Genetic Determinants of Diabetes in the Qatari Population

Abstract

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 [1]. 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. Additionally, over the past decade, studies have identified over 700 T2D risk loci in a variety of populations, mainly in European, Asian, and African. However, the genetic basis of T2D is underrepresented in the Middle East, despite the rapidly growing disease prevalence. We therefore focused on defining the genetic determinants of T2D in Qatari population using QBB cohort (T2D and subjects without diabetes). We conducted genome- wide association study (GWAS) of binary trait, T2D, with and without body mass index (BMI) adjustments. We analyzed GWAS data and replicated 223 known associations of SNPs with T2D in BMI-unadjusted model, and 246 known associations in BMI-adjusted models. Of which, 15 SNPs and 19 SNPs reached genome-wide significance at the TCF7L2 gene. Allele frequencies of replicated SNPs in Qatari population were strongly correlated to European (R2= 0.97), in comparisons to South Asian (R2= 0.94) and African (R2= 0.79). Herein, we also reported the identification of a novel variant rs143508949 at a novel locus between APOBEC3H and CBX7 genes in the BMI-unadjusted model. Furthermore, we conducted a meta-analysis of GWAS using genetic variants of European ancestry and detected 12 novel genetic variants at genome-wide association significance at multiple loci previously associated with T2D. In addition, we identified a novel locus reaching genome- wide significance on chromosome 12 in COQ5 gene. Additionally, we assessed the accuracy of predicting the risk of T2D with polygenic risk scoring panels derived from European- and multi-ancestry populations. Our analysis revealed that the predictive performance of multi- ancestry populations performed more effectively when applied to the Qatari population (QGP cohort). Our study provides important insights into the genetic anomalies associated with T2D and highlights novel genes, which may be targeted for clinical benefits, following further validations.

Date of Award	2023
Original language	American English
Awarding Institution	HBKU College of Health & Life Sciences