TY - JOUR A1 - Kirchler, Matthias A1 - Konigorski, Stefan A1 - Norden, Matthias A1 - Meltendorf, Christian A1 - Kloft, Marius A1 - Schurmann, Claudia A1 - Lippert, Christoph T1 - transferGWAS BT - GWAS of images using deep transfer learning JF - Bioinformatics N2 - Motivation: Medical images can provide rich information about diseases and their biology. However, investigating their association with genetic variation requires non-standard methods. We propose transferGWAS, a novel approach to perform genome-wide association studies directly on full medical images. First, we learn semantically meaningful representations of the images based on a transfer learning task, during which a deep neural network is trained on independent but similar data. Then, we perform genetic association tests with these representations. Results: We validate the type I error rates and power of transferGWAS in simulation studies of synthetic images. Then we apply transferGWAS in a genome-wide association study of retinal fundus images from the UK Biobank. This first-of-a-kind GWAS of full imaging data yielded 60 genomic regions associated with retinal fundus images, of which 7 are novel candidate loci for eye-related traits and diseases. Y1 - 2022 U6 - https://doi.org/10.1093/bioinformatics/btac369 SN - 1367-4803 SN - 1460-2059 VL - 38 IS - 14 SP - 3621 EP - 3628 PB - Oxford Univ. Press CY - Oxford ER - 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 -