Cross-GWAS coherence test at the gene and pathway level.

Proximal genetic variants are frequently correlated, implying that the corresponding effect sizes detected by genome-wide association studies (GWAS) are also not independent. Methods already exist to account for this when aggregating effects from a single GWAS across genes or pathways. Here we present a rigorous yet fast method for detecting genes with coherent association signals for two traits, facilitating cross-GWAS analyses. To this end, we devised a new significance test for the covariance of datapoints not drawn independently but with a known inter-sample covariance structure. We show that the distribution of its test statistic is a linear combination of χ2 distributions with positive and negative coefficients. The corresponding cumulative distribution function can be efficiently calculated with Davies' algorithm at high precision. We apply this general framework to test for dependence between SNP-wise effect sizes of two GWAS at the gene level. We extend this test to detect also gene-wise causal links. We demonstrate the utility of our method by uncovering potential shared genetic links between the severity of COVID-19 and (1) being prescribed class M05B medication (drugs affecting bone structure and mineralization), (2) rheumatoid arthritis, (3) vitamin D (25OHD), and (4) serum calcium concentrations. Our method detects a potential role played by chemokine receptor genes linked to TH1 versus TH2 immune response, a gene related to integrin beta-1 cell surface expression, and other genes potentially impacting the severity of COVID-19. Our approach will be useful for similar analyses involving datapoints with known auto-correlation structures.