Human Genetics

, Volume 124, Issue 2, pp 147–154 | Cite as

Exploration of the utility of ancestry informative markers for genetic association studies of African Americans with type 2 diabetes and end stage renal disease

  • Keith L. Keene
  • Josyf C. Mychaleckyj
  • Tennille S. Leak
  • Shelly G. Smith
  • Peter S. Perlegas
  • Jasmin Divers
  • Carl D. Langefeld
  • Barry I. Freedman
  • Donald W. Bowden
  • Michèle M. Sale
Original Investigations

Abstract

Admixture and population stratification are major concerns in genetic association studies. We wished to evaluate the impact of admixture using empirically derived data from genetic association studies of African Americans (AA) with type 2 diabetes (T2DM) and end-stage renal disease (ESRD). Seventy ancestry informative markers (AIMs) were genotyped in 577 AA with T2DM–ESRD, 596 AA controls, 44 Yoruba Nigerian (YRI) and 39 European American (EA) controls. Genotypic data and association results for eight T2DM candidate gene studies in our AA population were included. Ancestral estimates were calculated using FRAPPE, ADMIXMAP and STRUCTURE for all AA samples, using varying numbers of AIMs (25, 50, and 70). Ancestry estimates varied significantly across all three programs with the highest estimates obtained using STRUCTURE, followed by ADMIXMAP; while FRAPPE estimates were the lowest. FRAPPE estimates were similar using varying numbers of AIMs, while STRUCTURE estimates using 25 AIMs differed from estimates using 50 and 70 AIMs. Female T2DM-ESRD cases showed higher mean African proportions as compared to female controls, male cases, and male controls. Age showed a weak but significant correlation with individual ancestral estimates in AA cases (r 2 = 0.101; P = 0.019) and in the combined set (r 2 = 0.131; P = 3.57 × 10−5). The absolute difference between frequencies in parental populations, absolute δ, was correlated with admixture impact for dominant, additive, and recessive genotypic models of association. This study presents exploratory analyses of the impact of admixture on studies of AA with T2DM-ESRD and supports the use of ancestral proportions as a means of reducing confounding effects due to admixture.

Notes

Acknowledgments

We thank the individuals recruited as cases and controls for their participation, recruiters Joyce Byers and Mitzie Spainhour, technician Candace Gordon, programmer Matt Stiegert, and Mark Hansen and colleagues at Illumina Inc. This work was supported by grants DK066358, DK072550, DK070941, the Wake Forest University General Clinical Research Center M01 RR07122, and a Career Development Award from the American Diabetes Association (MMS).

Supplementary material

439_2008_532_MOESM1_ESM.doc (476 kb)
Supplementary material (doc 476 kb)

