Trans-Ethnic Fine-Mapping of Lipid Loci Identifies Population-Specific Signals and Allelic Heterogeneity That Increases the Trait Variance Explained

Ying Wu, Lindsay L. Waite, Anne U. Jackson, Wayne H.H. Sheu, Steven Buyske, Devin Absher, Donna K. Arnett, Eric Boerwinkle, Lori L. Bonnycastle, Cara L. Carty, Iona Cheng, Barbara Cochran, Damien C. Croteau-Chonka, Logan Dumitrescu, Charles B. Eaton, Nora Franceschini, Xiuqing Guo, Brian E. Henderson, Lucia A. Hindorff, Eric KimLeena Kinnunen, Pirjo Komulainen, Wen Jane Lee, Loic Le Marchand, Yi Lin, Jaana Lindström, Oddgeir Lingaas-Holmen, Sabrina L. Mitchell, Narisu Narisu, Jennifer G. Robinson, Fred Schumacher, Alena Stančáková, Jouko Sundvall, Yun Ju Sung, Amy J. Swift, Wen Chang Wang, Lynne Wilkens, Tom Wilsgaard, Alicia M. Young, Linda S. Adair, Christie M. Ballantyne, Petra Bůžková, Aravinda Chakravarti, Francis S. Collins, David Duggan, Alan B. Feranil, Low Tone Ho, Yi Jen Hung, Steven C. Hunt, Kristian Hveem, Jyh Ming J. Juang, Antero Y. Kesäniemi, Johanna Kuusisto, Markku Laakso, Timo A. Lakka, I. Te Lee, Mark F. Leppert, Tara C. Matise, Leena Moilanen, Inger Njølstad, Ulrike Peters, Thomas Quertermous, Rainer Rauramaa, Jerome I. Rotter, Jouko Saramies, Jaakko Tuomilehto, Matti Uusitupa, Tzung Dau Wang, Michael Boehnke, Christopher A. Haiman, Yii Der I. Chen, Charles Kooperberg, Themistocles L. Assimes, Dana C. Crawford, Chao A. Hsiung, Kari E. North, Karen L. Mohlke

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere1003379
JournalPLoS genetics
Volume9
Issue number3
DOIs
StatePublished - 2013

ASJC Scopus subject areas

  • Ecology, Evolution, Behavior and Systematics
  • Molecular Biology
  • Genetics
  • Genetics(clinical)
  • Cancer Research

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    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., ... 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]. https://doi.org/10.1371/journal.pgen.1003379