We next focused on the locus of ANGPTL3 (Figure 4A), another HLC eGene that did not independently qualify as an eGene in the GTEx liver cohort, although it qualified as an eGene in a cohort of ~1000 liver samples (Teslovich et al., 2010). In duplicate MPRA experiments, we profiled the regulatory activity of 210 variants linked (r2 ≥ 0.5) to the lead SNP at the locus (Table S9). The top MPRA SNP in the locus was rs10889356 (Figure 2C). In Europeans, rs10889356 is tightly linked to rs2131925 (r2 = 0.90), the lead SNP in the locus in the GLGC study, with each alternate allele copy of rs2131925 associated with a 4.9 mg/dL change in TG (Teslovich et al., 2010). ANGPTL3, which is generally believed to be the functional gene at this locus, encodes a liver-specific secreted protein that increases blood cholesterol and triglyceride levels in mice (Koishi et al., 2002) and in humans (Musunuru et al., 2010a). ANGPTL3 lies within an intron of DOCK7, a poorly understood non-liver-specific gene. As with the CPNE1/ERGIC3 locus, we used several complementary approaches to interrogate the relationship of rs10889356 with ANGPTL3 and DOCK7.
