cardiovascularКардиоваскулярная терапия и профилактикаCardiovascular Therapy and Prevention1728-88002619-0125«SILICEA-POLIGRAF» LLC10.15829/1728-8800-2024-4275XMWWLScardiovascular-4275Research ArticleОБЗОРЫ ЛИТЕРАТУРЫREVIEW ARTICLESПолнофеномные исследования ассоциаций как исследовательский инструмент для выявления новых патогенетических связейPhenome-wide association studies as a research tool for identifying new pathogenetic linkshttps://orcid.org/0000-0003-1489-9670МашкинаН. А.MashkinaN. A.

Наталья Александровна Машкина — аспирант.

Москва

Moscow

hrychewa2018@yandex.ruhttps://orcid.org/0000-0001-7989-0760ЕршоваА. И.ErshovaA. I.

Александра Игоревна Ершова — д.м.н., зам. директора по фундаментальной науке.

Москва

Moscow

alersh@mail.ruhttps://orcid.org/0000-0001-5397-5387КопыловаО. В.KopylovaO. V.

Оксана Викторовна Копылова — к.м.н., с.н.с. лаборатории клиномики.

Москва

Moscow

sivoksana@yandex.ruhttps://orcid.org/0000-0002-4453-8430ДрапкинаО. М.DrapkinaO. M.

Оксана Михайловна Драпкина — д.м.н., профессор, директор, руководитель отдела фундаментальных прикладных аспектов ожирения.

Москва

Moscow

drapkina@bk.ruФГБУ "Национальный медицинский исследовательский центр терапии и профилактической медицины" Минздрава РоссииNational Medical Research Center for Therapy and Preventive Medicine202413022025231242754275Copyright © Машкина Н.А., Ершова А.И., Копылова О.В., Драпкина О.М., 20252025Машкина Н.А., Ершова А.И., Копылова О.В., Драпкина О.М.Mashkina N.A., Ershova A.I., Kopylova O.V., Drapkina O.M.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://cardiovascular.elpub.ru/jour/article/view/4275

Накопление биообразцов, связанных с большими массивами клинических данных (данные электронных медицинских карт, эпидемиологических и других крупномасштабных исследований), сделало возможным проведение исследований, направленных на изучение ассоциаций между генетическими вариантами и фенотипами, в частности полнофеномных исследований ассоциаций (PheWAS), изначально разработанных для проверки одного или нескольких генетических вариантов, связанных с заболеванием или клиническим симптомом, на предмет ассоциаций с другими фенотипами. PheWAS позволяют выявлять новые генетические и фенотипические ассоциации, дифференцировать истинную плейотропию и клиническую коморбидность, выделять новые подтипы заболеваний, а также находить новые мишени для лекарств. Будущие усилия, направленные на интеграцию широкого и надежного сбора фенотипических данных, а также усовершенствование инструментов для проведения PheWAS создадут ценный ресурс для более эффективного анализа генома и фенома, что приведет к новым открытиям в персонализированной медицине.

The accumulation of biospecimens associated with large-scale clinical data (data from electronic medical records, epidemiological and other large-scale studies) has made it possible to conduct studies aimed at studying associations between genetic variants and phenotypes, in particular, phenome-wide association studies (PheWAS). It was originally designed to test one or more genetic variants associated with a disease or clinical symptom for associations with other phenotypes. PheWAS can identify novel genetic and phenotypic associations, differentiate true pleiotropy and clinical comorbidity, identify new disease subtypes, and identify new drug targets. Future efforts to integrate broad and robust phenotypic data collection and improve PheWAS tools will provide a valuable resource for more efficient genome-phenome analysis, leading to new discoveries in personalized medicine.

