Genetic determinants of lipid traits in diverse populations from the population Architecture using Genomics and Epidemiology (PAGE) study

Logan Dumitrescu, Cara L. Carty, Kira Taylor, Fredrick R. Schumacher, Lucia A. Hindorff, José L. Ambite, Garnet Anderson, Lyle G. Best, Kristin Brown-Gentry, Petra Bůžková, Christopher S. Carlson, Barbara Cochran, Shelley A. Cole, Richard B. Devereux, Dave Duggan, Charles B. Eaton, Myriam Fornage, Nora Franceschini, Jeff Haessler, Barbara V. Howard & 16 others Karen Johnson, Sandra Laston, Laurence N. Kolonel, Elisa T. Lee, Jean W. MacCluer, Teri A. Manolio, Sarah A. Pendergrass, Miguel Quibrera, Ralph V. Shohet, Lynne R. Wilkens, Christopher A. Haiman, Loïc Le Marchand, Steven Buyske, Charles Kooperberg, Kari E. North, Dana C. Crawford

Research output: Contribution to journalArticle

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Abstract

For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%,64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.

Original languageEnglish (US)
Article numbere1002138
JournalPLoS Genetics
Volume7
Issue number6
DOIs
StatePublished - Jun 1 2011

Fingerprint

epidemiology
Genomics
genomics
Epidemiology
high density lipoprotein cholesterol
lipid
HDL Cholesterol
Genome-Wide Association Study
Lipids
low density lipoprotein cholesterol
LDL Cholesterol
Mexican Americans
Single Nucleotide Polymorphism
lipids
North American Indians
American Indians
Population
triacylglycerols
African Americans
Hispanic Americans

All Science Journal Classification (ASJC) codes

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

Cite this

Dumitrescu, L., Carty, C. L., Taylor, K., Schumacher, F. R., Hindorff, L. A., Ambite, J. L., ... Crawford, D. C. (2011). Genetic determinants of lipid traits in diverse populations from the population Architecture using Genomics and Epidemiology (PAGE) study. PLoS Genetics, 7(6), [e1002138]. https://doi.org/10.1371/journal.pgen.1002138

Genetic determinants of lipid traits in diverse populations from the population Architecture using Genomics and Epidemiology (PAGE) study. / Dumitrescu, Logan; Carty, Cara L.; Taylor, Kira; Schumacher, Fredrick R.; Hindorff, Lucia A.; Ambite, José L.; Anderson, Garnet; Best, Lyle G.; Brown-Gentry, Kristin; Bůžková, Petra; Carlson, Christopher S.; Cochran, Barbara; Cole, Shelley A.; Devereux, Richard B.; Duggan, Dave; Eaton, Charles B.; Fornage, Myriam; Franceschini, Nora; Haessler, Jeff; Howard, Barbara V.; Johnson, Karen; Laston, Sandra; Kolonel, Laurence N.; Lee, Elisa T.; MacCluer, Jean W.; Manolio, Teri A.; Pendergrass, Sarah A.; Quibrera, Miguel; Shohet, Ralph V.; Wilkens, Lynne R.; Haiman, Christopher A.; Le Marchand, Loïc; Buyske, Steven; Kooperberg, Charles; North, Kari E.; Crawford, Dana C.

In: PLoS Genetics, Vol. 7, No. 6, e1002138, 01.06.2011.

