Exome sequencing-based identification of novel type 2 diabetes risk allele loci in the Qatari population

PLoS One. 2018 Sep 13;13(9):e0199837. doi: 10.1371/journal.pone.0199837. eCollection 2018.

Abstract

Background: Type 2 diabetes (T2D) susceptibility is influenced by genetic and lifestyle factors. To date, the majority of genetic studies of T2D have been in populations of European and Asian descent. The focus of this study is on genetic variations underlying T2D in Qataris, a population with one of the highest incidences of T2D worldwide.

Results: Illumina HiSeq exome sequencing was performed on 864 Qatari subjects (574 T2D cases, 290 controls). Sequence kernel association test (SKAT) gene-based analysis identified an association for low frequency potentially deleterious variants in 6 genes. However, these findings were not replicated by SKAT analysis in an independent cohort of 12,699 exomes, primarly due to the absence of low frequency potentially deleterious variants in 5 of the 6 genes. Interestingly one of the genes identified, catenin beta 1 (CTNNB1, β-catenin), is the key effector of the Wnt pathway and interacts with the nuclear receptor transcription factor 7-like 2 (TCF7L2), variants which are the most strongly associated with risk of developing T2D worldwide. Single variant analysis did not identify any associated variants, suggesting the SKAT association signal was not driven by individual variants. None of the 6 associated genes were among 634 previously described T2D genes.

Conclusions: The observation that genes not previously linked to T2D in prior studies of European and Asian populations are associated with T2D in Qatar provides new insights into the complexity of T2D pathogenesis and emphasizes the importance of understudied populations when assessing genetic variation in the pathogenesis of common disorders.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles*
  • Diabetes Mellitus, Type 2 / genetics*
  • Exome*
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Qatar
  • Risk Factors
  • Transcription Factor 7-Like 2 Protein / genetics*
  • Wnt Signaling Pathway / genetics*
  • beta Catenin / genetics*

Substances

  • CTNNB1 protein, human
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 2 Protein
  • beta Catenin

Grants and funding

This grant was supported by QNRF NPRP 09-741-3-193 and general funds of the Department of Genetic Medicine, Weill Cornell Medical College. Hamad Medical Corporation (HMC), is not a commercial company, but the premier not-for-profit health care provider for Doha, Qatar. The authors who are employees of HMC have the same no conflict as the other authors on this paper. The studies reported in this paper were grant supported (Qatar Foundation). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.