Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms

Hum Mol Genet. 2016 May 15;25(10):2070-2081. doi: 10.1093/hmg/ddw048. Epub 2016 Feb 23.

Abstract

To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci.

Publication types

  • Meta-Analysis

MeSH terms

  • Alleles
  • Asian People / genetics
  • Black or African American / genetics
  • Chromosome Mapping*
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p18 / genetics
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / pathology
  • Female
  • Genetic Association Studies*
  • Genetic Predisposition to Disease*
  • Humans
  • KCNQ1 Potassium Channel / genetics
  • Linkage Disequilibrium
  • Male
  • Polymorphism, Single Nucleotide
  • RNA-Binding Proteins / genetics
  • Regulatory Elements, Transcriptional / genetics
  • White People / genetics
  • tRNA Methyltransferases / genetics

Substances

  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • Cyclin-Dependent Kinase Inhibitor p18
  • IGF2BP2 protein, human
  • KCNQ1 Potassium Channel
  • KCNQ1 protein, human
  • RNA-Binding Proteins
  • tRNA Methyltransferases
  • CDKAL1 protein, human