Powerful and efficient SNP-set association tests across multiple phenotypes using GWAS summary data.

Motivation: Many GWAS conducted in the past decade have identified tens of thousands of disease related variants, which in total explained only part of the heritability for most traits. There remain many more genetics variants with small effect sizes to be discovered. This has motivated the development of sequencing studies with larger sample sizes and increased resolution of genotyped variants, e.g., the ongoing NHLBI Trans-Omics for Precision Medicine (TOPMed) whole genome sequencing project. An alternative approach is the development of novel and more powerful statistical methods. The current dominating approach in the field of GWAS analysis is the "single trait single variant" association test, despite the fact that most GWAS are conducted in deeply-phenotyped cohorts with many correlated traits measured. In this paper, we aim to develop rigorous methods that integrate multiple correlated traits and multiple variants to improve the power to detect novel variants. In recognition of the difficulty of accessing raw genotype and phenotype data due to privacy and logistic concerns, we develop methods that are applicable to publicly available GWAS summary data.

Results: We build rigorous statistical models for GWAS summary statistics to motivate novel multi-trait SNP-set association tests, including variance component test, burden test and their adaptive test, and develop efficient numerical algorithms to quickly compute their analytical p-values. We implement the proposed methods in an open source R package. We conduct thorough simulation studies to verify the proposed methods rigorously control type I errors at the genome-wide significance level, and further demonstrate their utility via comprehensive analysis of GWAS summary data for multiple lipids traits and glycemic traits. We identified many novel loci that were not detected by the individual trait based GWAS analysis.

Availability: We have implemented the proposed methods in an R package freely available at https://www.github.com/baolinwu/MSKAT.

Supplementary information: Supplementary materials provide more technical details and analysis results, and are available at Bioinformatics online.