Interaction molecular QTL mapping discovers cellular and environmental modifiers of genetic regulatory effects.

Kasela S, Aguet F, Kim-Hellmuth S, Brown BC, Nachun DC, Tracy RP, Durda P, Liu Y, Taylor KD, Johnson WC, Van Den Berg D, Gabriel S, Gupta N, Smith JD, Blackwell TW, Rotter JI, Ardlie KG, Manichaikul A, Rich SS, Barr RG, Lappalainen T

Am. J. Hum. Genet. 111 (1) 133-149 [2024-01-04; online 2024-01-06]

Bulk-tissue molecular quantitative trait loci (QTLs) have been the starting point for interpreting disease-associated variants, and context-specific QTLs show particular relevance for disease. Here, we present the results of mapping interaction QTLs (iQTLs) for cell type, age, and other phenotypic variables in multi-omic, longitudinal data from the blood of individuals of diverse ancestries. By modeling the interaction between genotype and estimated cell-type proportions, we demonstrate that cell-type iQTLs could be considered as proxies for cell-type-specific QTL effects, particularly for the most abundant cell type in the tissue. The interpretation of age iQTLs, however, warrants caution because the moderation effect of age on the genotype and molecular phenotype association could be mediated by changes in cell-type composition. Finally, we show that cell-type iQTLs contribute to cell-type-specific enrichment of diseases that, in combination with additional functional data, could guide future functional studies. Overall, this study highlights the use of iQTLs to gain insights into the context specificity of regulatory effects.

PubMed 38181730

DOI 10.1016/j.ajhg.2023.11.013

Crossref 10.1016/j.ajhg.2023.11.013

pmc: PMC10806864
pii: S0002-9297(23)00431-7