Improved Detection of Common Variants Associated with Schizophrenia by Leveraging Pleiotropy with Cardiovascular-Disease Risk Factors
Open accessAbstract
Several lines of evidence suggest that genome-wide association studies (GWASs) have the potential to explain more of the "missing heritability" of common complex phenotypes. However, reliable methods for identifying a larger proportion of SNPs are currently lacking. Here, we present a genetic-pleiotropy-informed method for improving gene discovery with the use of GWAS summary-statistics data. We applied this methodology to identify additional loci associated with schizophrenia (SCZ), a highly heritable disorder with significant missing heritability. Epidemiological and clinical studies suggest comorbidity between SCZ and cardiovascular-disease (CVD) risk factors, including systolic blood pressure, triglycerides, low- and high-density lipoprotein, body mass index, waist-to-hip ratio, and type 2 diabetes. Using stratified quantile-quantile plots, we show enrichment of SNPs associated with SCZ as a function of the association with several CVD risk factors and a corresponding reduction in false discovery rate (FDR). We validate this "pleiotropic enrichment" by demonstrating increased replication rate across independent SCZ substudies. Applying the stratified FDR method, we identified 25 loci associated with SCZ at a conditional FDR level of 0.01. Of these, ten loci are associated with both SCZ and CVD risk factors, mainly triglycerides and low- and high-density lipoproteins but also waist-to-hip ratio, systolic blood pressure, and body mass index. Together, these findings suggest the feasibility of using genetic-pleiotropy-informed methods for improving gene discovery in SCZ and identifying potential mechanistic relationships with various CVD risk factors.
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Several factors contribute to the early and frequent development of cardiovascular disease in this population, including genetic vulnerability, metabolic adverse effects of antipsychotics, insufficient treatment of somatic comorbidity, and unhealthy lifestyle.
“Several factors contribute to the early and frequent development of cardiovascular disease in this population, including genetic vulnerability 5 , metabolic adverse effects of antipsychotics 6,7 , insufficient treatment of somatic comorbidity 8 , and unhealthy lifestyle 9 .”
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- Authors
- Andreassen, O. A., Djurovic, S., Thompson, W. K., Schork, A. J., Kendler, K. S., O’Donovan, M. C., Rujescu, D., Werge, T., van de Bunt, M., Morris, A. P., McCarthy, M. I., Roddey, J. C., McEvoy, L. K., Desikan, R. S., & Dale, A. M.
- Affiliations
- Oslo University Hospital (NO)
- University of California San Diego (US)
- Virginia Commonwealth University (US)
- Cardiff University (GB)
- Martin Luther University Halle-Wittenberg (DE)
- University of Copenhagen (DK)
- Centre for Human Genetics (GB)
- Corresponding author
- Andreassen, Ole A.
- Dale, Anders M.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 92
- Issue
- 2
- Pages
- 197-209
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3567279
- OpenAlex
- W2072408668
- Cited by
- 506
- References
- 53
- Citations by year
- 2026: 24 · 2025: 32 · 2024: 46 · 2023: 46 · 2022: 46 · 2021: 51 · 2020: 40 · 2019: 36 · 2018: 31 · 2017: 39 · 2016: 28 · 2015: 42 · 2014: 24 · 2013: 19
- FWCI
- 24.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- VU Research Portal (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- UCL Discovery (University College London) (submittedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (submittedVersion)
- Lirias (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Stiftelsen Kristian Gerhard Jebsen
- Wellcome Trust (098017, 090532)
- Norges Forskningsråd
- National Institutes of Health
- National Institute on Aging (R01AG031224)
- National Institute on Drug Abuse (RC2DA029475)
- National Institute of Biomedical Imaging and Bioengineering (R01EB000790, T32EB005970)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD061414)
- 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, common genetic variants, missing heritability, pleiotropy, cardiovascular risk factors, triglycerides, lipoproteins, systolic blood pressure, body mass index, waist-to-hip ratio, type 2 diabetes, gene discovery, replication
- MeSH terms
- Cardiovascular Diseases, Humans, Phenotype, Risk Factors, Schizophrenia, Reproducibility of Results, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Genetic Loci, Genetic Pleiotropy
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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