Abstract
The prevalence of type 2 diabetes (T2D) is greater in populations of African descent compared to European-descent populations. Genetic risk factors may underlie the disparity in disease prevalence. Genome-wide association studies (GWAS) have identified >60 common genetic variants that contribute to T2D risk in populations of European, Asian, African and Hispanic descent. These studies have not comprehensively examined population differences in cumulative risk allele load. To investigate the relationship between risk allele load and T2D risk, 46 T2D single nucleotide polymorphisms (SNPs) in 43 loci from GWAS in European, Asian, and African-derived populations were genotyped in 1,990 African Americans (n = 963 T2D cases, n = 1,027 controls) and 1,644 European Americans (n = 719 T2D cases, n = 925 controls) ascertained and recruited using a common protocol in the southeast United States. A genetic risk score (GRS) was constructed from the cumulative risk alleles for each individual. In African American subjects, risk allele frequencies ranged from 0.024 to 0.964. Risk alleles from 26 SNPs demonstrated directional consistency with previous studies, and 3 SNPs from ADAMTS9, TCF7L2, and ZFAND6 showed nominal evidence of association (p < 0.05). African American individuals carried 38–67 (53.7 ± 4.0, mean ± SD) risk alleles. In European American subjects, risk allele frequencies ranged from 0.084 to 0.996. Risk alleles from 36 SNPs demonstrated directional consistency, and 10 SNPs from BCL11A, PSMD6, ADAMTS9, ZFAND3, ANK1, CDKN2A/B, TCF7L2, PRC1, FTO, and BCAR1 showed evidence of association (p < 0.05). European American individuals carried 38–65 (50.9 ± 4.4) risk alleles. African Americans have a significantly greater burden of 2.8 risk alleles (p = 3.97 × 10−89) compared to European Americans. However, GRS modeling showed that cumulative risk allele load was associated with risk of T2D in European Americans, but only marginally in African Americans. This result suggests that there are ethnic-specific differences in genetic architecture underlying T2D, and that these differences complicate our understanding of how risk allele load impacts disease susceptibility.
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References
Bento JL, Palmer ND, Zhong M et al (2008) Heterogeneity in gene loci associated with type 2 diabetes on human chromosome 20q13.1. Genomics 92:226–234. doi:10.1016/j.ygeno.2008.06.004
Buetow KH, Edmonson M, MacDonald R et al (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 98:581–584. doi:10.1073/pnas.021506298
Centers for Disease Control and Prevention (2012) Diabetes Report Card 2012. Centers for Disease Control and Prevention, US Department of Health and Human Services, Atlanta
Cheng C-Y, Reich D, Haiman CA et al (2012) African ancestry and its correlation to type 2 diabetes in African Americans: a genetic admixture analysis in three US population cohorts. PLoS One 7:e32840. doi:10.1371/journal.pone.0032840
Cho YS, Chen C-H, Hu C et al (2012) Meta-analysis of genome-wide association studies identifies eight new loci for type 2 diabetes in east Asians. Nat Genet 44:67–72. doi:10.1038/ng.1019
Cooke JN, Bostrom MA, Hicks PJ et al (2012a) Polymorphisms in MYH9 are associated with diabetic nephropathy in European Americans. Nephrol Dial Transplant 27:1505–1511. doi:10.1093/ndt/gfr522
Cooke JN, Ng MCY, Palmer ND et al (2012b) Genetic risk assessment of type 2 diabetes-associated polymorphisms in African Americans. Diabetes Care 35:287–292. doi:10.2337/dc11-0957
Cui B, Zhu X, Xu M et al (2011) A genome-wide association study confirms previously reported loci for type 2 diabetes in Han Chinese. PLoS One 6:e22353. doi:10.1371/journal.pone.0022353
Diabetes Genetics Initiative of Broad Institute of Harvard and MIT, Lund University, and Novartis Institutes of BioMedical Research, Saxena R, Voight BF et al (2007) Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels. Science 316:1331–1336. doi:10.1126/science.1142358