полнофеномные исследования ассоциацийгеномфенотипфеномвариант нуклеотидной последовательностиPhenome-wide association studiesgenomephenotypephenomesequence variantReferencesDenny JC, Ritchie MD, Basford MA, et al. PheWAS: demonstrating the feasibility of a phenome-wide scan to discover gene-disease associations. Bioinformatics. 2010;26(9):1205-10. doi:10.1093/BIOINFORMATICS/BTQ126.Denny JC, Ritchie MD, Basford MA, et al. PheWAS: demonstrating the feasibility of a phenome-wide scan to discover gene-disease associations. Bioinformatics. 2010;26(9):1205-10. doi:10.1093/BIOINFORMATICS/BTQ126.Denny JC, Bastarache L, Roden DM. Phenome-Wide Association Studies as a Tool to Advance Precision Medicine. Annu Rev Genomics Hum Genet. 2016;17(1):353-73. doi:10.1146/annurevgenom-090314-024956.Denny JC, Bastarache L, Roden DM. Phenome-Wide Association Studies as a Tool to Advance Precision Medicine. Annu Rev Genomics Hum Genet. 2016;17(1):353-73. doi:10.1146/annurevgenom-090314-024956.Liu TY, Liao WL, Wang TY, et al. Genome-wide association study of hyperthyroidism based on electronic medical record from Taiwan. Front Med. 2022;9. doi:10.3389/fmed.2022.830621.Liu TY, Liao WL, Wang TY, et al. Genome-wide association study of hyperthyroidism based on electronic medical record from Taiwan. Front Med. 2022;9. doi:10.3389/fmed.2022.830621.Liu S, Crawford DC. Maturation and application of phenomewide association studies. Trends Genet. 2022;38(4):353-63. doi:10.1016/j.tig.2021.12.002.Liu S, Crawford DC. Maturation and application of phenomewide association studies. Trends Genet. 2022;38(4):353-63. doi:10.1016/j.tig.2021.12.002.Wang L, Zhang X, Meng X, et al. Methodology in phenomewide association studies: a systematic review. J Med Genet. 2021;58(11):720-8. doi:10.1136/jmedgenet-2021-107696.Wang L, Zhang X, Meng X, et al. Methodology in phenomewide association studies: a systematic review. J Med Genet. 2021;58(11):720-8. doi:10.1136/jmedgenet-2021-107696.Roden DM. Phenome‐wide association studies: a new method for functional genomics in humans. J Physiol. 2017;595(12):4109-15. doi:10.1113/JP273122.Roden DM. Phenome‐wide association studies: a new method for functional genomics in humans. J Physiol. 2017;595(12):4109-15. doi:10.1113/JP273122.Verma A, Verma SS, Pendergrass SA, et al. eMERGE PhenomeWide Association Study (PheWAS) identifies clinical associations and pleiotropy for stop-gain variants. BMC Med Genomics. 2016; 9(S1):32. doi:10.1186/s12920-016-0191-8.Verma A, Verma SS, Pendergrass SA, et al. eMERGE PhenomeWide Association Study (PheWAS) identifies clinical associations and pleiotropy for stop-gain variants. BMC Med Genomics. 2016; 9(S1):32. doi:10.1186/s12920-016-0191-8.Wu P, Gifford A, Meng X, et al. Mapping ICD-10 and ICD-10-CM Codes to Phecodes: Workflow Development and Initial Evaluation. JMIR Med Informatics. 2019;7(4):e14325. doi:10.2196/14325.Wu P, Gifford A, Meng X, et al. Mapping ICD-10 and ICD-10-CM Codes to Phecodes: Workflow Development and Initial Evaluation. JMIR Med Informatics. 2019;7(4):e14325. doi:10.2196/14325.Passero K, He X, Zhou J, et al. Phenome-wide association studies on cardiovascular health and fatty acids considering phenotype quality control practices for epidemiological data. Pac Symp Biocomput. 2020;25:659-70.Passero K, He X, Zhou J, et al. Phenome-wide association studies on cardiovascular health and fatty acids considering phenotype quality control practices for epidemiological data. Pac Symp Biocomput. 