Syracuse

Introduction: Type 2 diabetes (T2D) is a multifactorial disease involving genetic and environmental components. Several genome-wide association studies (GWAS) have been conducted to decipher potential genetic aberrations promoting the onset of this metabolic disorder. These GWAS have identified over 400 associated variants, mostly in the intronic or intergenic regions. Recently, a growing number of exome genotyping or exome sequencing experiments have identified coding variants associated with T2D. Such studies were mainly conducted in European populations, and the few candidate-gene replication studies in North African populations revealed inconsistent results. In the present study, we aimed to discover the coding genetic etiology of T2D in the Tunisian population.

We carried out a pilot Exome Wide Association Study (EWAS) on 50 Tunisian individuals. Single variant analysis was performed as implemented in PLINK on potentially deleterious coding variants. Subsequently, we applied genebased and gene-set analyses using MAGMA software to identify genes and pathways associated with T2D. Potential signals were further replicated in an existing large in-silico dataset, involving up to 177116 European individuals.

Results: Our analysis revealed, for the first time, promising associations between T2D and variations in MYORG gene, implicated in the skeletal muscle fiber development. Gene-set analysis identified two candidate pathways having nominal associations with T2D in our study samples, namely the positive regulation of neuron apoptotic process and the regulation of mucus secretion. These two pathways are implicated in the neurogenerative alterations and in the Frontiers in Endocrinology frontiersin.org 01