DIAbetes Genetics Replication And Meta-analysis (DIAGRAM) Consortium, Asian Genetic Epidemiology Network Type 2 Diabetes (AGEN-T2D) Consortium, South Asian Type 2 Diabetes (SAT2D) Consortium et al (2014) Genome-wide trans-ancestry meta-analysis provides insight into the genetic architecture of type 2 diabetes susceptibility. Nat Genet 46:234–244. doi:10.1038/ng.2897
Freedman BI, Yu H, Anderson PJ et al (2000) Genetic analysis of nitric oxide and endothelin in end-stage renal disease. Nephrol Dial Transplant 15:1794–1800
Haiman CA, Fesinmeyer MD, Spencer KL et al (2012) Consistent directions of effect for established type 2 diabetes risk variants across populations: the population architecture using Genomics and Epidemiology (PAGE) Consortium. Diabetes 61:1642–1647. doi:10.2337/db11-1296
Harris MI, Flegal KM, Cowie CC et al (1998) Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in US adults. The Third National Health and Nutrition Examination Survey, 1988–1994. Diabetes Care 21:518–524
Hivert M-F, Jablonski KA, Perreault L et al (2011) Updated genetic score based on 34 confirmed type 2 diabetes loci is associated with diabetes incidence and regression to normoglycemia in the diabetes prevention program. Diabetes 60:1340–1348. doi:10.2337/db10-1119
Huang J, Ellinghaus D, Franke A et al (2012) 1000 Genomes-based imputation identifies novel and refined associations for the Wellcome Trust Case Control Consortium phase 1 Data. Eur J Hum Genet 20:801–805. doi:10.1038/ejhg.2012.3
Imamura M, Maeda S, Yamauchi T et al (2012) A single-nucleotide polymorphism in ANK1 is associated with susceptibility to type 2 diabetes in Japanese populations. Hum Mol Genet 21:3042–3049. doi:10.1093/hmg/dds113
Johnson AD, Handsaker RE, Pulit SL et al (2008) SNAP: a web-based tool for identification and annotation of proxy SNPs using HapMap. Bioinformatics 24:2938–2939. doi:10.1093/bioinformatics/btn564
Kooner JS, Saleheen D, Sim X et al (2011) Genome-wide association study in individuals of South Asian ancestry identifies six new type 2 diabetes susceptibility loci. Nat Genet 43:984–989. doi:10.1038/ng.921
Lewis JP, Palmer ND, Hicks PJ et al (2008) Association analysis in African Americans of European-derived type 2 diabetes single nucleotide polymorphisms from whole-genome association studies. Diabetes 57:2220–2225. doi:10.2337/db07-1319
Lyssenko V, Jonsson A, Almgren P et al (2008) Clinical risk factors, DNA variants, and the development of type 2 diabetes. N Engl J Med 359:2220–2232. doi:10.1056/NEJMoa0801869
Maskarinec G, Grandinetti A, Matsuura G et al (2009) Diabetes prevalence and body mass index differ by ethnicity: the multiethnic cohort. Ethn Dis 19:49–55
McDonough CW, Palmer ND, Hicks PJ et al (2011) A genome wide association study for diabetic nephropathy genes in African Americans. Kidney Int 79:563–572. doi:10.1038/ki.2010.467
Meigs JB, Shrader P, Sullivan LM et al (2008) Genotype score in addition to common risk factors for prediction of type 2 diabetes. N Engl J Med 359:2208–2219. doi:10.1056/NEJMoa0804742
Morris AP, Voight BF, Teslovich TM et al (2012) Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 44:981–990. doi:10.1038/ng.2383
Ng MCY, Shriner D, Chen BH et al (2014) Meta-analysis of genome-wide association studies in african americans provides insights into the genetic architecture of type 2 diabetes. PLoS Genet 10:e1004517. doi:10.1371/journal.pgen.1004517
Ng MCY, Saxena R, Li J et al (2013) Transferability and fine mapping of type 2 diabetes loci in African Americans: the candidate gene association resource plus study. Diabetes 62:965–976. doi:10.2337/db12-0266
Palmer ND, McDonough CW, Hicks PJ et al (2012) A genome-wide association search for type 2 diabetes genes in African Americans. PLoS One 7:e29202. doi:10.1371/journal.pone.0029202
Parra EJ, Below JE, Krithika S et al (2011) Genome-wide association study of type 2 diabetes in a sample from Mexico City and a meta-analysis of a Mexican-American sample from Starr County, Texas. Diabetologia 54:2038–2046. doi:10.1007/s00125-011-2172-y
