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

Sarah L. O’Beirne, Jacqueline Salit, Juan L. Rodriguez-Flores, Michelle R. Staudt, Charbel Abi Khalil, Khalid Adnan Mohamed A. Fakhro, Amal Robay, Monica D. Ramstetter, Joel Malek, Mahmoud Zirie, Amin Jayyousi, Ramin Badii, Ajayeb Al Nabet Al-Marri, Abdulbari Bener, Mai Mahmoud, Maria J. Chiuchiolo, Alya Al-Shakaki, Omar Chidiac, Dora Stadler, Jason G. Mezey & 1 others Ronald Crystal

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article numbere0199837
JournalPLoS One
Volume13
Issue number9
DOIs
Publication statusPublished - 1 Sep 2018

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Exome
Medical problems
noninsulin-dependent diabetes mellitus
Type 2 Diabetes Mellitus
Alleles
alleles
loci
Genes
Population
genes
T Cell Transcription Factor 1
pathogenesis
seeds
Qatar
Catenins
genetic variation
Wnt Signaling Pathway
testing
beta Catenin
Cytoplasmic and Nuclear Receptors

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Exome sequencing-based identification of novel type 2 diabetes risk allele loci in the Qatari population. / O’Beirne, Sarah L.; Salit, Jacqueline; Rodriguez-Flores, Juan L.; Staudt, Michelle R.; Abi Khalil, Charbel; Fakhro, Khalid Adnan Mohamed A.; Robay, Amal; Ramstetter, Monica D.; Malek, Joel; Zirie, Mahmoud; Jayyousi, Amin; Badii, Ramin; Al-Marri, Ajayeb Al Nabet; Bener, Abdulbari; Mahmoud, Mai; Chiuchiolo, Maria J.; Al-Shakaki, Alya; Chidiac, Omar; Stadler, Dora; Mezey, Jason G.; Crystal, Ronald.

In: PLoS One, Vol. 13, No. 9, e0199837, 01.09.2018.

Research output: Contribution to journalArticle

O’Beirne, SL, Salit, J, Rodriguez-Flores, JL, Staudt, MR, Abi Khalil, C, Fakhro, KAMA, Robay, A, Ramstetter, MD, Malek, J, Zirie, M, Jayyousi, A, Badii, R, Al-Marri, AAN, Bener, A, Mahmoud, M, Chiuchiolo, MJ, Al-Shakaki, A, Chidiac, O, Stadler, D, Mezey, JG & Crystal, R 2018, 'Exome sequencing-based identification of novel type 2 diabetes risk allele loci in the Qatari population', PLoS One, vol. 13, no. 9, e0199837. https://doi.org/10.1371/journal.pone.0199837
O’Beirne, Sarah L. ; Salit, Jacqueline ; Rodriguez-Flores, Juan L. ; Staudt, Michelle R. ; Abi Khalil, Charbel ; Fakhro, Khalid Adnan Mohamed A. ; Robay, Amal ; Ramstetter, Monica D. ; Malek, Joel ; Zirie, Mahmoud ; Jayyousi, Amin ; Badii, Ramin ; Al-Marri, Ajayeb Al Nabet ; Bener, Abdulbari ; Mahmoud, Mai ; Chiuchiolo, Maria J. ; Al-Shakaki, Alya ; Chidiac, Omar ; Stadler, Dora ; Mezey, Jason G. ; Crystal, Ronald. / Exome sequencing-based identification of novel type 2 diabetes risk allele loci in the Qatari population. In: PLoS One. 2018 ; Vol. 13, No. 9.
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AU - O’Beirne, Sarah L.

AU - Salit, Jacqueline

AU - Rodriguez-Flores, Juan L.

AU - Staudt, Michelle R.

AU - Abi Khalil, Charbel

AU - Fakhro, Khalid Adnan Mohamed A.

AU - Robay, Amal

AU - Ramstetter, Monica D.

AU - Malek, Joel

AU - Zirie, Mahmoud

AU - Jayyousi, Amin

AU - Badii, Ramin

AU - Al-Marri, Ajayeb Al Nabet

AU - Bener, Abdulbari

AU - Mahmoud, Mai

AU - Chiuchiolo, Maria J.

AU - Al-Shakaki, Alya

AU - Chidiac, Omar

AU - Stadler, Dora

AU - Mezey, Jason G.

AU - Crystal, Ronald

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N2 - 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.

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