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Title: Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained
Authors: Wu Y.
Waite L.L.
Jackson A.U.
Sheu W.-H.H.
Buyske S.
Absher D.
Arnett D.K.
Boerwinkle E.
Bonnycastle L.L.
Carty C.L.
Cheng I.
Cochran B.
Croteau-Chonka D.C.
Dumitrescu L.
Eaton C.B.
Franceschini N.
Guo X.
Henderson B.E.
Hindorff L.A.
Kim E.
Kinnunen L.
Komulainen P.
Lee W.-J.
Le Marchand L.
Lin Y.
Lindström J.
Lingaas-Holmen O.
Mitchell S.L.
Narisu N.
Robinson J.G.
Schumacher F.
Stančáková A.
Sundvall J.
Sung Y.-J.
Swift A.J.
Wang W.-C.
Wilkens L.
Wilsgaard T.
Young A.M.
Adair L.S.
Ballantyne C.M.
Bůžková P.
Chakravarti A.
Collins F.S.
Duggan D.
Feranil A.B.
Ho L.-T.
Hung Y.-J.
Hunt S.C.
Hveem K.
Juang J.-M.J.
Kesäniemi A.Y.
Kuusisto J.
Laakso M.
Lakka T.A.
Lee I.-T.
Leppert M.F.
Matise T.C.
Moilanen L.
Njølstad I.
Peters U.
Quertermous T.
Rauramaa R.
Rotter J.I.
Saramies J.
Tuomilehto J.
Uusitupa M.
Wang T.-D.
Boehnke M.
Haiman C.A.
Chen Y.-D.I.
Kooperberg C.
Assimes T.L.
Crawford D.C.
Hsiung C.A.
North K.E.
Mohlke K.L.
Keywords: high density lipoprotein cholesterol
low density lipoprotein cholesterol
ABCA1 gene
ABO gene
African American
APOA5 gene
controlled study
GCKR gene
gene locus
gene mapping
genetic association
genetic heterogeneity
genetic trait
Lcat gene
lipid blood level
PCSK9 gene
population genetics
PPP1R3B gene
single nucleotide polymorphism
African Americans
Apolipoproteins A
Cholesterol, HDL
Cholesterol, LDL
European Continental Ancestry Group
Genome-Wide Association Study
Lipoproteins, HDL
Lipoproteins, LDL
Proprotein Convertases
Serine Endopeptidases
Issue Date: 2013
Publisher: Public Library of Science
Citation: Wu Y., Waite L.L., Jackson A.U., Sheu W.-H.H., Buyske S., Absher D., Arnett D.K., Boerwinkle E., Bonnycastle L.L., Carty C.L., Cheng I., Cochran B., Croteau-Chonka D.C., Dumitrescu L., Eaton C.B., Franceschini N., Guo X., Henderson B.E., Hindorff L.A., Kim E., Kinnunen L., Komulainen P., Lee W.-J., Le Marchand L., Lin Y., Lindström J., Lingaas-Holmen O., Mitchell S.L., Narisu N., Robinson J.G., Schumacher F., Stančáková A., Sundvall J., Sung Y.-J., Swift A.J., Wang W.-C., Wilkens L., Wilsgaard T., Young A.M., Adair L.S., Ballantyne C.M., Bůžková P., Chakravarti A., Collins F.S., Duggan D., Feranil A.B., Ho L.-T., Hung Y.-J., Hunt S.C., Hveem K., Juang J.-M.J., Kesäniemi A.Y., Kuusisto J., Laakso M., Lakka T.A., Lee I.-T., Leppert M.F., Matise T.C., Moilanen L., Njølstad I., Peters U., Quertermous T., Rauramaa R., Rotter J.I., Saramies J., Tuomilehto J., Uusitupa M., Wang T.-D., Boehnke M., Haiman C.A., Chen Y.-D.I., Kooperberg C., Assimes T.L., Crawford D.C., Hsiung C.A., North K.E., Mohlke K.L. (2013). Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained. PLoS Genetics 9 (3) : e1003379. ScholarBank@NUS Repository.
Abstract: Genome-wide association studies (GWAS) have identified ~100 loci associated with blood lipid levels, but much of the trait heritability remains unexplained, and at most loci the identities of the trait-influencing variants remain unknown. We conducted a trans-ethnic fine-mapping study at 18, 22, and 18 GWAS loci on the Metabochip for their association with triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C), respectively, in individuals of African American (n = 6,832), East Asian (n = 9,449), and European (n = 10,829) ancestry. We aimed to identify the variants with strongest association at each locus, identify additional and population-specific signals, refine association signals, and assess the relative significance of previously described functional variants. Among the 58 loci, 33 exhibited evidence of association at P<1?10-4 in at least one ancestry group. Sequential conditional analyses revealed that ten, nine, and four loci in African Americans, Europeans, and East Asians, respectively, exhibited two or more signals. At these loci, accounting for all signals led to a 1.3- to 1.8-fold increase in the explained phenotypic variance compared to the strongest signals. Distinct signals across ancestry groups were identified at PCSK9 and APOA5. Trans-ethnic analyses narrowed the signals to smaller sets of variants at GCKR, PPP1R3B, ABO, LCAT, and ABCA1. Of 27 variants reported previously to have functional effects, 74% exhibited the strongest association at the respective signal. In conclusion, trans-ethnic high-density genotyping and analysis confirm the presence of allelic heterogeneity, allow the identification of population-specific variants, and limit the number of candidate SNPs for functional studies.
Source Title: PLoS Genetics
ISSN: 15537390
DOI: 10.1371/journal.pgen.1003379
Appears in Collections:Staff Publications

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