References

  1. Brancati FL, Kao WH, Folsom AR, Watson RL, Szklo M (2000) Incident type 2 diabetes mellitus in African American and white adults: the atherosclerosis risk in communities study. JAMA 283:2253–2259PubMedCrossRefGoogle Scholar
  2. Buetow KH, Edmonson M, MacDonald R, Clifford R, Yip P, Kelley J, Little DP, Strausberg R, Koester H, Cantor CR, Braun A (2001) High-throughput development and characterization of a genomewide collection of gene-based single nucleotide polymorphism markers by chip-based matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Proc Natl Acad Sci USA 98:581–584PubMedCrossRefGoogle Scholar
  3. Elbein SC (2007) Evaluation of polymorphisms known to contribute to risk for diabetes in African and African–American populations. Curr Opin Clin Nutr Metab Care 10:415–419PubMedCrossRefGoogle Scholar
  4. Fernandez JR, Shiver MD (2004) Using genetic admixture to study the biology of obesity traits and to map genes in admixed populations. Nutr Rev 62:S69–S74PubMedCrossRefGoogle Scholar
  5. Fernandez JR, Shriver MD, Beasley TM, Rafla-Demetrious N, Parra E, Albu J, Nicklas B, Ryan AS, McKeigue PM, Hoggart CL, Weinsier RL, Allison DB (2003) Association of African genetic admixture with resting metabolic rate and obesity among women. Obes Res 11:904–911PubMedCrossRefGoogle Scholar
  6. Freedman BI, Yu H, Spray BJ, Rich SS, Rothschild CB, Bowden DW (1997) Genetic linkage analysis of growth factor loci and end-stage renal disease in African Americans. Kidney Int 51:819–825PubMedCrossRefGoogle Scholar
  7. Freedman BI, Volkova NV, Satko SG, Krisher J, Jurkovitz C, Soucie JM, McClellan WM (2005) Population-based screening for family history of end-stage renal disease among incident dialysis patients. Am J Nephrol 25:529–535PubMedCrossRefGoogle Scholar
  8. Goodman MJ, Chung CS (1975) Diabetes mellitus: discrimination between single locus and multifactorial models of inheritance. Clin Genet 8:66–74PubMedCrossRefGoogle Scholar
  9. Hawkes CH (1997) Twin studies in diabetes mellitus. Diabet Med 14:347–352PubMedCrossRefGoogle Scholar
  10. Lind JM, Hutcheson-Dilks HB, Williams SM, Moore JH, Essex M, Ruiz-Pesini E, Wallace DC, Tishkoff SA, O’Brien SJ, Smith MW (2007) Elevated male European and female African contributions to the genomes of African American individuals. Hum Genet 120:713–722PubMedCrossRefGoogle Scholar
  11. Long JC (1991) The genetic structure of admixed populations. Genetics 127:417–428PubMedGoogle Scholar
  12. Kaiser Family Foundation (2007) State Health Facts Online. http://www.statehealthfacts.org/
  13. Keene KL, Mychaleckyj JC, Smith SG, Leak TS, Perlegas PS, Langefeld CD, Freedman BI, Rich SS, Bowden DW, Sale MM (2008a) Association of the distal region of the ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) gene with type 2 diabetes in an African American Population enriched for nephropathy. Diabetes 57(4):1057–1062PubMedCrossRefGoogle Scholar
  14. Keene KL, Mychaleckyj JC, Smith SG, Leak TS, Perlegas PS, Langefeld CD, Herrington DM, Freedman BI, Rich SS, Bowden DW, Sale MM (2008b) Comprehensive evaluation of the estrogen receptor alpha gene reveals further evidence for association with type 2 diabetes enriched for nephropathy in an African American population. Hum Genet 123(4):333–341PubMedCrossRefGoogle Scholar
  15. Louet JF, LeMay C, Mauvais-Jarvis F (2004) Antidiabetic actions of estrogen: insight from human and genetic mouse models. Curr Atheroscler Rep 6:180–185PubMedCrossRefGoogle Scholar
  16. Margolis KL, Bonds DE, Rodabough RJ, Tinker L, Phillips LS, Allen C, Bassford T, Burke G, Torrens J, Howard BV (2004) Effect of oestrogen plus progestin on the incidence of diabetes in postmenopausal women: results from the Women’s Health Initiative Hormone Trial. Diabetologia 47:1175–1187PubMedCrossRefGoogle Scholar
  17. McClellan W, Speckman R, McClure L, Howard V, Campbell RC, Cushman M, Audhya P, Howard G, Warnock DG (2007) Prevalence and characteristics of a family history of end-stage renal disease among adults in the United States population: reasons for geographic and racial differences in stroke (REGARDS) renal cohort study. J Am Soc Nephrol 18:1344–1352PubMedCrossRefGoogle Scholar
  18. McKeigue PM, Carpenter JR, Parra EJ, Shriver MD (2000) Estimation of admixture and detection of linkage in admixed populations by a Bayesian approach: application to African–American populations. Ann Hum Genet 64:171–186PubMedCrossRefGoogle Scholar
  19. McLean DC Jr, Spruill I, Argyropoulos G, Page GP, Shriver MD, Garvey WT (2005) Mitochondrial DNA (mtDNA) haplotypes reveal maternal population genetic affinities of Sea Island Gullah-speaking African Americans. Am J Phys Anthropol 127:427–438PubMedCrossRefGoogle Scholar
  20. Neel JV (1999) Diabetes mellitus: a “thrifty” genotype rendered detrimental by “progress”? 1962. Bull World Health Organ 77:694–703 Discussion 692–693PubMedGoogle Scholar
  21. Parra EJ, Kittles RA, Argyropoulos G, Pfaff CL, Hiester K, Bonilla C, Sylvester N, Parrish-Gause D, Garvey WT, Jin L, McKeigue PM, Kamboh MI, Ferrell RE, Pollitzer WS, Shriver MD (2001) Ancestral proportions and admixture dynamics in geographically defined African Americans living in South Carolina. Am J Phys Anthropol 114:18–29PubMedCrossRefGoogle Scholar
  22. Pfaff CL, Barnholtz-Sloan J, Wagner JK, Long JC (2004) Information on ancestry from genetic markers. Genet Epidemiol 26:305–315PubMedCrossRefGoogle Scholar
  23. Pritchard JK, Stephens M, Donnelly P (2000) Inference of population structure using multilocus genotype data. Genetics 155(2):945–959PubMedGoogle Scholar
  24. Reed FA, Tishkoff SA (2006) African human diversity, origins and migrations. Curr Opin Genet Dev 16:597–605PubMedCrossRefGoogle Scholar
  25. Reiner AP, Ziv E, Lind DL, Nievergelt CM, Schork NJ, Cummings SR, Phong A, Burchard EG, Harris TB, Psaty BM, Kwok PY (2005) Population structure, admixture, and aging-related phenotypes in African American adults: the Cardiovascular Health Study. Am J Hum Genet 76:463–477PubMedCrossRefGoogle Scholar
  26. Reiner AP, Carlson CS, Ziv E, Iribarren C, Jaquish CE, Nickerson DA (2007) Genetic ancestry, population sub-structure, and cardiovascular disease-related traits among African–American participants in the CARDIA Study. Hum Genet 121:565–575PubMedCrossRefGoogle Scholar
  27. Rotimi C, Cooper R, Cao G, Sundarum C, McGee D (1994) Familial aggregation of cardiovascular diseases in African–American pedigrees. Genet Epidemiol 11:397–407PubMedCrossRefGoogle Scholar
  28. Sale MM, Smith SG, Mychaleckyj JC, Keene KL, Langefeld CD, Leak TS, Hicks PJ, Bowden DW, Rich SS, Freedman BI (2007) Variants of the transcription factor 7-like 2 (TCF7L2) gene are associated with type 2 diabetes in an African-American population enriched for nephropathy. Diabetes 56(10):2638–2642PubMedCrossRefGoogle Scholar
  29. Seed M (2002) The choice of hormone replacement therapy or statin therapy in the treatment of hyperlipidemic postmenopausal women. Atheroscler Suppl 3:53–63PubMedCrossRefGoogle Scholar
  30. Shaffer JR, Kammerer CM, Reich D, McDonald G, Patterson N, Goodpaster B, Bauer DC, Li J, Newman AB, Cauley JA, Harris TB, Tylavsky F, Ferrell RE, Zmuda JM (2007) Genetic markers for ancestry are correlated with body composition traits in older African Americans. Osteoporos Int 18:733–741PubMedCrossRefGoogle Scholar
  31. Shriver MD, Parra EJ, Dios S, Bonilla C, Norton H, Jovel C, Pfaff C, Jones C, Massac A, Cameron N, Baron A, Jackson T, Argyropoulos G, Jin L, Hoggart CJ, McKeigue PM, Kittles RA (2003) Skin pigmentation, biogeographical ancestry and admixture mapping. Hum Genet 112:387–399PubMedGoogle Scholar
  32. Smith MW, Patterson N, Lautenberger JA, Truelove AL, McDonald GJ, Waliszewska A, Kessing BD, Malasky MJ, Scafe C, Le E, De Jager PL, Mignault AA, Yi Z, De The G, Essex M, Sankale JL, Moore JH, Poku K, Phair JP, Goedert JJ, Vlahov D, Williams SM, Tishkoff SA, Winkler CA, De La Vega FM, Woodage T, Sninsky JJ, Hafler DA, Altshuler D, Gilbert DA, O’Brien SJ, Reich D (2004) A high-density admixture map for disease gene discovery in african americans. Am J Hum Genet 74:1001–1013PubMedCrossRefGoogle Scholar
  33. Tang H, Peng J, Wang P, Risch NJ (2005) Estimation of individual admixture: analytical and study design considerations. Genet Epidemiol 28:289–301PubMedCrossRefGoogle Scholar
  34. Tsai HJ, Choudhry S, Naqvi M, Rodriguez-Cintron W, Burchard EG, Ziv E (2005) Comparison of three methods to estimate genetic ancestry and control for stratification in genetic association studies among admixed populations. Hum Genet 118:424–433PubMedCrossRefGoogle Scholar
  35. Yu H, Bowden DW, Spray BJ, Rich SS, Freedman BI (1996) Linkage analysis between loci in the renin-angiotensin axis and end-stage renal disease in African Americans. J Am Soc Nephrol 7:2559–2564PubMedGoogle Scholar

Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • Keith L. Keene
    • 1
    • 2
    • 3
  • Josyf C. Mychaleckyj
    • 1
    • 2
    • 4
    • 5
  • Tennille S. Leak
    • 1
  • Shelly G. Smith
    • 1
  • Peter S. Perlegas
    • 6
  • Jasmin Divers
    • 7
  • Carl D. Langefeld
    • 7
  • Barry I. Freedman
    • 5
  • Donald W. Bowden
    • 1
    • 5
    • 6
  • Michèle M. Sale
    • 1
    • 2
    • 3
    • 5
    • 8
  1. 1.Center for Human GenomicsWake Forest University School of MedicineWinston-SalemUSA
  2. 2.Center for Public Health GenomicsUniversity of VirginiaCharlottesvilleUSA
  3. 3.Department of Biochemistry and Molecular GeneticsUniversity of VirginiaCharlottesvilleUSA
  4. 4.Public Health SciencesUniversity of VirginiaCharlottesvilleUSA
  5. 5.Department of Internal MedicineWake Forest University School of MedicineWinston-SalemUSA
  6. 6.Department of BiochemistryWake Forest University School of MedicineWinston-SalemUSA
  7. 7.Department of Biostatistical SciencesWake Forest University School of MedicineWinston-SalemUSA
  8. 8.Department of MedicineUniversity of VirginiaVAUSA

Personalised recommendations