Genome-Wide Linkage and Admixture Mapping of Type 2 Diabetes in African American Families from the American Diabetes Association GENNID Cohort

Abstract

Objective: We used a single nucleotide polymorphism map in a large cohort of 580 African American families to identify regions linked to type 2 diabetes (T2D), T2D age of diagnosis (AOD), and body mass index (BMI).

Research Design and Methods: After removing outliers and problematic samples, we conducted linkage analysis using 5914 SNPs in 1344 individuals from 530 families. Linkage analysis was conducted using variance components for T2D, AOD, and BMI and nonparametric (NPL) analyses. Ordered subset analyses were conducted ranking on AOD, BMI, waist circumference, waist:hip ratio, and amount of European admixture. Admixture mapping was conducted using 4486 markers not in linkage disequilibrium.

Results: The strongest signal for T2D (lod 4.53) was a broad peak on chromosome 2, with weaker linkage to AOD (lod 1.82). T2D and AOD were linked to chromosome 13p (3 cM – 22 cM; lod 2.42 and 2.46, respectively). AOD was linked to 18p (66 cM, 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, VAMPs 5 and 8, CKD8, INSIG2, IPF1, PAX8, IL18R1, members of the IL1 and IL1 receptor families, and MAP4K4. These studies provide a complementary approach to genome-wide association scans to identify causative genes for African American diabetes.