Very low-depth sequencing in a founder population identifies a cardioprotective APOC3 signal missed by genome-wide imputation

Cohort-wide very low-depth whole-genome sequencing (WGS) can comprehensively capture low-frequency sequence variation for the cost of a dense genome-wide genotyping array. Here, we analyse 1x sequence data across the APOC3 gene in a founder population from the island of Crete in Greece (n=1239) and find significant evidence for association with blood triglyceride levels with the previously reported R19X cardioprotective null mutation (β=-1.09, r=0.163, P=8.2 x 10^-11) and a second loss of function mutation, rs138326449 (β=-1.17,σ=0.188, P=1.14 x 10^-9). The signal cannot be recapitulated by imputing genome-wide genotype data on a large reference panel of 5122 individuals including 249 with 4x WGS data from the same population. Gene-level meta-analysis with other studies reporting burden signals at APOC3 provides robust evidence for a replicable cardioprotective rare variant aggregation (P=3.2 x 10^-31, n=13 480).