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Phenotype integration improves power and preserves specificity in biobank-based genetic studies of major depressive disorder.
Nat. Genet. 55, 2082-2093 (2023)
Biobanks often contain several phenotypes relevant to diseases such as major depressive disorder (MDD), with partly distinct genetic architectures. Researchers face complex tradeoffs between shallow (large sample size, low specificity/sensitivity) and deep (small sample size, high specificity/sensitivity) phenotypes, and the optimal choices are often unclear. Here we propose to integrate these phenotypes to combine the benefits of each. We use phenotype imputation to integrate information across hundreds of MDD-relevant phenotypes, which significantly increases genome-wide association study (GWAS) power and polygenic risk score (PRS) prediction accuracy of the deepest available MDD phenotype in UK Biobank, LifetimeMDD. We demonstrate that imputation preserves specificity in its genetic architecture using a novel PRS-based pleiotropy metric. We further find that integration via summary statistics also enhances GWAS power and PRS predictions, but can introduce nonspecific genetic effects depending on input. Our work provides a simple and scalable approach to improve genetic studies in large biobanks by integrating shallow and deep phenotypes.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Polygenic Risk Scores; Field Trials; Uk Biobank; Expression; Architecture; Prediction; Imputation; Variants; Symptoms; History
ISSN (print) / ISBN
1061-4036
e-ISSN
1546-1718
Journal
Nature Genetics
Quellenangaben
Volume: 55,
Issue: 12,
Pages: 2082-2093
Publisher
Nature Publishing Group
Publishing Place
New York, NY
Non-patent literature
Publications
Reviewing status
Peer reviewed
Institute(s)
Helmholtz Pioneer Campus (HPC)
Grants
National Science Foundation (NSF)
U.S. Department of Health & Human Services | National Institutes of Health (NIH)
U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
Lundbeckfonden (Lundbeck Foundation)
U.S. Department of Health & Human Services | National Institutes of Health (NIH)
U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (NIMH)
Lundbeckfonden (Lundbeck Foundation)