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Nat Commun. 2013;4:2872. doi: 10.1038/ncomms3872.

A rare functional cardioprotective APOC3 variant has risen in frequency in distinct population isolates.

Author information

1
Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
2
Department of Dietetics-Nutrition, Harokopio, University of Athens, Athens 17671, Greece.
3
1] Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
4
1] Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, CB10 1SD, UK.
5
1] Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK [2] Department of Statistics, University of Oxford, Oxford OX1 3TG, UK.
6
Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201-1595, USA.
7
Anogia Medical Centre, Anogia 74051, Greece.
8
Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.

Abstract

Isolated populations can empower the identification of rare variation associated with complex traits through next generation association studies, but the generalizability of such findings remains unknown. Here we genotype 1,267 individuals from a Greek population isolate on the Illumina HumanExome Beadchip, in search of functional coding variants associated with lipids traits. We find genome-wide significant evidence for association between R19X, a functional variant in APOC3, with increased high-density lipoprotein and decreased triglycerides levels. Approximately 3.8% of individuals are heterozygous for this cardioprotective variant, which was previously thought to be private to the Amish founder population. R19X is rare (<0.05% frequency) in outbred European populations. The increased frequency of R19X enables discovery of this lipid traits signal at genome-wide significance in a small sample size. This work exemplifies the value of isolated populations in successfully detecting transferable rare variant associations of high medical relevance.

PMID:
24343240
PMCID:
PMC3905724
DOI:
10.1038/ncomms3872
[Indexed for MEDLINE]
Free PMC Article

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