Molecular quantitative trait loci

Understanding functional effects of genetic variants is one of the key challenges in human genetics, as much of disease-associated variation is located in non-coding regions with typically unknown putative gene regulatory effects. One of the most important approaches in this field has been molecular quantitative trait locus (molQTL) mapping, where genetic variation is associated with molecular traits that can be measured at scale, such as gene expression, splicing and chromatin accessibility. The maturity of the field and large-scale studies have produced a rich set of established methods for molQTL analysis, with novel technologies opening up new areas of discovery. In this Primer, we discuss the study design, input data and statistical methods for molQTL mapping and outline the properties of the resulting data as well as popular downstream applications. We review both the limitations and caveats of molQTL mapping as well as future potential approaches to tackle them. With technological development now providing many complementary methods for functional characterization of genetic variants, we anticipate that molQTLs will remain an important part of this toolkit as the only existing approach that can measure human variation in its native genomic, cellular and tissue context.