Multiple Causal Variants Underlie Genetic Associations in Humans [article]

Nathan S Abell, Marianne K DeGorter, Michael Gloudemans, Emily Greenwald, Kevin S Smith, Zihuai S He, Stephen B Montgomery
2021 bioRxiv   pre-print
The majority of associations between genetic variation and human traits and diseases are non-coding and in strong linkage disequilibrium (LD) with surrounding genetic variation. In these cases, a single causal variant is often assumed to underlie the association, however no systematic assessment of the number of causal variants has been performed. In this study, we applied a massively parallel reporter assay (MPRA) in lymphoblastoid cells to functionally evaluate 49,256 allelic pairs,
more » ... ng 30,893 genetic variants in high, local linkage disequilibrium for 744 independent cis-expression quantitative trait loci (eQTL) and assessed each for colocalization across 114 traits. We identified 3,536 allele-independent regulatory regions containing 907 allele-specific regulatory variants, and found that 17.3% of eQTL contained more than one significant allelic effect. We show that detected regulatory variants are highly and specifically enriched for activating chromatin structures and allelic transcription factor binding, for which ETS-domain family members are a large driver. Integration of MPRA profiles with eQTL/complex trait colocalizations identified causal variant sets for associations with blood cell measurements, Multiple Sclerosis, Irritable Bowel Disease, and Crohns Disease. These results demonstrate that a sizable number of association signals are manifest through multiple, tightly-linked causal variants requiring high-throughput functional assays for fine-mapping.
doi:10.1101/2021.05.24.445471 fatcat:wldjlmqwqrdilfks7niljv772i