Schizophrenia susceptibility alleles are enriched for alleles that affect gene expression in adult human brain
Open accessAbstract
It is widely thought that alleles that influence susceptibility to common diseases, including schizophrenia, will frequently do so through effects on gene expression. As only a small proportion of the genetic variance for schizophrenia has been attributed to specific loci, this remains an unproven hypothesis. The International Schizophrenia Consortium (ISC) recently reported a substantial polygenic contribution to that disorder, and that schizophrenia risk alleles are enriched among single-nucleotide polymorphisms (SNPs) selected for marginal evidence for association (P<0.5) from genome-wide association studies (GWAS). It follows that if schizophrenia susceptibility alleles are enriched for those that affect gene expression, those marginally associated SNPs, which are also expression quantitative trait loci (eQTLs), should carry more true association signals compared with SNPs that are not marginally associated. To test this, we identified marginally associated (P<0.5) SNPs from two of the largest available schizophrenia GWAS data sets. We assigned eQTL status to those SNPs based upon an eQTL data set derived from adult human brain. Using the polygenic score method of analysis reported by the ISC, we observed and replicated the observation that higher probability cis-eQTLs predicted schizophrenia better than those with a lower probability for being a cis-eQTL. Our data support the hypothesis that alleles conferring risk of schizophrenia are enriched among those that affect gene expression. Moreover, our data show that notwithstanding the likely developmental origin of schizophrenia, studies of adult brain tissue can, in principle, allow relevant susceptibility eQTLs to be identified.
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Schizophrenia GWAS SNPs occur more often than chance in cis-regulatory functional genomic elements such as enhancers or eQTL SNPs.
“Indeed, GWAS SNPs associated with SCZ risk occur more often than expected by chance in cis-regulatory functional genomic elements, such as enhancers or eQTL SNPs3,21–24.”
From Gene expression elucidates functional impact of polygenic risk for schizophrenia (2016) · cites this paper as [22]
GWAS SNPs associated with schizophrenia risk occur more often than expected by chance in cis-regulatory functional genomic elements, such as enhancers or eQTL SNPs.
“Indeed, GWAS SNPs associated with SCZ risk occur more often than expected by chance in cis-regulatory functional genomic elements, such as enhancers or eQTL SNPs3,21–24.”
From Gene expression elucidates functional impact of polygenic risk for schizophrenia (2016) · cites this paper as [22]
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- Authors
- Richards, A. L., Jones, L., Moskvina, V, Kirov, G., Gejman, P. V., Levinson, D. F., Sanders, A. R., Molecular Genetics of Schizophrenia Collaboration (MGS), International Schizophrenia Consortium (ISC), Purcell, S., Visscher, P. M., Craddock, N., Owen, M. J., Holmans, P., & O'Donovan, M. C.
- Affiliations
- Cardiff University (GB)
- Endeavor Health (US)
- Stanford University (US)
- Broad Institute (US)
- QIMR Berghofer Medical Research Institute (AU)
- ORCID
- Venue
- Molecular Psychiatry
- Published
- 2011-02-22
- Volume
- 17
- Issue
- 2
- Pages
- 193-201
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC4761872
- OpenAlex
- W2029926013
- Cited by
- 123
- References
- 33
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 3 · 2023: 4 · 2022: 6 · 2021: 1 · 2020: 4 · 2019: 7 · 2018: 11 · 2017: 11 · 2016: 13 · 2015: 12 · 2014: 18 · 2013: 10 · 2012: 14
- FWCI
- 9.78
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- UCL Discovery (University College London) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Funders
- Wellcome Trust
- Medical Research Council
- National Institute of Mental Health (U01MH046276, P50MH066392, R01MH060879)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- schizophrenia, genetic susceptibility, expression quantitative trait loci, cis-eQTL, polygenic risk score, single nucleotide polymorphisms, polygenic architecture
- MeSH terms
- Alleles, Female, Gene Expression Regulation, Gene Frequency, Genotype, Humans, Male, Schizophrenia, Genetic Variation, Genome, Human, Logistic Models, Genetic Predisposition to Disease, Oligonucleotide Array Sequence Analysis, Polymorphism, Single Nucleotide, Gene Expression Profiling, Quantitative Trait Loci, Genome-Wide Association Study
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