Genetic Determinants of Diabetes in the Qatari Population

Diabetes mellitus is a metabolic disease characterized by chronic hyperglycemia as a consequence of insulin resistance and/or pancreatic β-cell dysfunction. Diabetes is an umbrella term that is subclassified into variety of types based on disease etiology. The monogenic form of diabetes is ascribed to the cause of a single-gene mutation resulting in diabetes-onset such as neonatal diabetes mellitus (NDM) and maturity-onset diabetes of the young (MODY). Whilst the polygenic form of diabetes is the result of variations in many genes in addition to gene-gene interactions and gene-environment interactions. The most common form of polygenic diabetes includes Type 2 diabetes mellitus (T2DM) and Type 1 diabetes mellitus (T1DM). In this study, we used Whole-genome sequencing of 14,364 subjects from the population-based Qatar biobank (QBB) cohort. Upon conducting phenotypic analysis, our findings revealed that ~20% of the studied population were classified as T2D, ~0.5% classified as T1D and ~75% are without diabetes.

First, we estimated the prevalence and genetic spectrum of MODY in the Middle Eastern population of Qatar based on 14 previously reported genes ascribed to be the cause of MODY, in addition to two potential genes associated with MODY, RFX6 and NKX6.1. Herein, we assessed genetic variation pathogenicity of the MODY genes to identify disease-causing mutations. We reported the identification of 22 MODY-gene mutations classified as disease-causing or likely disease causing in in the Human Genetic Mutation Database (HGMD) in 67 subjects.

In addition, we reported 28 potential novel MODY-causing mutations, ranking in top 1% of most deleterious mutations, in 34 subjects that have diabetes. Subsequently, we estimated MODY prevalence to range from 2.2-3.4% of diabetes patients in Qatar. Our study is the first to report the estimated MODY prevalence in the Middle East. However, further functional studies to assess the pathogenicity of the identified genetic variants is warranted.