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

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.

transferGWAS: GWAS of images using deep transfer learning.

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. AVAILABILITY AND IMPLEMENTATION: Our method is implemented in Python and available at https://github.com/mkirchler/transferGWAS/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.