Mendelian randomization accounting for correlated and uncorrelated pleiotropic effects using genome-wide summary statistics

Mendelian randomization (MR) is a valuable tool for detecting causal effects using genetic variant associations. Opportunities to apply MR are growing rapidly with the number of genome-wide association studies (GWAS). However, existing MR methods rely on strong assumptions that are often violated, leading to false positives. Correlated horizontal pleiotropy, which arises when variants affect both traits through a heritable shared factor, remains a particularly challenging problem. We propose a new MR method, Causal Analysis Using Summary Effect Estimates (CAUSE), that accounts for correlated and uncorrelated horizontal pleiotropic effects. We demonstrate in simulations that CAUSE avoids more false positives induced by correlated horizontal pleiotropy than other methods. Applied to traits studied in recent GWAS, we find that CAUSE detects causal relationships with strong literature support and avoids identifying most unlikely relationships. Our results suggest that shared heritable factors are common and may lead to many false positives using alternative methods.