Conditional analysis of multiple quantitative traits based on marginal GWAS summary statistics

ABSTRACT There has been an increasing interest in joint association testing of multiple traits for possible pleiotropic effects. However, even in the presence of pleiotropy, most of the existing methods cannot distinguish direct and indirect effects of a genetic variant, say single‐nucleotide polymorphism (SNP), on multiple traits, and a conditional analysis of a trait adjusting for other traits is perhaps the simplest and most common approach to addressing this question. However, without individual‐level genotypic and phenotypic data but with only genome‐wide association study (GWAS) summary statistics, as typical with most large‐scale GWAS consortium studies, we are not aware of any existing method for such a conditional analysis. We propose such a conditional analysis, offering formulas of necessary calculations to fit a joint linear regression model for multiple quantitative traits. Furthermore, our method can also accommodate conditional analysis on multiple SNPs in addition to on multiple quantitative traits, which is expected to be useful for fine mapping. We provide numerical examples based on both simulated and real GWAS data to demonstrate the effectiveness of our proposed approach, and illustrate possible usefulness of conditional analysis by contrasting its result differences from those of standard marginal analyses.