Integrating multi-omics and multi-context QTL data with GWAS reveals the genetic architecture of complex traits and improves the discovery of risk genes.

Recent studies showed that expression QTLs, even from trait-related tissues, explained a small fraction of complex trait heritability. A natural strategy to close this gap is to incorporate molecular QTLs (molQTLs) beyond gene expression, across diverse tissue/cellular contexts. Yet, integrating such QTL data presents analytical challenges. Molecular traits often share QTLs or have QTLs in high LD, complicating the attribution of GWAS signals to specific molecular traits. Our simulations showed that commonly used colocalization and TWAS methods have highly inflated false positive rates in such settings. Building on our earlier work, we developed multigroup causal TWAS (M-cTWAS), for integrating QTLs of different modalities and contexts. M-cTWAS is able to estimate the contribution of each group of molQTLs to the trait heritability, and using such information, identifies the causal molecular traits, informing the modalities and contexts through which genetic variations act on the phenotype. M-cTWAS showed improved control of false discoveries than commonly used methods. Using M-cTWAS, we found that QTLs of multiple modalities greatly increased the explained heritability compared to using eQTLs alone, and enabled the discovery of many more risk genes of a range of complex traits. In conclusion, M-cTWAS effectively integrates diverse molecular QTLs with GWAS to enable causal gene discovery.