Stratified Linkage Disequilibrium Score Regression reveals enrichment of eQTL effects on complex traits is not tissue specific

Both gene expression levels and eQTLs (expression quantitative trait loci) are partially tissue-specific, complicating the detection of eQTLs in tissues with limited sample availability, such as the brain. However, eQTL overlap between tissues might be non-trivial, allowing for inference of eQTL functioning in the brain via eQTLs measured in readily accessible tissues, e.g. whole blood. Using Stratified Linkage Disequilibrium Score Regression (SLDSR), we quantify the enrichment in GWAS signal of blood and brain eQTLs in genome-wide association study (GWAS) on 11 complex traits (schizophrenia, BMI, educational attainment, Crohns disease, rheumatoid arthritis, ulcerative colitis, age at menarche, coronary artery disease, height, LDL levels, and smoking behavior). Our analyses established significant enrichment of blood and brain eQTLs in their effects across all traits. As we do not know the true number of causal eQTLs, it is difficult to determine the precise magnitude of enrichment. We found no evidence for tissue-specific enrichment in GWAS signal for either eQTLs uniquely seen in the brain or whole blood. To follow up on our findings, we tested tissue-specific enrichment of eQTLs discovered in 44 tissues by the Genotype-Tissue Expression (GTEx) consortium, and, again, found no tissue-specific eQTL effects. We further integrated the GTEx eQTLs with SNPs associated with tissue-specific histone modifiers, and interrogate its effect on rheumatoid arthritis and schizophrenia. We observed substantially enriched effects on schizophrenia, though again not tissue-specific. Finally, we extracted eQTLs in tissue-specific differentially expressed genes, and determined their effects on rheumatoid arthritis and schizophrenia. We conclude that, while eQTLs are strongly enriched in GWAS signal, the enrichment is not specific to the tissue used in eQTL discovery. Therefore, working with relatively accessible tissues, such as whole blood, as proxy for eQTL discovery is sensible; and restricting lookups for GWAS hits to a specific tissue might not be advisable.