Ivanna Atava

Latvian Biomedical Research and Study Centre

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Jānis Kloviņš

Latvian Biomedical Research and Study Centre

Monta Brīvība

Latvian Biomedical Research and Study Centre

Raitis Pečulis

Latvian Biomedical Research and Study Centre

Raimonds Reščenko

Latvian Biomedical Research and Study Centre

Līga Birzniece

Latvian Biomedical Research and Study Centre

Ilze Elbere

Latvian Biomedical Research and Study Centre

Kaspars Megnis

Latvian Biomedical Research and Study Centre

Laura Ansone

Latvian Biomedical Research and Study Centre

Ivars Silamiķelis

Latvian Biomedical Research and Study Centre

Iveta Dzīvīte-Krišāne

Children's Clinical University Hospital

Cooperative Institutions

Latvian Biomedical Research and Study Centre

University of Latvia

Latvia University of Life Sciences and Technologies

Pauls Stradiņš Clinical University Hospital

Unidad de Cirugía Artroscópica

Foundation for Ichthyosis and Related Skin Types

European Atherosclerosis Society

Riga Stradiņš University

Children's Clinical University Hospital

BGI Group (China)

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Improved Genetic Characterization of Hypercholesterolemia in Latvian Patients with Familial Hypercholesterolemia: A Combined Monogenic and Polygenic Approach Using Whole-Genome Sequencing

International Journal of Molecular Sciences (2024)

Ivanna Atava Monta Brīvība Georgijs Nesterovics Vita Saripo Dainus Gilis

Despite the implementation of next-generation sequencing-based genetic testing on patients with clinical familial hypercholesterolemia (FH), most cases lack complete genetic characterization. We aim to investigate the utility of the polygenic risk score (PRS) in specifying the genetic background of patients from the Latvian Registry of FH (LRFH). We analyzed the whole-genome sequencing (WGS) data of the clinically diagnosed FH patients (n = 339) and controls selected from the Latvian reference population (n = 515). Variant pathogenicity in FH patients was classified according to the ACMG/AMP guidelines. The low-density lipoprotein cholesterol (LDL-C) and lipoprotein (a) (LPA) PRS were calculated based on the WGS data. We identified unique causative variants in 80 (23.6%) of the tested individuals (39 variants in FH genes and 4 variants in phenocopy genes, with 6 variants being novel). The LDL-C PRS was highly discriminative compared to the LPA PRS. Nevertheless, both PRS were able to explain the genetic cause of hypercholesterolemia in 26.3% of the remaining non-monogenic patients. The combined genetic analysis of monogenic and polygenic hypercholesterolemia resulted in 43.7% genetically explained hypercholesterolemia cases. Even though the application of PRS alone does not exclude monogenic testing in clinical FH patients, it is a valuable tool for diagnosis specification.

Phenocopy

10.3390/ijms252413466

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Identification Of Pathogenic Mutations And Application Of Polygenic Risk Scores In Early-Onset Diabetes Patients

Research Square (Research Square) (2024)

Ivanna Atava Raimonds Reščenko Monta Brīvība Līga Birzniece Ilze Elbere

Abstract Background: 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.

Polygenic risk score

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10.21203/rs.3.rs-5361647/v1

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Evaluating the Efficacy of Type 2 Diabetes Polygenic Risk Scores in an Independent European Population

International Journal of Molecular Sciences (2024)

Monta Brīvība Ivanna Atava Raitis Pečulis Ilze Elbere Laura Ansone

Numerous type 2 diabetes (T2D) polygenic risk scores (PGSs) have been developed to predict individuals’ predisposition to the disease. An independent assessment and verification of the best-performing PGS are warranted to allow for a rapid application of developed models. To date, only 3% of T2D PGSs have been evaluated. In this study, we assessed all (n = 102) presently published T2D PGSs in an independent cohort of 3718 individuals, which has not been included in the construction or fine-tuning of any T2D PGS so far. We further chose the best-performing PGS, assessed its performance across major population principal component analysis (PCA) clusters, and compared it with newly developed population-specific T2D PGS. Our findings revealed that 88% of the published PGSs were significantly associated with T2D; however, their performance was lower than what had been previously reported. We found a positive association of PGS improvement over the years (p-value = 8.01 × 10−4 with PGS002771 currently showing the best discriminatory power (area under the receiver operating characteristic (AUROC) = 0.669) and PGS003443 exhibiting the strongest association PGS003443 (odds ratio (OR) = 1.899). Further investigation revealed no difference in PGS performance across major population PCA clusters and when compared with newly developed population-specific PGS. Our findings revealed a positive trend in T2D PGS performance, consistently identifying high-T2D-risk individuals in an independent European population.

10.3390/ijms25021151

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

International Journal of Molecular Sciences (2023)

Raimonds Reščenko Monta Brīvība Ivanna Atava Vita Rovīte Raitis Pečulis

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.

Imputation (statistics)

dbSNP

Personal genomics

1000 Genomes Project

Human genetic variation

10.3390/ijms242015345

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Identification Of Pathogenic Mutations And Application Of Polygenic Risk Scores To Differentiate MODY Patients From Other Diabetes Types

Research Square (Research Square) (2024)

Ivanna Atava Raimonds Reščenko Monta Brīvība Līga Birzniece Ilze Elbere

Abstract Maturity-onset Diabetes of the Young (MODY) presents a diagnostic challenge, with a large proportion of cases lacking identifiable genetic mutations. This study investigates the genetic basis of MODY in a Latvian cohort comprising 66 suspected MODY families, contrasted with 177 non-diabetic controls. Employing panel-based and whole-genome sequencing (WGS), we identified 22 pathogenic mutations in three MODY genes ( GCK , HNF1A , and HNF4A ), eight of them being novel. We selected and tested the best-performing population specific type 1 diabetes (T1D) and type 2 diabetes (T2D) polygenic risk score (PRS) models on the established MODY 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 MODY cohort, it did not demonstrate an ability to discriminate between both MODY subgroups. In summary, our study demonstrates that the application of WGS improves diagnostic accuracy and highlights the potential of T1D-PRS as a critical tool for stratification of MODY suspected patients.

Polygenic risk score

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10.21203/rs.3.rs-4109118/v1

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