Research output: Contribution to journalArticle

Dumitrescu, L, Carty, CL, Taylor, K, Schumacher, FR, Hindorff, LA, Ambite, JL, Anderson, G, Best, LG, Brown-Gentry, K, Bůžková, P, Carlson, CS, Cochran, B, Cole, SA, Devereux, RB, Duggan, D, Eaton, CB, Fornage, M, Franceschini, N, Haessler, J, Howard, BV, Johnson, K, Laston, S, Kolonel, LN, Lee, ET, MacCluer, JW, Manolio, TA, Pendergrass, SA, Quibrera, M, Shohet, RV, Wilkens, LR, Haiman, CA, Le Marchand, L, Buyske, S, Kooperberg, C, North, KE & Crawford, DC 2011, 'Genetic determinants of lipid traits in diverse populations from the population Architecture using Genomics and Epidemiology (PAGE) study', PLoS Genetics, vol. 7, no. 6, e1002138. https://doi.org/10.1371/journal.pgen.1002138
Dumitrescu, Logan ; Carty, Cara L. ; Taylor, Kira ; Schumacher, Fredrick R. ; Hindorff, Lucia A. ; Ambite, José L. ; Anderson, Garnet ; Best, Lyle G. ; Brown-Gentry, Kristin ; Bůžková, Petra ; Carlson, Christopher S. ; Cochran, Barbara ; Cole, Shelley A. ; Devereux, Richard B. ; Duggan, Dave ; Eaton, Charles B. ; Fornage, Myriam ; Franceschini, Nora ; Haessler, Jeff ; Howard, Barbara V. ; Johnson, Karen ; Laston, Sandra ; Kolonel, Laurence N. ; Lee, Elisa T. ; MacCluer, Jean W. ; Manolio, Teri A. ; Pendergrass, Sarah A. ; Quibrera, Miguel ; Shohet, Ralph V. ; Wilkens, Lynne R. ; Haiman, Christopher A. ; Le Marchand, Loïc ; Buyske, Steven ; Kooperberg, Charles ; North, Kari E. ; Crawford, Dana C. / Genetic determinants of lipid traits in diverse populations from the population Architecture using Genomics and Epidemiology (PAGE) study. In: PLoS Genetics. 2011 ; Vol. 7, No. 6.
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abstract = "For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92{\%}) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48{\%}, 61{\%}, and 57{\%}), American Indians (45{\%},64{\%}, and 77{\%}), and Mexican Americans/Hispanics (57{\%}, 56{\%}, and 86{\%}). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.",
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T1 - Genetic determinants of lipid traits in diverse populations from the population Architecture using Genomics and Epidemiology (PAGE) study

AU - Dumitrescu, Logan

AU - Carty, Cara L.

AU - Taylor, Kira

AU - Schumacher, Fredrick R.

AU - Hindorff, Lucia A.

AU - Ambite, José L.

AU - Anderson, Garnet

AU - Best, Lyle G.

AU - Brown-Gentry, Kristin

AU - Bůžková, Petra

AU - Carlson, Christopher S.

AU - Cochran, Barbara

AU - Cole, Shelley A.

AU - Devereux, Richard B.

AU - Duggan, Dave

AU - Eaton, Charles B.

AU - Fornage, Myriam

AU - Franceschini, Nora

AU - Haessler, Jeff

AU - Howard, Barbara V.

AU - Johnson, Karen

AU - Laston, Sandra

AU - Kolonel, Laurence N.

AU - Lee, Elisa T.

AU - MacCluer, Jean W.

AU - Manolio, Teri A.

AU - Pendergrass, Sarah A.

AU - Quibrera, Miguel

AU - Shohet, Ralph V.

AU - Wilkens, Lynne R.

AU - Haiman, Christopher A.

AU - Le Marchand, Loïc

AU - Buyske, Steven

AU - Kooperberg, Charles

AU - North, Kari E.

AU - Crawford, Dana C.

PY - 2011/6/1

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N2 - For the past five years, genome-wide association studies (GWAS) have identified hundreds of common variants associated with human diseases and traits, including high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglyceride (TG) levels. Approximately 95 loci associated with lipid levels have been identified primarily among populations of European ancestry. The Population Architecture using Genomics and Epidemiology (PAGE) study was established in 2008 to characterize GWAS-identified variants in diverse population-based studies. We genotyped 49 GWAS-identified SNPs associated with one or more lipid traits in at least two PAGE studies and across six racial/ethnic groups. We performed a meta-analysis testing for SNP associations with fasting HDL-C, LDL-C, and ln(TG) levels in self-identified European American (~20,000), African American (~9,000), American Indian (~6,000), Mexican American/Hispanic (~2,500), Japanese/East Asian (~690), and Pacific Islander/Native Hawaiian (~175) adults, regardless of lipid-lowering medication use. We replicated 55 of 60 (92%) SNP associations tested in European Americans at p<0.05. Despite sufficient power, we were unable to replicate ABCA1 rs4149268 and rs1883025, CETP rs1864163, and TTC39B rs471364 previously associated with HDL-C and MAFB rs6102059 previously associated with LDL-C. Based on significance (p<0.05) and consistent direction of effect, a majority of replicated genotype-phentoype associations for HDL-C, LDL-C, and ln(TG) in European Americans generalized to African Americans (48%, 61%, and 57%), American Indians (45%,64%, and 77%), and Mexican Americans/Hispanics (57%, 56%, and 86%). Overall, 16 associations generalized across all three populations. For the associations that did not generalize, differences in effect sizes, allele frequencies, and linkage disequilibrium offer clues to the next generation of association studies for these traits.

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