TY  - GEN
A1  - Monti, Remo
A1  - Rautenstrauch, Pia
A1  - Ghanbari, Mahsa
A1  - Rani James, Alva
A1  - Kirchler, Matthias
A1  - Ohler, Uwe
A1  - Konigorski, Stefan
A1  - Lippert, Christoph
T1  - Identifying interpretable gene-biomarker associations with functionally informed kernel-based tests in 190,000 exomes
T2  - Zweitveröffentlichungen der Universität Potsdam : Reihe der Digital Engineering Fakultät
N2  - 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 mis- sense 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.
T3  - Zweitveröffentlichungen der Universität Potsdam : Reihe der Digital Engineering Fakultät - 16 
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:kobv:517-opus4-586078
IS  - 16
ER  - 
TY  - JOUR
A1  - Monti, Remo
A1  - Rautenstrauch, Pia
A1  - Ghanbari, Mahsa
A1  - Rani James, Alva
A1  - Kirchler, Matthias
A1  - Ohler, Uwe
A1  - Konigorski, Stefan
A1  - Lippert, Christoph
T1  - Identifying interpretable gene-biomarker associations with functionally informed kernel-based tests in 190,000 exomes
JF  - Nature Communications
N2  - 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 mis- sense 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.
Y1  - 2022
U6  - https://doi.org/10.1038/s41467-022-32864-2
SN  - 2041-1723
VL  - 13
PB  - Nature Publishing Group UK
CY  - London
ER  -