title: A rare functional cardioprotective APOC3 variant has risen in frequency in distinct population isolates.
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.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Ioanna
authors.initials: I
authors.lastname: Tachmazidou
authors.affiliation: Department of Dietetics-Nutrition, Harokopio, University of Athens, Athens 17671, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Dedoussis
authors.affiliation: 1] Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
authors.forename: Lorraine
authors.initials: L
authors.lastname: Southam
authors.affiliation: Department of Dietetics-Nutrition, Harokopio, University of Athens, Athens 17671, Greece.
authors.forename: Aliki-Eleni
authors.initials: AE
authors.lastname: Farmaki
authors.affiliation: 1] Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, CB10 1SD, UK.
authors.forename: Graham R S
authors.initials: GR
authors.lastname: Ritchie
authors.affiliation: 1] Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK [2] Department of Statistics, University of Oxford, Oxford OX1 3TG, UK.
authors.forename: Dionysia K
authors.initials: DK
authors.lastname: Xifara
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Matchan
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Hatzikotoulas
authors.affiliation: 1] Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK [2] Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
authors.forename: Nigel W
authors.initials: NW
authors.lastname: Rayner
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201-1595, USA.
authors.forename: Toni I
authors.initials: TI
authors.lastname: Pollin
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201-1595, USA.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: O'Connell
authors.affiliation: Division of Endocrinology, Diabetes, and Nutrition, University of Maryland School of Medicine, Baltimore, Maryland 21201-1595, USA.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Yerges-Armstrong
authors.affiliation: Anogia Medical Centre, Anogia 74051, Greece.
authors.forename: Chrysoula
authors.initials: C
authors.lastname: Kiagiadaki
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Kalliope
authors.initials: K
authors.lastname: Panoutsopoulou
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
authors.forename: Loukas
authors.initials: L
authors.lastname: Moutsianas
authors.affiliation: Anogia Medical Centre, Anogia 74051, Greece.
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Tsafantakis
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Tyler-Smith
authors.affiliation: Wellcome Trust Centre for Human Genetics, Oxford OX3 7BN, UK.
authors.forename: Gil
authors.initials: G
authors.lastname: McVean
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Yali
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053305:Apolipoprotein C-III / Q000235:genetics* / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control*; D005260:Female; D005787:Gene Frequency; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006115:Greece; D006239:Haplotypes; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000378:metabolism; D044465:White People / Q000235:genetics*
chemical_list: D053305:Apolipoprotein C-III; D008075:Lipoproteins, HDL; D014280:Triglycerides