Modeling tissue co-regulation estimates tissue-specific contributions to disease

Integrative analyses of genome-wide association studies and gene expression data have implicated many disease-critical tissues. However, co-regulation of genetic effects on gene expression across tissues impedes distinguishing biologically causal tissues from tagging tissues. In the present study, we introduce tissue co-regulation score regression (TCSC), which disentangles causal tissues from tagging tissues by regressing gene–disease association statistics (from transcriptome-wide association studies) on tissue co-regulation scores, reflecting correlations of predicted gene expression across genes and tissues. We applied TCSC to 78 diseases/traits (average n = 302,000) and gene expression prediction models for 48 GTEx tissues. TCSC identified 21 causal tissue–trait pairs at a 5% false discovery rate (FDR), including well-established findings, biologically plausible new findings (for example, aorta artery and glaucoma) and increased specificity of known tissue–trait associations (for example, subcutaneous adipose, but not visceral adipose, and high-density lipoprotein). TCSC also identified 17 causal tissue–trait covariance pairs at 5% FDR. In conclusion, TCSC is a precise method for distinguishing causal tissues from tagging tissues.