2020;25:659-70.Verma A, Bradford Y, Dudek S, et al. A simulation study investigating power estimates in phenome-wide association studies. BMC Bioinformatics. 2018;19(1):120. doi:10.1186/s12859-018-2135-0.Verma A, Bradford Y, Dudek S, et al. A simulation study investigating power estimates in phenome-wide association studies. BMC Bioinformatics. 2018;19(1):120. doi:10.1186/s12859-018-2135-0.Bastarache L, Denny JC, Roden DM. Phenome-Wide Association Studies. JAMA. 2022;327(1):75. doi:10.1001/jama.2021.20356.Bastarache L, Denny JC, Roden DM. Phenome-Wide Association Studies. JAMA. 2022;327(1):75. doi:10.1001/jama.2021.20356.Hebbring SJ. The challenges, advantages and future of phenomewide association studies. Immunology. 2014;141(2):157-65. doi:10.1111/imm.12195.Hebbring SJ. The challenges, advantages and future of phenomewide association studies. Immunology. 2014;141(2):157-65. doi:10.1111/imm.12195.Pendergrass SA, Brown-Gentry K, Dudek S, et al. Phenome-Wide Association Study (PheWAS) for Detection of Pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network. Gibson G, ed. PLoS Genet. 2013;9(1):e1003087. doi:10.1371/journal.pgen.1003087.Pendergrass SA, Brown-Gentry K, Dudek S, et al. Phenome-Wide Association Study (PheWAS) for Detection of Pleiotropy within the Population Architecture using Genomics and Epidemiology (PAGE) Network. Gibson G, ed. PLoS Genet. 2013;9(1):e1003087. doi:10.1371/journal.pgen.1003087.Evangelou E, Ioannidis JPA. Meta-analysis methods for genomewide association studies and beyond. Nat Rev Genet. 2013; 14(6):379-89. doi:10.1038/nrg3472.Evangelou E, Ioannidis JPA. Meta-analysis methods for genomewide association studies and beyond. Nat Rev Genet. 2013; 14(6):379-89. doi:10.1038/nrg3472.Simonti CN, Vernot B, Bastarache L, et al. The phenotypic legacy of admixture between modern humans and Neandertals. Science. 2016;351(6274):737-41. doi:10.1126/science.aad2149.Simonti CN, Vernot B, Bastarache L, et al. The phenotypic legacy of admixture between modern humans and Neandertals. Science. 2016;351(6274):737-41. doi:10.1126/science.aad2149.Thériault S, Dina C, Messika-Zeitoun D, et al. Genetic Association Analyses Highlight IL6, ALPL, and NAV1 As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis. Circ Genomic Precis Med. 2019;12(10):e002617. doi:10.1161/CIRCGEN.119.002617.Thériault S, Dina C, Messika-Zeitoun D, et al. Genetic Association Analyses Highlight IL6, ALPL, and NAV1 As 3 New Susceptibility Genes Underlying Calcific Aortic Valve Stenosis. Circ Genomic Precis Med. 2019;12(10):e002617. doi:10.1161/CIRCGEN.119.002617.Leppert B, Millard LAC, Riglin L, et al. A cross-disorder PRSpheWAS of 5 major psychiatric disorders in UK Biobank. Zhu X, ed. PLOS Genet. 2020;16(5):e1008185. doi:10.1371/journal.pgen.1008185.Leppert B, Millard LAC, Riglin L, et al. A cross-disorder PRSpheWAS of 5 major psychiatric disorders in UK Biobank. Zhu X, ed. PLOS Genet. 2020;16(5):e1008185. doi:10.1371/journal.pgen.1008185.Плотников Д. Ю. Менделевская рандомизация: применение генетической информации в эпидемиологических исследованиях (обзор). Научные результаты биомедицинских исследований. 2023; 9(2):158-72. doi:10.18413/2658-6533-2023-9-2-0-1.Plotnikov DY. Mendelian randomization: using genetic information in epidemiological studies (review). Research Results in Biomedicine. 2023;9(2):158-72. (In Russ.) doi:10.18413/2658-6533-2023-9-2-0-1.Reay WR, Kiltschewskij DJ, Di Biase MA, et al. Genetic influences on circulating retinol and its relationship to human health. Nat Commun. 