Functional validation at TENM2. (A) Coordinated peaks at TENM2 with driver caPeak273749 (purple arrow) and two promoter peaks for TENM2 (orange arrows). Read depth–normalized ATAC signal tracks averaged by genotype for rs7726117, which is the lead variant in the 1 kb and 1 Mb caQTL analyses. (B) Colocalized GWAS (GGT), eQTL (TENM2), and caQTL (caPeak273749) associations. The caQTL lead variant (rs7726117) is indicated in each plot by a purple diamond, and colors represent LD r2 values from 1000G Europeans. (C) Correlation of driver peak counts with counts of two TENM2 promoter peaks: peak273726 (the 5′-most promoter) and peak273774 (the more-downstream promoter). Points are colored by the genotype of rs7726117. Peak counts were normalized by the covariates used for caQTL mapping: sex, two genotype PCs, and 25 ATAC PCs. (D) Transcriptional activity in HepG2 cells of a 329 bp DNA element spanning caPeak273749 and containing rs7726117. The DNA element was tested in both orientations relative to the genome. (EV) Empty vector. Symbols represent two independently transfected wells for each of four independent clones for each allele; bars indicate mean and standard deviation; P-values are from t-tests of allelic differences. (E) Predicted mechanism at the TENM2 locus. The rs7726117-A allele shows higher transcriptional activity and is associated with greater liver chromatin accessibility, higher liver expression of TENM2, and lower plasma levels of gamma-glutamyltransferase.
