Analysis of Intellectual Disability Copy Number Variants for Association With Schizophrenia
Open accessAbstract
IMPORTANCE: At least 11 rare copy number variants (CNVs) have been shown to be major risk factors for schizophrenia (SZ). These CNVs also increase the risk for other neurodevelopmental disorders, such as intellectual disability. It is possible that additional intellectual disability-associated CNVs increase the risk for SZ but have not yet been implicated in SZ because of previous studies being underpowered. OBJECTIVE: To examine whether additional CNVs implicated in intellectual disability represent novel SZ risk loci. DESIGN, SETTING, AND PARTICIPANTS: We used single-nucleotide polymorphism (SNP) array data to evaluate a set of 51 CNVs implicated in intellectual disability (excluding the known SZ loci) in a large data set of patients with SZ and healthy persons serving as controls recruited in a variety of settings. We analyzed a new sample of 6934 individuals with SZ and 8751 controls and combined those data with previously published large data sets for a total of 20 403 cases of SZ and 26 628 controls. MAIN OUTCOMES AND MEASURES: Burden analysis of CNVs implicated in intellectual disability (excluding known SZ CNVs) for association with SZ. Association of individual intellectual disability CNV loci with SZ. RESULTS: Of data on the 20 403 cases (6151 [30.15%] female) and 26 628 controls (14 252 [53.52%] female), 51 intellectual disability CNVs were analyzed. Collectively, intellectual disability CNVs were significantly enriched for SZ (P = 1.0 × 10-6; odds ratio [OR], 1.9 [95% CI, 1.46-2.49]). Of the 51 CNVs tested, 19 (37%) were more common in SZ cases; only 4 (8%) were more common in controls (no observations were made for the remaining 28 [55%] loci). One novel locus, deletion at 16p12.1, was significantly associated with SZ after correction for multiple testing (rate in SZ, 33 [0.16%]; rate in controls, 12 [0.05%]; corrected P = .017; OR, 3.3; 95% CI, 1.61-7.05), and 2 loci reached nominal levels of significance (deletions at 2q11.2: 6 [0.03%] vs 1 [0.004%]; OR, 9.3; 95% CI, 1.03-447.76; corrected P > .99; and duplications at 10q11.21q11.23: 5 [0.2%] vs 0 [0.03%]; OR, infinity; 95% CI, 1.26-infinity; corrected P = .71). Our new data set also provided independent support for the 11 SZ risk loci previously reported to be associated with the disorder and for the protective effect of 22q11.2 duplication. CONCLUSIONS AND RELEVANCE: A large proportion of CNV loci implicated in intellectual disability are risk factors for SZ, but the available sample size precludes statistical confirmation for additional individual loci.
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Rare variant overlaps exist in liability to schizophrenia, autism spectrum disorder, and developmental disorder.
“There are rare variant overlaps in liability to schizophrenia, autism spectrum disorder (ASD) and developmental disorder (DD)8,30,31.”
From Mapping genomic loci implicates genes and synaptic biology in schizophrenia (2022) · cites this paper as [31]
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- Authors
- Rees, E., Kendall, K., Pardiñas, A. F., Legge, S. E., Pocklington, A., Escott-Price, V., MacCabe, J. H., Collier, D. A., Holmans, P., O’Donovan, M. C., Owen, M. J., Walters, J. T. R., & Kirov, G.
- Affiliations
- Cardiff University (GB)
- Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, Wales
- King's College London (GB)
- Corresponding author
- Kirov, George
- ORCID
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2016-09-01
- Volume
- 73
- Issue
- 9
- Pages
- 963
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC5014093
- OpenAlex
- W2510482597
- Cited by
- 162
- References
- 22
- Citations by year
- 2026: 13 · 2025: 18 · 2024: 19 · 2023: 18 · 2022: 13 · 2021: 19 · 2020: 19 · 2019: 19 · 2018: 13 · 2017: 8 · 2016: 3
- FWCI
- 11.46
- Type
- journal article
- Language
- en
- Open access
- green
- kclpure.kcl.ac.uk
- Licence
- other-oa
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (publishedVersion, other-oa)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Funders
- Wellcome Trust
- Medical Research Council (MR/L023784/2, MR/L011794/1, MR/P005748/1, MR/L010305/1)
- National Heart, Lung, and Blood Institute (HHSN268201100011C, HHSN268201100011I, U01HL089856, U01HL089897)
- National Institute of Mental Health (U01MH046276, R01MH059566, U01MH046318, R01MH059571, R01MH060879, R01MH059565, R01MH081800, R01MH060870, U01MH046289, U01MH079469, R01MH061675, R01MH059586, R01MH059588, R01MH067257, U01MH079470, R01MH059587)
- National Institute on Drug Abuse (P50DA019706)
- National Human Genome Research Institute (U01HG004446, HHSN268200782096C)
- National Eye Institute (R01EY016514, R01EY016835, R01EY020483, R01EY016482)
- National Cancer Institute (P50CA097007, R01CA133996, P01CA089392, R01CA088363, R01CA120120, P01CA107584, P50CA084724, P50CA093459)
- National Institute of Environmental Health Sciences (R01ES011740)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- copy number variation, intellectual disability, schizophrenia, genetic susceptibility loci, 1q21.1 deletion
- MeSH terms
- Adult, Clozapine, Drug Resistance, Female, Genotype, United Kingdom, Humans, Male, Intellectual Disability, Reference Values, Risk, Schizophrenia, Cohort Studies, Comorbidity, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genetic Loci, DNA Copy Number Variations
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