2024;15(1):1490. doi:10.1038/s41467-024-45779-x.Reay WR, Kiltschewskij DJ, Di Biase MA, et al. Genetic influences on circulating retinol and its relationship to human health. Nat Commun. 2024;15(1):1490. doi:10.1038/s41467-024-45779-x.Lumsden AL, Mulugeta A, Zhou A, Hyppönen E. Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank. eBioMedicine. 2020;59:102954. doi:10.1016/j.ebiom.2020.102954.Lumsden AL, Mulugeta A, Zhou A, Hyppönen E. Apolipoprotein E (APOE) genotype-associated disease risks: a phenome-wide, registry-based, case-control study utilising the UK Biobank. eBioMedicine. 2020;59:102954. doi:10.1016/j.ebiom.2020.102954.Namjou B, Marsolo K, Caroll RJ, et al. Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eosinophilic Esophagitis. Front Genet. 2014;5. doi:10.3389/fgene.2014.00401.Namjou B, Marsolo K, Caroll RJ, et al. Phenome-wide association study (PheWAS) in EMR-linked pediatric cohorts, genetically links PLCL1 to speech language development and IL5-IL13 to Eosinophilic Esophagitis. Front Genet. 2014;5. doi:10.3389/fgene.2014.00401.Denny JC, Bastarache L, Ritchie MD, et al. Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data. Nat Biotechnol. 2013;31(12):1102-11. doi:10.1038/nbt.2749.Denny JC, Bastarache L, Ritchie MD, et al. Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data. Nat Biotechnol. 2013;31(12):1102-11. doi:10.1038/nbt.2749.Li X, Meng X, He Y, et al. Genetically determined serum urate levels and cardiovascular and other diseases in UK Biobank cohort: A phenome-wide mendelian randomization study. Rahimi K, ed. PLOS Med. 2019;16(10):e1002937. doi:10.1371/journal.pmed.1002937.Li X, Meng X, He Y, et al. Genetically determined serum urate levels and cardiovascular and other diseases in UK Biobank cohort: A phenome-wide mendelian randomization study. Rahimi K, ed. PLOS Med. 2019;16(10):e1002937. doi:10.1371/journal.pmed.1002937.Zheutlin AB, Dennis J, Karlsson Linnér R, et al. Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia in 106,160 Patients Across Four Health Care Systems. Am J Psychiatry. 2019;176(10):846-55. doi:10.1176/appi.ajp.2019.18091085.Zheutlin AB, Dennis J, Karlsson Linnér R, et al. Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia in 106,160 Patients Across Four Health Care Systems. Am J Psychiatry. 2019;176(10):846-55. doi:10.1176/appi.ajp.2019.18091085.Safarova MS, Satterfield BA, Fan X, et al. A phenome-wide association study to discover pleiotropic effects of PCSK9, APOB, and LDLR. NPJ Genomic Med. 2019;4(1):3. doi:10.1038/s41525019-0078-7.Safarova MS, Satterfield BA, Fan X, et al. A phenome-wide association study to discover pleiotropic effects of PCSK9, APOB, and LDLR. NPJ Genomic Med. 2019;4(1):3. doi:10.1038/s41525019-0078-7.Nam Y, Jung SH, Yun JS, et al. Discovering comorbid diseases using an inter-disease interactivity network based on biobankscale PheWAS data. Wren J, ed. Bioinformatics. 2023;39(1). doi:10.1093/bioinformatics/btac822.Nam Y, Jung SH, Yun JS, et al. Discovering comorbid diseases using an inter-disease interactivity network based on biobankscale PheWAS data. Wren J, ed. Bioinformatics. 2023;39(1). doi:10.1093/bioinformatics/btac822.Prinzbach A, Moosavinasab S, Rust S, et al. Comorbidities in Childhood Celiac Disease. J Pediatr Gastroenterol Nutr. 2018; 67(4):488-93. doi:10.1097/MPG.0000000000002020.Prinzbach A, Moosavinasab S, Rust S, et al. Comorbidities in Childhood Celiac Disease. J Pediatr Gastroenterol Nutr. 2018; 67(4):488-93. doi:10.1097/MPG.0000000000002020.Chen SY, Chen YC, Liu TY, et al. Novel Genes Associated With Atrial Fibrillation and the Predictive Models for AF Incorporating Polygenic Risk Score and PheWAS-Derived Risk Factors. Can J Cardiol. 