Abstract
SNP rs7903146 in the Wnt pathway’s TCF7L2 gene is the variant most significantly associated with type 2 diabetes to date, with associations observed across diverse populations. We sought to determine whether variants in other Wnt pathway genes are also associated with this disease. We evaluated 69 genes involved in the Wnt pathway, including TCF7L2, for associations with type 2 diabetes in 2632 African American cases and 2596 controls from the Black Women’s Health Study. Tag SNPs for each gene region were genotyped on a custom Affymetrix Axiom Array, and imputation was performed to 1000 Genomes Phase 3 data. Gene-based analyses were conducted using the adaptive rank truncated product (ARTP) statistic. The PSMD2 gene was significantly associated with type 2 diabetes after correction for multiple testing (corrected p = 0.016), based on the nine most significant single variants in the +/- 20 kb region surrounding the gene, which includes nearby genes EIF4G1, ECE2, and EIF2B5. Association data on four of the nine variants were available from an independent sample of 8284 African American cases and 15,543 controls; associations were in the same direction, but weak and not statistically significant. TCF7L2 was the only other gene associated with type 2 diabetes at nominal p <0.01 in our data. One of the three variants in the best gene-based model for TCF7L2, rs114770437, was not correlated with the GWAS index SNP rs7903146 and may represent an independent association signal seen only in African ancestry populations. Data on this SNP were not available in the replication sample.
Highlights
African American women experience a greater burden from type 2 diabetes compared to U.S women of European ancestry
genome-wide association studies (GWAS) locus TCF7L2, was associated with a nominal p
The most significantly associated variant in the TCF7L2 region was the GWAS index SNP rs7903146 (p = 1.0 x 10−5), which was associated with a ~20% increased risk of type 2 diabetes
Summary
African American women experience a greater burden from type 2 diabetes compared to U.S women of European ancestry. Β-catenin would avoid destruction even in the absence of Wnt ligands, thereby accumulating in the cytoplasm and nucleus and binding to TCF7L2 and other transcription factors These transcription factors would act mostly as transcriptional activators, and overexpression of some of their target genes may lead to diabetes pathology. With this type of scenario in mind, the present study was initiated to investigate genes involved in the β-catenin destruction complex for evidence of variants that may impact risk of type 2 diabetes in AA women. Given the small effect sizes generally seen for common susceptibility variants, the present analyses utilized gene-based testing in an attempt to identify important genes with multiple risk variants that might otherwise be missed in a SNP-based approach
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