Abstract The severity of COVID-19 disease is partly determined by host genetic factors that have been reported by GWAS. We evaluated nine previously reported genome-wide significant associations regardless of the disease severity in a representative sample from the population of Latvia. Our cohort consisted of 475 SARS-CoV-2 positive cases, from which 146 were hospitalized individuals and 2217 controls. We found three variants from Neanderthal introgression event at the 3p21.31 region to be significantly associated with increased risk of SARS-CoV-2 infection and hospitalization status. The strongest association was displayed by rs71325088 with Bonferroni adjusted P=0.007, OR=1.46 [95% CI 1.17-1.81]. We performed fine-mapping by exploring 1 Mb region at 3p21.31 locus and identified 9 SNPs with even lower p-values with the strongest association estimated for rs2191031 P=5e-05, OR = 1.40[CI 95% 1.19-1.64] located in the LZTFL1. We show clear replication of 3p.21.31 locus in an independent cohort which favors further functional investigation of leading variants.
AbstractBackground: Maturity-onset Diabetes of the Young (MODY) presents a diagnostic challenge, with a large proportion of cases lacking identifiable genetic mutations, which could lead to sub-optimal medical treatment and, subsequently, a decline in patients’ life quality. This study investigates the utility of polygenic risk score (PRS) in distinguishing monogenic diabetes from early-onset type 1 diabetes (T1D) and type 2 diabetes (T2D) cases to enhance diagnostic accuracy. Methods: We investigated the genetic basis of early-onset diabetes in a Latvian cohort comprising 66 patients, contrasted with 174 non-diabetic controls, using whole-genome sequencing (WGS). Results: We identified 22 causative mutations in three MODY genes (GCK, HNF1A,and HNF4A), eight of them being novel. We selected and tested the best-performing population specific T1D and T2D PRS models on the established diabetic cohort and controls. Patients without genetically confirmed MODY had a significantly higher risk for T1D compared to controls. A 75% centile of T1D-PRS included only 8.7% of the genetically confirmed MODY patients, compared to 34% of patients without mutations, providing good specificity for the identification of indicative T1D at this PRS range. While T2D-PRS was increased in the diabetic cohort, it did not demonstrate an ability to discriminate between MODY-positive and negative subgroups. Conclusions: Our study demonstrates that the application of WGS improves diagnostic accuracy and highlights the potential of T1D-PRS as a critical tool for the stratification of MODY-suspected patients.
Abstract Background Type 2 diabetes complications cause a serious emotional and economical burden to patients and healthcare systems globally. Management of both acute and chronic complications of diabetes, which dramatically impair the quality of patients' life, is still an unsolved issue in diabetes care, suggesting a need for early identification of individuals with high risk for developing diabetes complications. Methods We performed a genome-wide association study in 601 type 2 diabetes patients after stratifying them according to the presence or absence of four types of diabetes complications: diabetic neuropathy, diabetic nephropathy, macrovascular complications, and ophthalmic complications. Results The analysis revealed ten novel associations showing genome-wide significance, including rs1132787 ( GYPA, OR = 2.71; 95% CI = 2.02–3.64) and diabetic neuropathy, rs2477088 ( PDE4DIP , OR = 2.50; 95% CI = 1.87–3.34), rs4852954 ( NAT8 , OR = 2.27; 95% CI = 2.71–3.01), rs6032 ( F5 , OR = 2.12; 95% CI = 1.63–2.77), rs6935464 ( RPS6KA2 , OR = 2.25; 95% CI = 6.69–3.01) and macrovascular complications, rs3095447 ( CCDC146 , OR = 2.18; 95% CI = 1.66–2.87) and ophthalmic complications. By applying the targeted approach of previously reported susceptibility loci we managed to replicate three associations: MAPK14 (rs3761980, rs80028505) and diabetic neuropathy, APOL1 (rs136161) and diabetic nephropathy. Conclusions Together these results provide further evidence for the implication of genetic factors in the development of type 2 diabetes complications and highlight several potential key loci, able to modify the risk of developing these conditions. Moreover, the candidate variant approach proves a strong and consistent effect for multiple variants across different populations.
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