Trans-ethnic Meta-analysis and Functional Annotation Illuminates the Genetic Architecture of Fasting Glucose and Insulin

Am J Hum Genet. 2016 Jul 7;99(1):56-75. doi: 10.1016/j.ajhg.2016.05.006. Epub 2016 Jun 16.

Abstract

Knowledge of the genetic basis of the type 2 diabetes (T2D)-related quantitative traits fasting glucose (FG) and insulin (FI) in African ancestry (AA) individuals has been limited. In non-diabetic subjects of AA (n = 20,209) and European ancestry (EA; n = 57,292), we performed trans-ethnic (AA+EA) fine-mapping of 54 established EA FG or FI loci with detailed functional annotation, assessed their relevance in AA individuals, and sought previously undescribed loci through trans-ethnic (AA+EA) meta-analysis. We narrowed credible sets of variants driving association signals for 22/54 EA-associated loci; 18/22 credible sets overlapped with active islet-specific enhancers or transcription factor (TF) binding sites, and 21/22 contained at least one TF motif. Of the 54 EA-associated loci, 23 were shared between EA and AA. Replication with an additional 10,096 AA individuals identified two previously undescribed FI loci, chrX FAM133A (rs213676) and chr5 PELO (rs6450057). Trans-ethnic analyses with regulatory annotation illuminate the genetic architecture of glycemic traits and suggest gene regulation as a target to advance precision medicine for T2D. Our approach to utilize state-of-the-art functional annotation and implement trans-ethnic association analysis for discovery and fine-mapping offers a framework for further follow-up and characterization of GWAS signals of complex trait loci.

Publication types

  • Meta-Analysis

MeSH terms

  • African Continental Ancestry Group / genetics
  • Asian Continental Ancestry Group / genetics
  • Blood Glucose / genetics*
  • Continental Population Groups / genetics*
  • Diabetes Mellitus, Type 2 / genetics*
  • Enhancer Elements, Genetic / genetics
  • Ethnic Groups / genetics*
  • European Continental Ancestry Group / genetics
  • Fasting / metabolism*
  • Female
  • Gene Frequency / genetics
  • Genome-Wide Association Study
  • Humans
  • Insulin / metabolism*
  • Insulin Resistance / genetics
  • Introns / genetics
  • Islets of Langerhans / metabolism
  • Male
  • Molecular Sequence Annotation
  • Polymorphism, Single Nucleotide / genetics
  • Quantitative Trait Loci / genetics
  • Transcription Factors / metabolism

Substances

  • Blood Glucose
  • Insulin
  • Transcription Factors

Grant support