vavilovВавиловский журнал генетики и селекцииVavilov Journal of Genetics and Breeding2500-3259Institute of Cytology and Genetics of Siberian Branch of the RAS10.18699/VJ19.585vavilov-2396Research ArticleМОЛЕКУЛЯРНЫЕ МАРКЕРЫ В ГЕНЕТИКЕ И СЕЛЕКЦИИBIOINFORMATICS AND SYSTEM BIOLOGYIn silico поиск генов, контролирующих ишемическую болезнь сердцаIn silico mapping of coronary artery disease genesЗоркольцеваИ. В.ZorkoltsevaI. V.

Новосибирск

Novosibirsk

zor@bionet.nsc.ruБелоноговаН. М.BelonogovaN. M.

Новосибирск

Novosibirsk

СвищёваГ. Р.SvishchevaG. R.

Новосибирск; Москва

Novosibirsk; Moscow

КириченкоА. В.KirichenkoA. V.

Новосибирск

Novosibirsk

АксеновичТ. И.AxenovichT. I.

Новосибирск

Novosibirsk

Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Cytology and Genetics, SB RASRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Институт общей генетики им. Н.И. Вавилова Российской академии наукРоссияInstitute of Cytology and Genetics, SB RAS; Vavilov Institute of General Genetics, RASRussian FederationФедеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Новосибирский национальный исследовательский государственный университетРоссияInstitute of Cytology and Genetics, SB RAS; Novosibirsk State UniversityRussian Federation20190901202023810371046Copyright © Зоркольцева И.В., Белоногова Н.М., Свищёва Г.Р., Кириченко А.В., Аксенович Т.И., 20202020Зоркольцева И.В., Белоногова Н.М., Свищёва Г.Р., Кириченко А.В., Аксенович Т.И.Zorkoltseva I.V., Belonogova N.M., Svishcheva G.R., Kirichenko A.V., Axenovich T.I.This work is licensed under a Creative Commons Attribution 4.0 License.https://vavilov.elpub.ru/jour/article/view/2396

К настоящему времени с помощью крупномасштабных полногеномных исследований обнаружено более 100 локусов, ассоциированных с ишемической болезнью сердца (ИБС). Для некоторых из нескольких сотен генов, лежащих в этих локусах, была показана их роль в патогенезе болезни. Тем не менее основные генетические механизмы и конкретные гены, контролирующие заболевание, все еще полностью не известны. Данное исследование посвящено in silico поиску новых генов, контролирующих ИБС. Проведен региональный анализ ассоциаций, при котором все полиморфные варианты внутри гена анализируются одновременно. Материалом для анализа служили результаты полногеномного анализа ассоциаций, депонированные в открытых базах данных MICAD (120 575 человек, 85 112 маркеров) и UK Biobank (337 199 человек, 10 894 597 маркеров). Использовался программный пакет sumFREGAT, в котором реализован широкий спектр новых методов для тестирования генных ассоциаций с помощью суммарных статистик. Всего было обнаружено 88 генов. Из них 44 являются уже известными для ИБС генами. Кроме того, в известных локусах нами идентифицировано 28 дополнительных генов, которые можно рассматривать в качестве новых генов-кандидатов. 16 генов (AGPAT4, ARHGEF12, BDP1, DHX58, EHBP1, FBF1, HSPB9, NPBWR2, PDLIM5, PLCB3, PLEKHM2, POU2F3, PRKD2, TMEM136, TTC29 и UTP20), обнаруженных нами вне известных локусов, являются новыми. Информация о функциональной роли этих генов позволяет рассматривать многие из них в качестве кандидатов для ИБС. Среди набора идентифицированных генов 41 ген не имел значимых сигналов полногеномного анализа ассоциаций и был идентифицирован только благодаря одновременному рассмотрению всех вариантов внутри гена в рамках регионального анализа ассоциаций. Полученные результаты демонстрируют, что региональный анализ ассоциаций представляет собой мощный инструмент для поиска новых генов. Он применим для анализа различных признаков и болезней с использованием накопленных в мире огромных объемов данных, полученных с помощью полногеномного анализа ассоциаций. Такие исследования общедоступны, поскольку не требуют дополнительных материальных затрат.

To date, more than 100 loci associated with coronary artery disease (CAD) have been detected in large-scale genome-wide studies. For some of the several hundreds of genes located in these loci, roles in the pathogenesis of the disease have been shown. However, the genetic mechanisms and specific genes controlling this disease are still not fully understood. This study is aimed at in silico search for new CAD genes. We performed a gene-based association analysis, where all polymorphic variants within a gene are analyzed simultaneously. The analysis was based on the results of the genome-wide association studies (GWAS) available from the open databases MICAD (120,575 people, 85,112 markers) and UK Biobank (337,199 people, 10,894,597 markers). We used the sumFREGAT package implementing a wide range of new methods for gene-based association analysis using summary statistics. We found 88 genes demonstrating significant gene-based associations. Forty-four of the identified genes were already known as CAD genes. Furthermore, we identified 28 additional genes in the known CAD loci. They can be considered as new candidate genes. Finally, we identified sixteen new genes (AGPAT4, ARHGEF12, BDP1, DHX58, EHBP1, FBF1, HSPB9, NPBWR2, PDLIM5, PLCB3, PLEKHM2, POU2F3, PRKD2, TMEM136, TTC29 and UTP20) outside the known loci. Information about the functional role of these genes allows us to consider many of them as candidates for CAD. The 41 identified genes did not have significant GWAS signals and they were identified only due to simultaneous consideration of all variants within the gene in the framework of gene-based analysis. These results demonstrate that gene-based association analysis is a powerful tool for gene mapping. The method can utilize huge amounts of GWAS results accumulated in the world to map different traits and diseases. This type of studies is widely available, as it does not require additional material costs.

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The authors declare that there are no conflicts of interest present.