Fig. 7: Trimodal QTLs overlap variants associated with healthy and pathological traits.

A Pie chart showing the number of cQTLs intersecting GWAS loci through LD (light blue) or the same variant (dark blue). B Number of cQTLs in each of the GWAS trait categories from the Experimental Factor Ontology (EFO). C Example of a trimodal locus with evidence for causal mediation associated with a human trait: mean platelet volume. The forest plot on the left shows the result of the mediation analysis, summarising the three effects (ACME, ADE and Total Effect; (dot—mean effect, lines—95% bootstrap confidence intervals; non-significant if spanning 0; two-sided p values were computed using the non-parametric bootstrap procedure in the R package mediation¹⁵⁸). Since the ADE confidence interval spans 0 in this case, this is an example of full mediation. On the right, the locus plot at ABHD2 shows the intersection between the trimodal QTL locus and the GWAS locus for mean platelet volume (yellow highlighted region). The letters in circles represent the three modalities in the mediation model: SNPs/haplotype, i.e. the genetic variants in the GUESS set (treatment, X), the ATAC-seq signal (mediator, M) and chromatin contact with the eGene promoter (outcome, Y). ATAC-signal is shown as −log₁₀(p value) pileups determined by Genrich¹⁴⁰. D Evidence from Open Targets Genetics⁶² for eQTL signals for ABHD2 in monocytes colocalising with the GWAS signal for mean platelet volume⁶⁷. The H3 value shows the posterior probability of two different causal variants, and H4 is the posterior probability of one causal variant, with the log₂ ratio showing the posterior probability evidence for versus against shared causal variants. The final column shows the LD, as a measure of r², between the lead eQTL variant and the trimodal QTL, rs12438271. The locus plot in (C) was generated using the Plotgardener R package¹²⁵. Source data for A–C are available on OSF¹⁶⁸.