Genome-Wide Linkage and Admixture Mapping of Type 2 Diabetes in African American Families From the American Diabetes Association GENNID (Genetics of NIDDM) Study Cohort

Genome-Wide Linkage and Admixture Mapping of Type 2 Diabetes in African American Families From the American Diabetes Association GENNID (Genetics of NIDDM) Study Cohort Steven C. Elbein 1 2 , Swapan K. Das 1 2 , D. Michael Hallman 3 , Craig L. Hanis 3 and Sandra J. Hasstedt 4 1 Division of Endocrinology, Department of Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 2 Research and Medical Services, Central Arkansas Veterans Healthcare System, Little Rock, Arkansas 3 Human Genetics Center, School of Public Health, University of Texas Health Science Center, Houston, Texas 4 Department of Human Genetics, University of Utah Health Sciences Center, Salt Lake City, Utah Corresponding author: Steven C. Elbein, elbeinstevenc{at}uams.edu Abstract OBJECTIVE— We used a single nucleotide polymorphism (SNP) map in a large cohort of 580 African American families to identify regions linked to type 2 diabetes, age of type 2 diabetes diagnosis, and BMI. RESEARCH DESIGN AND METHODS— After removing outliers and problematic samples, we conducted linkage analysis using 5,914 SNPs in 1,344 individuals from 530 families. Linkage analysis was conducted using variance components for type 2 diabetes, age of type 2 diabetes diagnosis, and BMI and nonparametric linkage analyses. Ordered subset analyses were conducted ranking on age of type 2 diabetes diagnosis, BMI, waist circumference, waist-to-hip ratio, and amount of European admixture. Admixture mapping was conducted using 4,486 markers not in linkage disequilibrium. RESULTS— The strongest signal for type 2 diabetes (logarithm of odds [LOD] 4.53) was a broad peak on chromosome 2, with weaker linkage to age of type 2 diabetes diagnosis (LOD 1.82). Type 2 diabetes and age of type 2 diabetes diagnosis were linked to chromosome 13p (3–22 cM; LOD 2.42 and 2.46, respectively). Age of type 2 diabetes diagnosis was linked to 18p (66 cM; LOD 2.96). We replicated previous reports on chromosome 7p (79 cM; LOD 2.93). Ordered subset analysis did not overlap with linkage of unselected families. The best admixture score was on chromosome 12 (90 cM; P = 0.0003). CONCLUSIONS— The linkage regions on chromosomes 7 (27–78 cM) and 18p overlap prior reports, whereas regions on 2p and 13p linkage are novel. Among potential candidate genes implicated are TCF7L1 , VAMP5, VAMP8, CDK8 , INSIG2 , IPF1 , PAX8 , IL18R1 , members of the IL1 and IL1 receptor families, and MAP4K4 . These studies provide a compleme