Admixture mapping and fine-mapping of type 2 diabetes susceptibility loci in African American women

J Hum Genet. 2018 Nov;63(11):1109-1117. doi: 10.1038/s10038-018-0503-2. Epub 2018 Aug 22.

Abstract

African American women are disproportionately affected by type 2 diabetes. Genetic factors may explain part of the excess risk. More than 100 genetic variants have been associated with risk of type 2 diabetes, but most studies have been conducted in white populations. Two genome-wide association studies (GWAS) in African Americans have identified three novel genetic variants only. We conducted admixture mapping using 2918 ancestral informative markers in 2632 cases of type 2 diabetes, and 2596 controls nested in the ongoing Black Women's Health Study cohort, with the goal of identifying genomic loci with local African ancestry associated with type 2 diabetes. In addition, we performed replication analysis of 71 previously identified index SNPs, and fine-mapped those genetic loci to identify better or new genetic variants associated with type 2 diabetes in African Americans. We found that individual African ancestry was associated with higher risk of type 2 diabetes. In addition, we identified two genomic regions, 3q26 and 12q23, with excess of African ancestry associated with higher risk of type 2 diabetes. Lastly, we replicated 8 out of 71 index SNPs from previous GWAS, including, for the first time in African Americans, the X-linked rs5945326 SNP near the DUSP9 gene. In addition, our fine-mapping efforts suggest independent signals at five loci. Our detailed analysis identified two genomic regions associated with risk of type 2 diabetes, and showed that many genetic risk variants are shared across ancestries.

MeSH terms

  • Adult
  • Aged
  • Black or African American / genetics*
  • Chromosome Mapping*
  • Chromosomes, Human, Pair 12 / genetics
  • Chromosomes, Human, Pair 3 / genetics
  • Diabetes Mellitus, Type 2 / genetics*
  • Dual-Specificity Phosphatases / genetics
  • Female
  • Genetic Loci*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Humans
  • Middle Aged
  • Mitogen-Activated Protein Kinase Phosphatases / genetics
  • Polymorphism, Single Nucleotide*

Substances

  • Mitogen-Activated Protein Kinase Phosphatases
  • DUSP9 protein, human
  • Dual-Specificity Phosphatases