ABSTRACT Background Type 2 diabetes (T2D) is a complex and highly heterogeneous disease driven in part by genetic predisposition and can be stratified into clinical subgroups to aid disease management. We recently grouped T2D subjects in the Qatar Biobank (QBB) cohort into Severe Insulin‐Deficient Diabetes (SIDD), Severe Insulin‐Resistant Diabetes (SIRD), Mild Obesity‐Related Diabetes (MOD) and Mild Age‐Related Diabetes (MARD) subtypes. Herein, we focused on the genetic makeup of these subtypes. Methods We used the QBB cohort (n = 13,808), of whom 2687 were with T2D, and comprehensively assessed polygenic risk scores (PGS) across T2D subtypes, investigated genetic loci associated with each subtype by leveraging the most recent and largest GWAS for T2D, evaluated SNP associations across T2D genetic clusters, and identified protein interaction pathways associated with these distinct T2D subtypes. Results MOD showed consistently lower PGS compared with other T2D subtypes across all tested scores. SIDD showed more associations with SNPs mapping to residual glycemic cluster compared with other T2D subtypes. The incremental analysis of PGS004838 demonstrated a high ΔAUC of 0.101 for SIDD and a moderate ΔAUC of 0.068 for SIRD, but not for MOD and MARD. Protein interaction analyses identified candidate subtype‐associated gene networks linked to pathways related to glucose homeostasis in SIDD, insulin signalling and hepatic metabolism in SIRD, body fat distribution in MOD and vascular‐related processes in MARD. Conclusion We found heterogeneous genetic architectures across clinically defined T2D subtypes in a Middle Eastern population. Our findings provide evidence supporting differential polygenic burden, subtype genetic associations and subtype‐associated biological pathways across T2D subtypes. These observations support the utility of subtype‐based genetic analyses for improving biological understanding of T2D heterogeneity.
N. Al-Thani, S. Toor, U. Umlai et al.· Diabetes, obesity and metabo...· 0 citations
Background and Objectives: Human populations show striking phenotypic disparities in traits and diseases, including responses to infectious diseases (IDs). The impact of host genetic diversity on infection susceptibility and outcomes is increasingly recognized, yet remains largely unknown in Qatar. Here, we explored the distribution of infection-related host genetic variants in Qatar. Materials and Methods: Infection-related genetic variants from the GWAS Catalog were analyzed in 6047 Qatari whole genomes from the Qatar Genome Program (QGP) and compared with populations from the 1000 Genomes Project (1000G). Results: Out of 272,610 GWAS Catalog associations, 1086 were related to ID susceptibility, resistance, severity, progression, clearance, response to treatment, or vaccination, and hence included in the subsequent analysis. A significant heterogeneity in the allelic frequencies (AFs) between Qatari (n = 6047) and the 1000G populations (n = 2504) was observed. The QGP cohort carries significantly lower AFs of most risk variants associated with susceptibility to tuberculosis, malaria, hepatitis, diarrheal disease, and shingles (up to 222-fold, p < 0.0001). Contrarily, an enrichment in the AFs of variants that increase the risk of chickenpox, plantar warts, pneumonia, urinary tract infections (UTIs), and leprosy was observed among Qatari individuals, yet with much smaller-fold differences (≤5-fold, p < 0.0001). In addition, most severity/chronicity-related variants were considerably less prevalent in the Qatari population (up to 20.5-fold). Analysis of variants associated with antibody response revealed a distinct genetic distribution, especially in Epstein–Barr virus (EBV) and Chlamydia pneumoniae infections (27.8- and 3-fold, respectively). Moreover, a variable inter-population allelic distribution was observed in SNPs related to measles, mumps, and rubella (MMR), smallpox, and hepatitis B virus (HBV) vaccine response, as well as variants linked to viral clearance, viral load, virus-induced progression to cancer, and response to treatment. Conclusions: These findings reveal substantial differences in pathogen-associated host variants in a diverse Qatari cohort and highlight the need for follow-up validation and future GWAS discovery efforts.
M. Smatti, Y. Al-Sarraj, O. Albagha et al.· Epidemiologia· 0 citations
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