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Identifying interpretable gene-biomarker associations with functionally informed kernel-based tests in 190,000 exomes

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Item Type:Article
Title:Identifying interpretable gene-biomarker associations with functionally informed kernel-based tests in 190,000 exomes
Creators Name:Monti, R. and Rautenstrauch, P. and Ghanbari, M. and James, A.R. and Kirchler, M. and Ohler, U. and Konigorski, S. and Lippert, C.
Abstract:Here we present an exome-wide rare genetic variant association study for 30 blood biomarkers in 191,971 individuals in the UK Biobank. We compare gene-based association tests for separate functional variant categories to increase interpretability and identify 193 significant gene-biomarker associations. Genes associated with biomarkers were ~ 4.5-fold enriched for conferring Mendelian disorders. In addition to performing weighted gene-based variant collapsing tests, we design and apply variant-category-specific kernel-based tests that integrate quantitative functional variant effect predictions for missense variants, splicing and the binding of RNA-binding proteins. For these tests, we present a computationally efficient combination of the likelihood-ratio and score tests that found 36% more associations than the score test alone while also controlling the type-1 error. Kernel-based tests identified 13% more associations than their gene-based collapsing counterparts and had advantages in the presence of gain of function missense variants. We introduce local collapsing by amino acid position for missense variants and use it to interpret associations and identify potential novel gain of function variants in PIEZO1. Our results show the benefits of investigating different functional mechanisms when performing rare-variant association tests, and demonstrate pervasive rare-variant contribution to biomarker variability.
Keywords:Diagnostic Markers, Genome-Wide Association Studies, Sequence Annotation
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group
Volume:13
Number:1
Page Range:5332
Date:10 September 2022
Official Publication:https://doi.org/10.1038/s41467-022-32864-2
PubMed:View item in PubMed
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https://edoc.mdc-berlin.de/20319/Preprint version

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