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Dahl, A.* ; Thompson, M.L.* ; An, U.* ; Krebs, M.D.* ; Appadurai, V.* ; Border, R.* ; Bacanu, S.A.* ; Werge, T.* ; Flint, J.* ; Schork, A.J.* ; Sankararaman, S.* ; Kendler, K.S.* ; Cai, N.

Phenotype integration improves power and preserves specificity in biobank-based genetic studies of major depressive disorder.

Nat. Genet. 55, 2082-2093 (2023)
Publ. Version/Full Text DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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
Corresponding Author
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 Article Number: , Supplement: ,
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)