Whole-Genome Sequencing of 502 Individuals from Latvia: The First Step towards a Population-Specific Reference of Genetic Variation.

Despite rapid improvements in the accessibility of whole-genome sequencing (WGS), understanding the extent of human genetic variation is limited by the scarce availability of genome sequences from underrepresented populations. Developing the population-scale reference database of Latvian genetic variation may fill the gap in European genomes and improve human genomics research. In this study, we analysed a high-coverage WGS dataset comprising 502 individuals selected from the Genome Database of the Latvian Population. An assessment of variant type, location in the genome, function, medical relevance, and novelty was performed, and a population-specific imputation reference panel (IRP) was developed. We identified more than 18.2 million variants in total, of which 3.3% so far are not represented in gnomAD and dbSNP databases. Moreover, we observed a notable though distinct clustering of the Latvian cohort within the European subpopulations. Finally, our findings demonstrate the improved performance of imputation of variants using the Latvian population-specific reference panel in the Latvian population compared to established IRPs. In summary, our study provides the first WGS data for a regional reference genome that will serve as a resource for the development of precision medicine and complement the global genome dataset, improving the understanding of human genetic variation.

Novel susceptibility loci identified in a genome-wide association study of type 2 diabetes complications in population of Latvia.

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.