Transferability and Fine Mapping of genome-wide associated loci for lipids in African Americans

BMC Medical Genetics

Charles N Rotimi³  Michael F Christman²  Norman P Gerry²  Alan Herbert¹  Hanxia Huang³  Daniel Shriner³  Jie Zhou³  Guanjie Chen³  Ayo P Doumatey³  Katherine G Meilleur⁴  Amy R Bentley³  Adebowale Adeyemo³ 

[1] Department of Genetics and Genomics, Boston University, Boston, MA, USA;Coriell Institute for Medical Research, Camden, NJ, USA;Center for Research on Genomics and Global Health, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA;National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, USA

关键词: Ethnicity;    Genome-wide association study;    African Americans;    Genetics;    Lipids;   

Others  :  1177794
DOI  :  10.1186/1471-2350-13-88

 received in 2012-03-05, accepted in 2012-09-11,  发布年份 2012

【 摘 要 】

Background

A recent, large genome-wide association study (GWAS) of European ancestry individuals has identified multiple genetic variants influencing serum lipids. Studies of the transferability of these associations to African Americans remain few, an important limitation given interethnic differences in serum lipids and the disproportionate burden of lipid-associated metabolic diseases among African Americans.

Methods

We attempted to evaluate the transferability of 95 lipid-associated loci recently identified in European ancestry individuals to 887 non-diabetic, unrelated African Americans from a population-based sample in the Washington, DC area. Additionally, we took advantage of the generally reduced linkage disequilibrium among African ancestry populations in comparison to European ancestry populations to fine-map replicated GWAS signals.

Results

We successfully replicated reported associations for 10 loci (CILP2/SF4, STARD3, LPL, CYP7A1, DOCK7/ANGPTL3, APOE, SORT1, IRS1, CETP, and UBASH3B). Through trans-ethnic fine-mapping, we were able to reduce associated regions around 75% of the loci that replicated.

Conclusions

Between this study and previous work in African Americans, 40 of the 95 loci reported in a large GWAS of European ancestry individuals also influence lipid levels in African Americans. While there is now evidence that the lipid-influencing role of a number of genetic variants is observed in both European and African ancestry populations, the still considerable lack of concordance highlights the importance of continued ancestry-specific studies to elucidate the genetic underpinnings of these traits.