Perry JRB, Voight BF, Yengo L et al (2012) Stratifying type 2 diabetes cases by BMI identifies genetic risk variants in LAMA1 and enrichment for risk variants in lean compared to obese cases. PLoS Genet 8:e1002741. doi:10.1371/journal.pgen.1002741
Qi L, Hu FB, Hu G (2008) Genes, environment, and interactions in prevention of type 2 diabetes: a focus on physical activity and lifestyle changes. Curr Mol Med 8:519–532
Qi L, Cornelis MC, Kraft P et al (2010) Genetic variants at 2q24 are associated with susceptibility to type 2 diabetes. Hum Mol Genet 19:2706–2715. doi:10.1093/hmg/ddq156
Rung J, Cauchi S, Albrechtsen A et al (2009) Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia. Nat Genet 41:1110–1115. doi:10.1038/ng.443
Sale MM, Freedman BI, Langefeld CD et al (2004) A genome-wide scan for type 2 diabetes in African-American families reveals evidence for a locus on chromosome 6q. Diabetes 53:830–837
Shu XO, Long J, Cai Q et al (2010) Identification of new genetic risk variants for type 2 diabetes. PLoS Genet 6:e1001127. doi:10.1371/journal.pgen.1001127
Sim X, Ong RT-H, Suo C et al (2011) Transferability of type 2 diabetes implicated loci in multi-ethnic cohorts from Southeast Asia. PLoS Genet 7:e1001363. doi:10.1371/journal.pgen.1001363
Steinthorsdottir V, Thorleifsson G, Reynisdottir I et al (2007) A variant in CDKAL1 influences insulin response and risk of type 2 diabetes. Nat Genet 39:770–775. doi:10.1038/ng2043
Takeuchi F, Serizawa M, Yamamoto K et al (2009) Confirmation of multiple risk loci and genetic impacts by a genome-wide association study of type 2 diabetes in the Japanese population. Diabetes 58:1690–1699. doi:10.2337/db08-1494
Tang H, Peng J, Wang P, Risch NJ (2005) Estimation of individual admixture: analytical and study design considerations. Genet Epidemiol 28:289–301. doi:10.1002/gepi.20064
Timpson NJ, Lindgren CM, Weedon MN et al (2009) Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data. Diabetes 58:505–510. doi:10.2337/db08-0906
Tsai F-J, Yang C-F, Chen C-C et al (2010) A genome-wide association study identifies susceptibility variants for type 2 diabetes in Han Chinese. PLoS Genet 6:e1000847. doi:10.1371/journal.pgen.1000847
Unoki H, Takahashi A, Kawaguchi T et al (2008) SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat Genet 40:1098–1102. doi:10.1038/ng.208
Voight BF, Scott LJ, Steinthorsdottir V et al (2010) Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis. Nat Genet 42:579–589. doi:10.1038/ng.609
Waters KM, Stram DO, Hassanein MT et al (2010) Consistent association of type 2 diabetes risk variants found in Europeans in diverse racial and ethnic groups. PLoS Genet. doi:10.1371/journal.pgen.1001078
Wellcome Trust Case Control Consortium (2007) Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 447:661–678. doi:10.1038/nature05911
Yamauchi T, Hara K, Maeda S et al (2010) A genome-wide association study in the Japanese population identifies susceptibility loci for type 2 diabetes at UBE2E2 and C2CD4A-C2CD4B. Nat Genet 42:864–868. doi:10.1038/ng.660
Yu H, Bowden DW, Spray BJ et al (1998) Identification of human plasma kallikrein gene polymorphisms and evaluation of their role in end-stage renal disease. Hypertension 31:906–911
Zeggini E, Weedon MN, Lindgren CM et al (2007) Replication of genome-wide association signals in UK samples reveals risk loci for type 2 diabetes. Science 316:1336–1341. doi:10.1126/science.1142364
Zeggini E, Scott LJ, Saxena R et al (2008) Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet 40:638–645. doi:10.1038/ng.120
Acknowledgments
The authors would like to thank all study participants for their time and effort. This work was supported by NIH grants R01 DK066358 and R01 DK053591 to DWB.
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Keaton, J.M., Cooke Bailey, J.N., Palmer, N.D. et al. A comparison of type 2 diabetes risk allele load between African Americans and European Americans. Hum Genet 133, 1487–1495 (2014). https://doi.org/10.1007/s00439-014-1486-5
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DOI: https://doi.org/10.1007/s00439-014-1486-5