Integrating molecular quantitative trait loci (xQTLs) into genome-wide association studies (GWAS) facilitates mechanistic interpretation of genetic associations for complex traits. The expanding volume and diversity of xQTL datasets, however, make effective integration challenging. Here, we introduce xMAGIC, a scalable method for integrating a vast number of multi-omic xQTL datasets across multiple contexts with GWAS. This is achieved by linking epigenetic marks to target genes and then combining all expression and epigenetic association signals for a gene into a single gene-trait association test. Applied to 45 human complex traits and 428 xQTL datasets, xMAGIC identified colocalized xQTLs and putative effector genes for 75.4% of GWAS loci. For example, at the VRK2 locus for major depressive disorder, xMAGIC identified the gene by synthesizing evidence from mQTLs across multiple tissues and a cell-type-specific eQTL in oligodendrocytes, demonstrating its strength in integrating diverse, context-dependent signals. An online platform implementing xMAGIC is available at https://yanglab.westlake.edu.cn/xMAGIC/.
 

xMAGIC, Multi-omics and cross-context, xQTL, putative effector genes