【 授权许可】

   
2012 Adeyemo et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Teslovich TM, Musunuru K, Smith AV, Edmondson AC, Stylianou IM, Koseki M, Pirruccello JP, Ripatti S, Chasman DI, Willer CJ, et al.: Biological, clinical and population relevance of 95 loci for blood lipids. Nature 2010, 466(7307):707-713.
• [2]Gu Q, Burt VL, Paulose-Ram R, Yoon S, Gillum RF: High blood pressure and cardiovascular disease mortality risk among U.S. adults: the third National Health and Nutrition Examination Survey mortality follow-up study. Ann Epidemiol 2008, 18(4):302-309.
• [3]Hurley LP, Dickinson LM, Estacio RO, Steiner JF, Havranek EP: Prediction of cardiovascular death in racial/ethnic minorities using Framingham risk factors. Circ Cardiovasc Qual Outcomes 2010, 3(2):181-187.
• [4]Cowie CC, Rust KF, Byrd-Holt DD, Eberhardt MS, Flegal KM, Engelgau MM, Saydah SH, Williams DE, Geiss LS, Gregg EW: Prevalence of diabetes and impaired fasting glucose in adults in the U.S. population: National Health And Nutrition Examination Survey 1999–2002. Diabetes Care 2006, 29(6):1263-1268.
• [5]Heidenreich PA, Trogdon JG, Khavjou OA, Butler J, Dracup K, Ezekowitz MD, Finkelstein EA, Hong Y, Johnston SC, Khera A, et al.: Forecasting the Future of Cardiovascular Disease in the United States. Circulation 2011, 123(8):933-944.
• [6]Lettre G, Palmer CD, Young T, Ejebe KG, Allayee H, Benjamin EJ, Bennett F, Bowden DW, Chakravarti A, Dreisbach A, et al.: Genome-Wide Association Study of Coronary Heart Disease and Its Risk Factors in 8,090 African Americans: The NHLBI CARe Project. PLoS Genet 2011, 7(2):e1001300.
• [7]Dumitrescu L, Carty CL, Taylor K, Schumacher FR, Hindorff LA, Ambite JL, Anderson G, Best LG, Brown-Gentry K, Bůžková P, et al.: Genetic Determinants of Lipid Traits in Diverse Populations from the Population Architecture using Genomics and Epidemiology (PAGE) Study. PLoS Genet 2011, 7(6):e1002138.
• [8]Shriner D, Adeyemo A, Gerry NP, Herbert A, Chen G, Doumatey A, Huang H, Zhou J, Christman MF, Rotimi CN: Transferability and fine-mapping of genome-wide associated loci for adult height across human populations. PLoS One 2009, 4(12):e8398.
• [9]McCarroll SA, Kuruvilla FG, Korn JM, Cawley S, Nemesh J, Wysoker A, Shapero MH, de Bakker PIW, Maller JB, Kirby A, et al.: Integrated detection and population-genetic analysis of SNPs and copy number variation. Nat Genet 2008, 40(10):1166-1174.
• [10]Gao X, Starmer J: AWclust: point-and-click software for non-parametric population structure analysis. BMC Bioinformatics 2008., 9(77)
• [11]Gauderman W, Morrison J: QUANTO 1.1: A computer program for power and sample size calculations for genetic-epidemiology studies. 2006. http://hydra.usc.edu/gxe webcite
• [12]Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MAR, Bender D, Maller J, Sklar P, de Bakker PIW, Daly MJ, et al.: PLINK: A Tool Set for Whole-Genome Association and Population-Based Linkage Analyses. The American Journal of Human Genetics 2007, 81(3):559-575.
• [13]Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D: Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 2006, 38(8):904-909.
• [14]Adeyemo A, Gerry N, Chen G, Herbert A, Doumatey A, Huang H, Zhou J, Lashley K, Chen Y, Christman M, et al.: A genome-wide association study of hypertension and blood pressure in African Americans. PLoS Genet 2009, 5(7):e1000564.
• [15]Chanock S, Manolio TA, Boehnke M, Boerwinkle E, Hunter D, Thomas G, Hirschhorn J, Abecasis G, Altshuler D, Bailey-Wilson J, et al.: Replicating genotype-phenotype associations. Nature 2007, 447(7145):655-660.
• [16]Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, Nickerson DA: Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet 2004, 74(1):106-120.
• [17]Ramos E, Chen G, Shriner D, Doumatey A, Gerry NP, Herbert A, Huang H, Zhou J, Christman MF, Adeyemo A, et al.: Replication of genome-wide association studies (GWAS) loci for fasting plasma glucose in African-Americans. Diabetologia 2011, 54(4):783-788.
• [18]Pe'er I, Yelensky R, Altshuler D, Daly MJ: Estimation of the multiple testing burden for genomewide association studies of nearly all common variants. Genetic Epidemiology 2008, 32(4):381-385.
• [19]Teo YY, Sim X: Patterns of linkage disequilibrium in different populations: implications and opportunities for lipid-associated loci identified from genome-wide association studies. Curr Opin Lipidol 2010, 21(2):104-115.
• [20]Adeyemo A, Rotimi C: Genetic variants associated with complex human diseases show wide variation across multiple populations. Public Health Genomics 2010, 13(2):72-79.
• [21]Ntzani EE, Liberopoulos G, Manolio TA, Ioannidis JP: Consistency of genome-wide associations across major ancestral groups. Hum Genet 2012, 131(7):1057-1071.
• [22]Ridker PM, Pare G, Parker AN, Zee RY, Miletich JP, Chasman DI: Polymorphism in the CETP gene region, HDL cholesterol, and risk of future myocardial infarction: Genomewide analysis among 18 245 initially healthy women from the Women's Genome Health Study. Circ Cardiovasc Genet 2009, 2(1):26-33.
• [23]A Catalog of Published Genome-Wide Association Studies. [http://www.genome.gov/26525384 webcite]
• [24]Kristiansson K, Perola M, Tikkanen E, Kettunen J, Surakka I, Havulinna AS, Stančáková A, Barnes C, Widen E, Kajantie E, et al.: Genome-Wide Screen for Metabolic Syndrome Susceptibility Loci Reveals Strong Lipid Gene Contribution But No Evidence for Common Genetic Basis for Clustering of Metabolic Syndrome Traits / CLINICAL PERSPECTIVE. Circulation: Cardiovascular Genetics 2012, 5(2):242-249.
• [25]Chambers JC, Elliott P, Zabaneh D, Zhang W, Li Y, Froguel P, Balding D, Scott J, Kooner JS: Common genetic variation near MC4R is associated with waist circumference and insulin resistance. Nat Genet 2008, 40(6):716-718.
• [26]Zabaneh D, Balding DJ: A Genome-Wide Association Study of the Metabolic Syndrome in Indian Asian Men. PLoS One 2010, 5(8):e11961.
• [27]Sabatti C, Service SK, Hartikainen A-L, Pouta A, Ripatti S, Brodsky J, Jones CG, Zaitlen NA, Varilo T, Kaakinen M, et al.: Genome-wide association analysis of metabolic traits in a birth cohort from a founder population. Nat Genet 2009, 41(1):35-46.
• [28]Hiura Y, Shen C-S, Kokubo Y, Okamura T, Morisaki T, Tomoike H, Yoshida T, Sakamoto H, Goto Y, Nonogi H, et al.: Identification of Genetic Markers Associated With High-Density Lipoprotein-Cholesterol by Genome-Wide Screening in a Japanese Population: The Suita Study. Circulation Journal 2009, 73(6):1119-1126.