Generating SNP Pairs for Interaction Testing

To generate SNP pairs for each gene, we first identified all common SNPs within the gene’s cis-regulatory region. To be considered common, variants had to have a MAF > 5% when all ethnicities were combined. Based on cis-eQTL analyses,²² the cis-regulatory region was defined as starting 500 kb upstream of the gene’s start and ending 500 kb downstream of the gene’s stop (including the gene itself); gene boundaries were taken from ENSEMBL. Previously, these variants were individually tested for association with the gene’s expression level in the discovery dataset by Veyrieras et al.²² Based on this analysis, we filtered out SNPs whose marginal effects were not nominally associated with gene expression (excluded p > 0.05), under the hypothesis that nominally associated variants may represent weak marginal effects from a true underlying interaction. We then considered all possible SNP pairs among the remaining variants. Once this was done for each gene, more than 21 million SNP pairs were generated for interaction testing.