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Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.

Publication ,  Journal Article
Wu, Y; Waite, LL; Jackson, AU; Sheu, WH-H; Buyske, S; Absher, D; Arnett, DK; Boerwinkle, E; Bonnycastle, LL; Carty, CL; Cheng, I; Cochran, B ...
Published in: PLoS Genet
March 2013

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.

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Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

March 2013

Volume

9

Issue

3

Start / End Page

e1003379

Location

United States

Related Subject Headings

  • White People
  • Triglycerides
  • Serine Endopeptidases
  • Proprotein Convertases
  • Proprotein Convertase 9
  • Lipoproteins, LDL
  • Lipoproteins, HDL
  • Humans
  • Genome-Wide Association Study
  • Developmental Biology
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Wu, Y., Waite, L. L., Jackson, A. U., Sheu, W.-H., Buyske, S., Absher, D., … 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 Genet, 9(3), e1003379. https://doi.org/10.1371/journal.pgen.1003379
Wu, Ying, Lindsay L. Waite, Anne U. Jackson, Wayne H-H Sheu, Steven Buyske, Devin Absher, Donna K. Arnett, et al. “Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.PLoS Genet 9, no. 3 (March 2013): e1003379. https://doi.org/10.1371/journal.pgen.1003379.
Wu Y, Waite LL, Jackson AU, Sheu WH-H, Buyske S, Absher D, et al. Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained. PLoS Genet. 2013 Mar;9(3):e1003379.
Wu, Ying, et al. “Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.PLoS Genet, vol. 9, no. 3, Mar. 2013, p. e1003379. Pubmed, doi:10.1371/journal.pgen.1003379.
Wu Y, Waite LL, Jackson AU, Sheu WH-H, Buyske S, Absher D, Arnett DK, Boerwinkle E, Bonnycastle LL, Carty CL, Cheng I, Cochran B, Croteau-Chonka DC, Dumitrescu L, Eaton CB, Franceschini N, Guo X, Henderson BE, Hindorff LA, Kim E, Kinnunen L, Komulainen P, Lee W-J, Le Marchand L, Lin Y, Lindström J, Lingaas-Holmen O, Mitchell SL, Narisu N, Robinson JG, Schumacher F, Stančáková A, Sundvall J, Sung Y-J, Swift AJ, Wang W-C, Wilkens L, Wilsgaard T, Young AM, Adair LS, Ballantyne CM, Bůžková P, Chakravarti A, Collins FS, Duggan D, Feranil AB, Ho L-T, Hung Y-J, Hunt SC, Hveem K, Juang J-MJ, Kesäniemi AY, Kuusisto J, Laakso M, Lakka TA, Lee I-T, Leppert MF, Matise TC, Moilanen L, Njølstad I, Peters U, Quertermous T, Rauramaa R, Rotter JI, Saramies J, Tuomilehto J, Uusitupa M, Wang T-D, Boehnke M, Haiman CA, Chen Y-DI, Kooperberg C, Assimes TL, Crawford DC, Hsiung CA, North KE, Mohlke KL. Trans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained. PLoS Genet. 2013 Mar;9(3):e1003379.

Published In

PLoS Genet

DOI

EISSN

1553-7404

Publication Date

March 2013

Volume

9

Issue

3

Start / End Page

e1003379

Location

United States

Related Subject Headings

  • White People
  • Triglycerides
  • Serine Endopeptidases
  • Proprotein Convertases
  • Proprotein Convertase 9
  • Lipoproteins, LDL
  • Lipoproteins, HDL
  • Humans
  • Genome-Wide Association Study
  • Developmental Biology