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


ABSTRACT: 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.

SUBMITTER: Timpson NJ 

PROVIDER: S-EPMC4167609 | biostudies-literature | 2014 Sep

REPOSITORIES: biostudies-literature

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

Timpson Nicholas J NJ   Walter Klaudia K   Min Josine L JL   Tachmazidou Ioanna I   Malerba Giovanni G   Shin So-Youn SY   Chen Lu L   Futema Marta M   Southam Lorraine L   Iotchkova Valentina V   Cocca Massimiliano M   Huang Jie J   Memari Yasin Y   McCarthy Shane S   Danecek Petr P   Muddyman Dawn D   Mangino Massimo M   Menni Cristina C   Perry John R B JR   Ring Susan M SM   Gaye Amadou A   Dedoussis George G   Farmaki Aliki-Eleni AE   Burton Paul P   Talmud Philippa J PJ   Gambaro Giovanni G   Spector Tim D TD   Smith George Davey GD   Durbin Richard R   Richards J Brent JB   Humphries Steve E SE   Zeggini Eleftheria E   Soranzo Nicole N  

Nature communications 20140916


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 Nort  ...[more]

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