2024;40(11):2117-27. doi:10.1016/j.cjca.2024.07.029.Chen SY, Chen YC, Liu TY, et al. Novel Genes Associated With Atrial Fibrillation and the Predictive Models for AF Incorporating Polygenic Risk Score and PheWAS-Derived Risk Factors. Can J Cardiol. 2024;40(11):2117-27. doi:10.1016/j.cjca.2024.07.029.Larsson SC, Wang L, Li X, Jiang F, Chen X, Mantzoros CS. Circulating lipoprotein(a) levels and health outcomes: Phenomewide Mendelian randomization and disease-trajectory analyses. Metabolism. 2022;137:155347. doi:10.1016/j.metabol.2022.155347.Larsson SC, Wang L, Li X, Jiang F, Chen X, Mantzoros CS. Circulating lipoprotein(a) levels and health outcomes: Phenomewide Mendelian randomization and disease-trajectory analyses. Metabolism. 2022;137:155347. doi:10.1016/j.metabol.2022.155347.Liu J, de Vries PS, Del Greco MF, et al. A multi-omics study of circulating phospholipid markers of blood pressure. Sci Rep. 2022;12(1):574. doi:10.1038/s41598-021-04446-7.Liu J, de Vries PS, Del Greco MF, et al. A multi-omics study of circulating phospholipid markers of blood pressure. Sci Rep. 2022;12(1):574. doi:10.1038/s41598-021-04446-7.Millwood IY, Bennett DA, Walters RG, et al. A phenome-wide association study of a lipoprotein-associated phospholipase A 2 loss-of-function variant in 90 000 Chinese adults. Int J Epidemiol. 2016;45(5):1588-99. doi:10.1093/ije/dyw087.Millwood IY, Bennett DA, Walters RG, et al. A phenome-wide association study of a lipoprotein-associated phospholipase A 2 loss-of-function variant in 90 000 Chinese adults. Int J Epidemiol. 2016;45(5):1588-99. doi:10.1093/ije/dyw087.Meng X, Li X, Timofeeva MN, et al. Phenome-wide Mendelianrandomization study of genetically determined vitamin D on multiple health outcomes using the UK Biobank study. Int J Epidemiol. 2019;48(5):1425-34. doi:10.1093/ije/dyz182.Meng X, Li X, Timofeeva MN, et al. Phenome-wide Mendelianrandomization study of genetically determined vitamin D on multiple health outcomes using the UK Biobank study. Int J Epidemiol. 2019;48(5):1425-34. doi:10.1093/ije/dyz182.Jerome RN, Joly MM, Kennedy N, et al. Leveraging Human Genetics to Identify Safety Signals Prior to Drug Marketing Approval and Clinical Use. Drug Saf. 2020;43(6):567-82. doi:10.1007/s40264-020-00915-6.Jerome RN, Joly MM, Kennedy N, et al. Leveraging Human Genetics to Identify Safety Signals Prior to Drug Marketing Approval and Clinical Use. Drug Saf. 2020;43(6):567-82. doi:10.1007/s40264-020-00915-6.Diogo D, Tian C, Franklin CS, et al. Phenome-wide association studies across large population cohorts support drug target validation. Nat Commun. 2018;9(1):4285. doi:10.1038/s41467018-06540-3.Diogo D, Tian C, Franklin CS, et al. Phenome-wide association studies across large population cohorts support drug target validation. Nat Commun. 2018;9(1):4285. doi:10.1038/s41467018-06540-3.Jerome RN, Pulley JM, Roden DM, et al. Using Human "Experiments of Nature" to Predict Drug Safety Issues: An Example with PCSK9 Inhibitors. Drug Saf. 2018;41(3):303-11. doi:10.1007/s40264-017-0616-0.Jerome RN, Pulley JM, Roden DM, et al. Using Human "Experiments of Nature" to Predict Drug Safety Issues: An Example with PCSK9 Inhibitors. Drug Saf. 2018;41(3):303-11. doi:10.1007/s40264-017-0616-0.

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