With very large sample sizes, population-based cohorts and biobanks provide an exciting opportunity to identify genetic components of complex traits. To analyze rare variants, gene or region-based multiple variant aggregate tests are commonly used to increase association test power. However, due to the substantial computation cost, existing region-based rare variant tests cannot analyze hundreds of thousands of samples while accounting for confounders, such as population stratification and sample relatedness. Here we propose a scalable generalized mixed model region-based association test that can handle large sample sizes and accounts for unbalanced case-control ratios for binary traits. This method, SAIGE-GENE, utilizes state-of-the-art optimization strategies to reduce computational and memory cost, and hence is applicable to exome-wide and genome-wide region-based analysis for hundreds of thousands of samples. Through the analysis of the HUNT study of 69,716 Norwegian samples and the UK Biobank data of 408,910 White British samples, we show that SAIGE-GENE can efficiently analyze large sample data (N > 400,000) with type I error rates well controlled.

Scalable generalized linear mixed model for region-based association tests in large biobanks and cohorts