A rare functional variant in APOC3 is associated with lipid traits and has risen in frequency in distinct population isolates. E. Zeggini1, G. Dedoussis2, L. Southam1,3, A.-E. Farmaki2, G. R. S. Ritchie1,4, D.-K. Xifara3,5, A. Matchan1, K. Hatzikotoulas1, N. W. Rayner3, Y. Chen1, C. Kiagiadaki6, K. Panoutsopoulou1, J. Schwartzentruber1, L. Moutsianas3, E. Tsafantakis6, C. Tyler-smith1, G. McVean3, Y. Xue1, I. Tachmazidou1, UK10K Consortium 1) Human Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridgeshire, United Kingdom; 2) Harokopio University Athens, Athens, Greece; 3) Wellcome Trust Centre for Human Genetics, Oxford, UK; 4) European Bioinformatics Institute, Hinxton, UK; 5) Department of Statistics, Oxford, UK; 6) Anogia Medical Centre, Anogia, Greece.

   Population isolates can enhance the power to detect association at low-frequency and rare sequence variation, because of potentially increased allele frequency and extended linkage disequilibrium. We have collected samples from two isolated populations in Greece (HELlenic Isolated Cohorts study, www.helic.org). All samples (n~3000) have information on a wide array of anthropometric, cardiometabolic, biochemical, haematological and diet-related traits. All individuals have been typed on the Illumina OmniExpress and HumanExome Beadchip platforms. In an analysis of HDL levels using exome chip data in 1256 individuals from the HELIC-MANOLIS study, we find striking evidence for association with common-frequency positive control variants in CETP (for example, rs1532624, p=1.1x10-11), the well-established HDL-associated locus. Despite the small sample size, we also find genome-wide significant evidence for association with a functional variant in APOC3 (rs76353203, R19X, p=4.6x10-9), which explains 2.9% of the trait variance. The T allele, which is the derived allele, changes an arginine residue into a stop codon in exon 2 of all 3 coding transcripts of the APOC3 gene. R19X is also significantly associated with decreased triglyceride levels (p=1.1x10-11) and explains 3.9% of trait variance. This cardioprotective effect is recapitulated in the strong association with high HDL as a dichotomised trait defined as >60mg/dl (p=4.3x10-10). We find that around 3.8% of samples are heterozygous for the mutation. Individuals with the R19X variant do not tend to be closely related, with 97.3% of carrier pairs having 10% of alleles identical by descent exome array-wide. R19X has previously been associated with HDL levels in the Amish founder population. The R19X minor allele is carried by 4 out of 3621 whole genome sequenced individuals in the UK10K study (MAF=0.05%). The increased frequency of R19X enables discovery of this signal at genome-wide significance in a small sample size. The sample size needed to detect the effect observed in HELIC at 80% power in an outbred European population is 67,000. APOC3 R19X constitutes the first known example of a clinically important variant that was previously thought to be private to a population but which has in fact drifted in frequency in two independent population isolates and is strongly associated with traits of high medical relevance.

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