Publication Type	Academic Article
Authors	O'Beirne S, Salit J, Rodriguez-Flores J, Staudt M, Abi Khalil C, Fakhro K, Robay A, Ramstetter M, Malek J, Zirie M, Jayyousi A, Badii R, Al-Nabet Al-Marri A, Bener A, Mahmoud M, Chiuchiolo M, Al-Shakaki A, Chidiac O, Stadler D, Mezey J, Crystal R
Journal	PLoS One
Volume	13
Issue	9
Pagination	e0199837
Date Published	09/13/2018
ISSN	1932-6203
Keywords	Alleles, Diabetes Mellitus, Type 2, Exome, Transcription Factor 7-Like 2 Protein, Wnt Signaling Pathway, beta Catenin
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.
DOI	10.1371/journal.pone.0199837
PubMed ID	30212457
PubMed Central ID	PMC6136697