2023 / 01

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DOI: 10.24075/brsmu.2023.001

METHOD

The approach to patient clustering based on the microchip data confined to distinct loci using the combinations of variants

Iulmetova LN, Kulemin NA, Sharova EI
About authors

Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of the Federal Medical Biological Agency, Moscow, Russia

Correspondence should be addressed: Elena I. Sharova
Malaya Pirogovskaya, 1 str. 3, Moscow, 119435, Russia; moc.liamg@87avorahs

About paper

Funding: the study was supported by the President of the Russian Federation (grant for young postdocs МК-2951.2022.1.4)

Acknowledgements: the authors thank dbGaP for providing access to the phs000421.v1.p1 and phs000001.v3.p1 datasets. The dataset with the dbGaP registration number phs000421.v1.p1 was obtained from the genetic study of Fuchs' endothelial corneal dystrophy (FECD) available from https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000421.v1.p1. The authors recognize the grants that have been used to support registration of cases and controls and would be used in this GWAS: R01EY016514 (DUEC, PI: Gordon Klintworth), R01EY016482 (CWRU, PI: Sudha Iyengar) and 1X01HG006619-01 (PI: Sudha Iyengar, Natalie Afshari). The authors express their gratitude to the FECD study participants and the FECD research team for their valuable contribution to this study. The dataset with the dbGaP registration number phs000001.v3.p1 was obtained from the Age-Related Eye Disease Study (AREDS) database available from https://www.ncbi.nlm.nih.gov/projects/gap/cgi-bin/study.cgi?study_id=phs000001.v3.p1. AREDS was funded by the National Eye Institute (N01-EY-0-2127). The authors thank the AREDS participants and research team for their valuable contribution to this study. The authors express their gratitude to L.O. Skorodumova, research fellow at the Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, for valuable suggestions, comments, and support.

Author contribution: Sharova EI — concept and selection of data; Sharova EI, Iulmetova LN — planning and selection of methods; Kulemin NA — project funding and management; Iulmetova LN — design and computation; Sharova EI, Iulmetova LN, Kulemin NA — discussion, manuscript writing and editing.

Compliance with ethical standards: the study was performed according to the principles of the Declaration of Helsinki using the data of the phs000421.v1.p1 and phs000001.v3.p1 projects, the access to which was approved and provided by dbGaP in accordance with the policy of approval and access to specific datasets.

Received: 2022-12-12 Accepted: 2023-01-20 Published online: 2023-02-12
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Fig. 1. Genome-wide association study results presented through a Manhattan plot. Points represent the assessed variants. Their positions on the x axis are determined by positions of the variants in the genome, while positions on the y axis represent the degree of the disease association (–log10 of the p-value)
Fig. 2. Heatmap visualization of clustering output. Columns represent variants patients, and rows represent patients various genomic variants. Annotations on the right show the distribution of the FECD samples and the control samples within each cluster
Fig. 3. Percentage of people with the repeat expansion and no repeat expansion in the TCF4 gene intron based on the data of our study (haplotype-based approach, carriers of minor alleles of the rs784257, rs72932578, rs618869 variants) and other studies. FECD — individuals with Fuchs' endothelial corneal dystrophy, Ctrl — control group
Fig. 4. Consistency of the repeat status determination results obtained by different approaches: based on the genotypes of the rs784257, rs72932578, rs618869 variants and haplotype-based. Left — for the repeat expansion carriers in the FECD group, right — for the repeat expansion carriers in the control group
Table 1. Characteristics of the study paticipants
Table 2. Distribution of probable repeat expansion carriers across the comparison groups
Table 3. Results of experimental studies of the percentage of people with the repeat expansion in TCF4 among patients with FECD and control samples of European ancestry
Table 4. Odds ratio of finding the expansion in the group of patients with FECD compared to the control group