGE (University of Geneva) (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Lirias (KU Leuven) (submittedVersion)
- HAL (submittedVersion, other-oa)
- Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Oskar-Bordeaux (Universite de Bordeaux) (submittedVersion)
- Universidad de Chile (submittedVersion, cc-by-nc-nd)
- SERVAL (Université de Lausanne) (submittedVersion)
- Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
- Research Publications (Maastricht University) (submittedVersion)
- NOVA (University of Newcastle Australia) (submittedVersion)
- Funders
- Brain and Behavior Research Foundation (Young Investigator Award)
- Gouvernement du Canada | Instituts de Recherche en Santé du Canada | CIHR Skin Research Training Centre (STAGE fellowship)
- Lap-Chee Tsui Fellowship for Research Excellence
- See funders listed under the NIMH International Consortium on Brain and Behavior in 22q11.2 Deletion Syndrome
- U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (U01MH101719, U01MH0101720, U01MH0101723, U01MH101722, EU01MH101724, R01MH085953, 1U01MH119736-01)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- 22q11.2 deletion syndrome, schizophrenia, polygenic risk score, risk prediction, intellectual disability, cognitive decline, verbal IQ, genetic overlap, phenotypic expression, risk stratification
- MeSH terms
- Adolescent, Adult, Aged, Child, Child, Preschool, DiGeorge Syndrome, Female, Humans, Male, Intellectual Disability, Middle Aged, Phenotype, Risk Factors, Schizophrenia, Genetic Variation, Cohort Studies, Multifactorial Inheritance, Young Adult, Cognitive Dysfunction
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