Genetic and epigenetic analysis of type 2 diabetes among Qatari families

Abstract

Type 2 diabetes (T2D) is a complex multifactorial disorder driven by both genetic and environmental factors. The rapid increase of T2D in Qatar -prevalence of 16.3% in 2014 according to the International Diabetes Federation (IDF) - motivated the introduction of genetic studies among this under-presented population. Major progress to study the genetic basis of T2D came from studying common variants. However, these variants were of mild effect sizes. Studies have been shifted from applying the common variants hypothesis towards the investigation of other genetic variables including rare variants, copy number variants (CNV) and epigenetic mechanisms. This PhD project is focused on identifying genomic risk factors of T2D among the Qatari population. Eight Qatari families were analysed using the advances in genotyping and sequencing technologies. Three analyses were carried out; the aim was to identify known or novel rare variants within candidate T2D genes, identification of potential large CNVs related to T2D and detection of methylation associations with T2D. Three data sets were generated for this PhD project; these were genome-wide genotyping arrays (Illumina HumanOmni2.5M bead chip), whole genome sequencing (WGS) (Illumina hiSeq2500 platform) and genome-wide methylation arrays (Illumina 450K BeadChip capturing more than 485,577 probes). I performed three analytical experiments for the aim of this PhD project. First, linkage analysis and runs of homozygosity in combination with WGS were used to map rare variants. Second, PennCNV prediction algorithm for CNV calling was applied aiming to identify rare T2D-related CNVs. Third, association test using a linear mixed model was used for the identification of methylation associations with T2D. The findings included the identification of three rare variants detected through WGS. One variant identified within known monogenic T2D gene (GCKR) and two variants detected within known T2D genes (IGFBP2 and TGM2). These genes are functionally related to T2D and replication analysis will be required to assess their contribution to T2D among Qataris. A number of large rare CNVs detected from CNV analysis in the second experiment of the project, but potential T2D genes were not found within candidate CNVs. Also, methylation analysis replicated a significant association with T2D at cg19693031 in TXNIP (p=5.28x10¯⁶) among Qataris. The identified candidate genes were proved to be involved in the pathogenesis of T2D by causing insulin resistance and beta-cell dysfunction.