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, = 0.163, P = 8.2 x 10–11) and a second loss of function mutation, rs138326449 (β = –1.17, = 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).

Source: Human Molecular Genetics - October 23, 2016 Category: Genetics & Stem Cells Authors: Gilly, A., Ritchie, G. R., Southam, L., Farmaki, A.-E., Tsafantakis, E., Dedoussis, G., Zeggini, E. Tags: ASSOCIATION STUDIES ARTICLES Source Type: research