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

Monday,2015-03-09 16:28 America/Los_Angeles — zdrager
TitleTrans-ethnic fine-mapping of lipid loci identifies population-specific signals and allelic heterogeneity that increases the trait variance explained.
Publication TypeJournal Article
Year of Publication2013
AuthorsWu, 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, Bůzková, 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-derI, Kooperberg, C, Assimes, TL, Crawford, DC, Hsiung, CA, North, KE, Mohlke, KL
JournalPLoS Genet
Volume9
Issue3
Paginatione1003379
Date Published2013 Mar
ISSN1553-7404
KeywordsAfrican Americans, Apolipoproteins A, Cholesterol, HDL, Cholesterol, LDL, European Continental Ancestry Group, Genome-Wide Association Study, Humans, Lipoproteins, HDL, Lipoproteins, LDL, Proprotein Convertases, Serine Endopeptidases, Triglycerides
Abstract<p>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.</p>
DOI10.1371/journal.pgen.1003379
Alternate JournalPLoS Genet.
PubMed ID23555291
PubMed Central IDPMC3605054
Grant List1Z01-HG000024 / HG / NHGRI NIH HHS / United States
2 R01 HL55673-12 / HL / NHLBI NIH HHS / United States
24152 / / PHS HHS / United States
32100-2 / / PHS HHS / United States
32105-6 / / PHS HHS / United States
32108-9 / / PHS HHS / United States
32111-13 / / PHS HHS / United States
32115 / / PHS HHS / United States
32118-32119 / / PHS HHS / United States
32122 / / PHS HHS / United States
42107-26 / / PHS HHS / United States
42129-32 / / PHS HHS / United States
44221 / / PHS HHS / United States
DK062370 / DK / NIDDK NIH HHS / United States
DK072193 / DK / NIDDK NIH HHS / United States
DK078150 / DK / NIDDK NIH HHS / United States
DK093757 / DK / NIDDK NIH HHS / United States
DK56350 / DK / NIDDK NIH HHS / United States
ES10126 / ES / NIEHS NIH HHS / United States
HL085144 / HL / NHLBI NIH HHS / United States
HL087647 / HL / NHLBI NIH HHS / United States
HL54471 / HL / NHLBI NIH HHS / United States
HL54472 / HL / NHLBI NIH HHS / United States
HL54473 / HL / NHLBI NIH HHS / United States
HL54495 / HL / NHLBI NIH HHS / United States
HL54496 / HL / NHLBI NIH HHS / United States
HL54497 / HL / NHLBI NIH HHS / United States
HL54509 / HL / NHLBI NIH HHS / United States
HL54515 / HL / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01WH22110 / WH / WHI NIH HHS / United States
P01CA33619 / CA / NCI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
P30 ES010126 / ES / NIEHS NIH HHS / United States
R01 CA63 / CA / NCI NIH HHS / United States
R01 DK072193 / DK / NIDDK NIH HHS / United States
R01 DK093757 / DK / NIDDK NIH HHS / United States
R01 HG000376 / HG / NHGRI NIH HHS / United States
R24 HD050924 / HD / NICHD NIH HHS / United States
R37CA54281 / CA / NCI NIH HHS / United States
RR20649 / RR / NCRR NIH HHS / United States
T32 GM007092 / GM / NIGMS NIH HHS / United States
TW05596 / TW / FIC NIH HHS / United States
U01 HG004790 / HG / NHGRI NIH HHS / United States
U01CA136792 / CA / NCI NIH HHS / United States
U01CA98758 / CA / NCI NIH HHS / United States
U01HG004790 / HG / NHGRI NIH HHS / United States
U01HG004798 / HG / NHGRI NIH HHS / United States
U01HG004801 / HG / NHGRI NIH HHS / United States
U01HG004801-01 / HG / NHGRI NIH HHS / United States
U01HG004802 / HG / NHGRI NIH HHS / United States
U01HG004803 / HG / NHGRI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States

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