PT - JOURNAL ARTICLE AU - Guhan Ram Venkataraman AU - Christopher DeBoever AU - Yosuke Tanigawa AU - Matthew Aguirre AU - Alexander G. Ioannidis AU - Hakhamanesh Mostafavi AU - Chris C. A. Spencer AU - Timothy Poterba AU - Carlos D. Bustamante AU - Mark J. Daly AU - Matti Pirinen AU - Manuel A. Rivas TI - Bayesian model comparison for rare variant association studies AID - 10.1101/257162 DP - 2021 Jan 01 TA - bioRxiv PG - 257162 4099 - http://biorxiv.org/content/early/2021/07/24/257162.short 4100 - http://biorxiv.org/content/early/2021/07/24/257162.full AB - Whole genome sequencing studies applied to large populations or biobanks with extensive phenotyping raise new analytic challenges. The need to consider many variants at a locus or group of genes simultaneously and the potential to study many correlated phenotypes with shared genetic architecture provide opportunities for discovery and inference that are not addressed by the traditional one variant, one phenotype association study. Here, we introduce a Bayesian model comparison approach that we refer to as MRP (Multiple Rare-variants and Phenotypes) for rare-variant association studies that considers correlation, scale, and direction of genetic effects across a group of genetic variants, phenotypes, and studies. The approach requires only summary statistic data. To demonstrate the efficacy of MRP, we apply our method to exome sequencing data (N = 184,698) across 2,019 traits from the UK Biobank, aggregating signals in genes. MRP demonstrates an ability to recover previously-verified signals such as associations between PCSK9 and LDL cholesterol levels. We additionally find MRP effective in conducting meta-analyses in exome data. Notable non-biomarker findings include associations between MC1R and red hair color and skin color, IL17RA and monocyte count, IQGAP2 and mean platelet volume, and JAK2 and platelet count and crit (mass). Finally, we apply MRP in a multi-phenotype setting; after clustering the 35 biomarker phenotypes based on genetic correlation estimates into four clusters, we find that joint analysis of these phenotypes results in substantial power gains for gene-trait associations, such as in TNFRSF13B in one of the clusters containing diabetes and lipid-related traits. Overall, we show that the MRP model comparison approach is able to improve upon useful features from widely-used meta-analysis approaches for rare variant association analyses and prioritize protective modifiers of disease risk.Competing Interest StatementM.A.R. is on the SAB of 54Gene, Related Sciences and scientific founder of Broadwing Bio and has advised BioMarin, Third Rock Ventures and MazeTx. C.D.B. is the Owner and President of C.D.B. Consulting, LTD. and also a Director at EdenRoc Sciences, LLC and Etalon DX, founder of Arc Bio LLC (formerly IdentifyGenomics LLC and BigData Bio LLC), and an SAB member of Imprimed, FaunaBio, Columbia Care, and Digitalis Ventures. He is also a Venture Partner at F-Prime Capital Partners. M.J.D. is a founder of MazeTx.