Common alleles contribute to schizophrenia in CNV carriers
Open accessAbstract
The genetic architecture of schizophrenia is complex, involving risk alleles ranging from common alleles of weak effect to rare alleles of large effect, the best exemplar of the latter being large copy number variants (CNVs). It is currently unknown whether pathophysiology in those with defined rare mutations overlaps with that in other individuals with the disorder who do not share the same rare mutation. Under an extreme heterogeneity model, carriers of specific high-penetrance mutations form distinct subgroups. In contrast, under a polygenic threshold model, high-penetrance rare allele carriers possess many risk factors, of which the rare allele is the only one, albeit an important, factor. Under the latter model, cases with rare mutations can be expected to share some common risk alleles, and therefore pathophysiological mechanisms, with cases without the same mutation. Here we show that, compared with controls, individuals with schizophrenia who have known pathogenic CNVs carry an excess burden of common risk alleles ( P =2.25 × 10 −17 ) defined from a genome-wide association study largely based on individuals without known CNVs. Our finding is not consistent with an extreme heterogeneity model for CNV carriers, but does offer support for the polygenic threshold model of schizophrenia. That this is so provides support for the notion that studies aiming to model the effects of rare variation may uncover pathophysiological mechanisms of relevance to those with the disorder more widely.
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Some pleiotropy of copy number variants may be due to modification by genetic risk scores, because even in individuals with autism spectrum disorder or schizophrenia carrying large-effect de novo mutations there appears to be an additive effect of common variation on phenotypic expression.
“Emerging evidence suggests that among other factors, some of this pleiotropy may be due to modification GRS because even in those with ASD or SCZ carrying large effect de novo mutations, there appears to be an additive effect of common variation on phenotypic expression (Tansey et al., 2016; Weiner et al., 2017).”
From Defining the genetic, genomic, cellular, and diagnostic architectures of psychiatric disorders (2019) · cites this paper as Tansey et al., 2016
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- Authors
- Tansey, K. E., Rees, E., Linden, D. E., Ripke, S., Chambert, K. D., Moran, J. L., McCarroll, S. A., Holmans, P., Kirov, G., Walters, J., Owen, M. J., & O'Donovan, M. C.
- Affiliations
- Cardiff University (GB)
- Broad Institute (US)
- Corresponding author
- Owen, M J
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2015-09-22
- Volume
- 21
- Issue
- 8
- Pages
- 1085-1089
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC4960448
- OpenAlex
- W1919612153
- Cited by
- 132
- References
- 33
- Citations by year
- 2026: 9 · 2025: 4 · 2024: 11 · 2023: 11 · 2022: 14 · 2021: 20 · 2020: 15 · 2019: 17 · 2018: 15 · 2017: 8 · 2016: 8
- FWCI
- 8.38
- Type
- journal article
- Language
- en
- Update notices
- erratum (2015-12-08)
- Open access
- hybrid
- doi.org
- Locations
- Molecular Psychiatry (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion, cc-by)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Johns Hopkins University
- Broad Institute
- European Commission (241909)
- Cardiff University (G0800509)
- Stanley Center for Psychiatric Research, Broad Institute
- Medical Research Council (MR/K004360/1, G0801418, MR/P005748/1, MR/L010305/1, G0800509)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- schizophrenia, copy number variation, genetic architecture, rare variants, deadweight loss, genome-wide association study, pathophysiology
- MeSH terms
- Alleles, Computer Simulation, Gene Frequency, Humans, Models, Genetic, Risk Factors, Schizophrenia, Genetic Predisposition to Disease, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Genome-Wide Association Study, DNA Copy Number Variations
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