@article{df42befeaddb4637b5ae552b01475e4f,
title = "Adjusting for common variant polygenic scores improves yield in rare variant association analyses",
abstract = "With the emergence of large-scale sequencing data, methods for improving power in rare variant association tests are needed. Here we show that adjusting for common variant polygenic scores improves yield in gene-based rare variant association tests across 65 quantitative traits in the UK Biobank (up to 20% increase at α = 2.6 × 10−6), without marked increases in false-positive rates or genomic inflation. Benefits were seen for various models, with the largest improvements seen for efficient sparse mixed-effects models. Our results illustrate how polygenic score adjustment can efficiently improve power in rare variant association discovery.",
author = "Jurgens, {Sean J.} and Pirruccello, {James P.} and Choi, {Seung Hoan} and Morrill, {Valerie N.} and Mark Chaffin and Lubitz, {Steven A.} and Lunetta, {Kathryn L.} and Ellinor, {Patrick T.}",
note = "Funding Information: We thank all UK Biobank participants, as this study would not have been possible without their contributions. P.T.E. is supported by the National Institutes of Health (grant nos. 1R01HL092577, 5RO1HL139731 and 1R01HL157635), the American Heart Association (grant no. 18SFRN34110082) and the European Union (grant no. MAESTRIA 965286). S.A.L. is supported by the National Institutes of Health (grant no. 1R01HL139731) and by the American Heart Association (grant no. 18SFRN34250007). S.J.J. is supported by an Amsterdam UMC Doctoral Fellowship, and by the Junior Clinical Scientist Fellowship from the Dutch Heart Foundation (grant no. 03-007-2022-0035). J.P.P. is supported by the John S. LaDue Memorial Fellowship for Cardiovascular Research and by the National Institutes of Health (grant no. 5K08HL159346). S.H.C. is supported by the National Institutes of Health (grant nos. R01HL149352, R01HL111024, 2R01HL127564-05A1, 1U01AG058589-01A1, 1U01AG068221-01A1 and 1R01HL164824-01), and was supported by the BioData Ecosystem Fellowship program. Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature America, Inc.",
year = "2023",
month = apr,
doi = "https://doi.org/10.1038/s41588-023-01342-w",
language = "English",
volume = "55",
pages = "544--548",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Publishing Group",
number = "4",
}