A rare variant in APOC3 is associated with plasma triglyceride and VLDL levels in Europeans.
Timpson NJ., Walter K., Min JL., Tachmazidou I., Malerba G., Shin SY., Chen L., Futema M., Southam L., Iotchkova V., Cocca M., Huang J., Memari Y., McCarthy S., Danecek P., Muddyman D., Mangino M., Menni C., Perry JR., Ring SM., Gaye A., Dedoussis G., Farmaki AE., Burton P., Talmud PJ., Gambaro G., Spector TD., Smith GD., Durbin R., Richards JB., Humphries SE., Zeggini E., Soranzo N., UK1OK Consortium Members None., UK1OK Consortium Members None.
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 ~0.25% (UK)) associated with plasma triglyceride (TG) levels (-1.43 s.d. (s.e.=0.27 per minor allele (P-value=8.0 × 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 × 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.