Scalable mixed model approaches for set-based association studies on large-scale categorical data analysis and its application to 450k exome sequencing data in UK Biobank

The ongoing release of large-scale sequencing data in the UK Biobank allows for identifying associations between rare variants and complex traits. SAIGE-GENE+ is a valid approach to conducting set-based association tests for quantitative and binary traits. However, for ordinal categorical phenotypes, applying SAIGE-GENE+ with treating the trait as quantitative or binarizing the trait can cause inflated type I error rates or power loss. In this study, we propose a novel method for rare-variant association tests, POLMM-GENE, in which a proportional odds logistic mixed model was used to characterize ordinal categorical phenotypes while adjusting for sample relatedness. POLMM-GENE fully utilizes the categorical nature of phenotypes and thus can well control type I error rates while remaining powerful. In the analyses of UK Biobank 450k whole exome-sequencing data for 5 ordinal categorical traits, POLMM-GENE identified 54 gene-phenotype associations.