Exploration of the utility of ancestry informative markers for genetic association studies of African Americans with type 2 diabetes and end stage renal disease.
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 , 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.
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ABSTRACT: African Americans have increased susceptibility to non-diabetic (non-DM) forms of end-stage renal disease (ESRD) and extensive evidence supports a genetic contribution. A genome-wide association study (GWAS) using pooled DNA was performed in 1,000 African Americans to detect associated genes. DNA from 500 non-DM ESRD cases and 500 non-nephropathy controls was quantified using gel electrophoresis and spectrophotometric analysis and pools of 50 case and 50 control DNA samples were created. DNA pools were genotyped in duplicate on the Illumina HumanHap550-Duo BeadChip. Normalization methods were developed and applied to array intensity values to reduce inter-array variance. Allele frequencies were calculated from normalized channel intensities and compared between case and control pools. Three SNPs had p values of <1.0E-6: rs4462445 (ch 13), rs4821469 (ch 22) and rs8077346 (ch 17). After normalization, top scoring SNPs (n = 65) were genotyped individually in 464 of the original cases and 478 of the controls, with replication in 336 non-DM ESRD cases and 363 non-nephropathy controls. Sixteen SNPs were associated with non-DM ESRD (p < 7.7E-4, Bonferroni corrected). Twelve of these SNPs are in or near the MYH9 gene. The four non-MYH9 SNPs that were associated with non-DM ESRD in the pooled samples were not associated in the replication set. Five SNPs that were modestly associated in the pooled samples were more strongly associated in the replication and/or combined samples. This is the first GWAS for non-DM ESRD in African Americans using pooled DNA. We demonstrate strong association between non-DM ESRD in African Americans with MYH9, and have identified additional candidate loci.Human Genetics 08/2010; 128(2):195-204. DOI:10.1007/s00439-010-0842-3 · 4.52 Impact Factor
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ABSTRACT: Polymorphisms in the adiponectin gene (ADIPOQ) have been associated with type 2 diabetes and diabetic nephropathy in type 1 diabetes, in mostly European-derived populations. A comprehensive association analysis of 24 single-nucleotide polymorphisms (SNPs) in the adiponectin gene was performed for type 2 diabetes and diabetic nephropathy in African Americans. The minor allele (A) in a single SNP in intron 1 (rs182052) was associated with diabetic nephropathy (P = 0.0015, odds ratio [OR] 1.37, CI 1.13-1.67, dominant model) in an African American sample of 851 case subjects with diabetic nephropathy and 871 nondiabetic control subjects in analyses incorporating adjustment for varying levels of racial admixture. This association remained significant after adjustment of the data for BMI, age, and sex (P = 0.0013-0.0004). We further tested this SNP for association with longstanding type 2 diabetes without nephropathy (n = 317), and evidence of association was also significant (P = 0.0054, OR 1.46, CI 1.12-1.91, dominant model) when compared with the same set of 871 nondiabetic control subjects. Combining the type 2 diabetes and diabetic nephropathy samples into a single group of case subjects (n = 1,168) resulted in the most significant evidence of association (P = 0.0003, OR 1.40, CI 1.17-1.67, dominant model). Association tests between age at onset of type 2 diabetes and the rs182052 genotypes also revealed significant association between the presence of the minor allele (A/A or A/G) and earlier onset of type 2 diabetes. The SNP rs182052 in intron 1 of the adiponectin gene is associated with type 2 diabetes in African Americans.Diabetes 01/2009; 58(2):499-504. DOI:10.2337/db08-0598 · 8.47 Impact Factor
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ABSTRACT: Type 2 diabetes is more prevalent in African-Americans (AFAs) and Hispanic-Americans (HAs) than in European-Americans. We assessed whether continental admixture was correlated with diabetes risk in these high-risk groups. We estimated the proportion of sub-Saharan African (AFR), Amerindian (AMI) and European admixture using 92 ancestry-informative marker genotypes in 16,476 AFA and HA women from the Women's Health Initiative. Cox regression models were used to examine the association between admixture and diabetes risk, with and without accounting for socioeconomic status (SES) and adiposity measurements. AFR admixture was significantly associated with diabetes risk in AFA women when adjusting for entry age, neighbourhood SES and BMI or waist/hip ratio (WHR) (all p < 0.0001). In HA women, AMI admixture had significant associations with diabetes risk that remained significant after adjustment for SES and BMI (all p < 0.0005). In both AFAs and HAs, SES showed significant negative associations while BMI or WHR had significant positive associations with diabetes risk, with and without adjustment for genetic admixture. In AFAs, admixture, SES and BMI/WHR each independently contribute to diabetes risk after accounting for each of the other factors; in HAs, admixture, SES and BMI each independently contribute to diabetes risk after accounting for each of the other factors, whereas admixture is not significantly associated with diabetes risk after accounting for SES and WHR. The findings emphasise the importance of considering both genetic and environmental causes in the aetiology of type 2 diabetes.Diabetologia 02/2012; 55(5):1329-37. DOI:10.1007/s00125-012-2486-4 · 6.88 Impact Factor