A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans

The analysis of rich catalogues of genetic variation from population-based sequencing provides an opportunity to screen for functional effects. Here we report a rare variant in APOC3 (rs138326449-A, minor allele frequency similar to 0.25% (UK)) associated with plasma triglyceride (TG) levels (-1.43 s.d. (s.e. = 0.27 per minor allele (P-value = 8.0 x 10(-8))) discovered in 3,202 individuals with low read-depth, whole-genome sequence. We replicate this in 12,831 participants from five additional samples of Northern and Southern European origin (-1.0 s.d. (s.e. = 0.173), P-value = 7.32 x 10(-9)). This is consistent with an effect between 0.5 and 1.5 mmol l (-1) dependent on population. We show that a single predicted splice donor variant is responsible for association signals and is independent of known common variants. Analyses suggest an independent relationship between rs138326449 and high-density lipoprotein (HDL) levels. This represents one of the first examples of a rare, large effect variant identified from whole-genome sequencing at a population scale.