Knowledge-Driven Analysis Identifies a Gene–Gene Interaction Affecting High-Density Lipoprotein Cholesterol Levels in Multi-Ethnic Populations
A) Discovery in ARIC EA cohort by testing all possible pairs of SNPs among the 125 previously associated SNPs , for each of the four traits, showing deviation from expectation for two of them, and pointing in each of these two cases to a single pair of interacting SNPs (Table 1). B) Fine mapping in ARIC EA by testing all possible pairs of SNPs in the 100 kb surrounding rs12916 and rs1532085 that were found from panel A (HDL-C). C) Validation by testing SNP pairs surrounding rs3846662 and rs2043085 (found from panel B; see also Table 1) in four additional cohorts, each pointing to significant gene-gene interaction between the two regions. For all, stage (iii) of the adaptive locus-based validation procedure is shown, though replication has already been successful in stage (ii) in the MESA EA cohort.