Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes,Nature Communications

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Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes
Nature Communications ( IF 14.7 ) Pub Date : 2021-05-10 , DOI: 10.1038/s41467-021-22338-2
Raha Pazoki _{1,

2} , Marijana Vujkovic _{3,

4} , Joshua Elliott _{1,

5} , Evangelos Evangelou _{1,

6} , Dipender Gill _{1,

7} , Mohsen Ghanbari _{8,

9} , Peter J van der Most ₁₀ , Rui Climaco Pinto _{1,

11} , Matthias Wielscher _{1,

12} , Matthias Farlik ₁₂ , Verena Zuber ₁ , Robert J de Knegt ₁₃ , Harold Snieder ₁₀ , André G Uitterlinden ₁₄ , , Julie A Lynch _{15,

16} , Xiyun Jiang ₂ , Saredo Said ₁ , David E Kaplan _{3,

4} , Kyung Min Lee _{15,

17} , Marina Serper _{3,

4} , Rotonya M Carr _{3,

4} , Philip S Tsao _{18,

19} , Stephen R Atkinson ₂₀ , Abbas Dehghan _{1,

11} , Ioanna Tzoulaki _{1,

6} , M Arfan Ikram ₈ , Karl-Heinz Herzig _{21,

22,

23} , Marjo-Riitta Järvelin _{1,

24,

25,

26} , Behrooz Z Alizadeh ₁₀ , Christopher J O'Donnell _{27,

28,

29} , Danish Saleheen ₃₀ , Benjamin F Voight _{3,

31,

32,

33} , Kyong-Mi Chang _{3,

4} , Mark R Thursz ₂₀ , Paul Elliott _{1,

7,

11,

34,

35} ,

Affiliation

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, London, UK.
Division of Biomedical Sciences, Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK.
Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Royal Surrey County Hospital, Guildford, Surrey, UK.
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
British Heart Foundation Centre of Research Excellence, Imperial College London, London, UK.
Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
UK Dementia Research Institute, Imperial College London, London, UK.
Department of Dermatology, Medical University of Vienna, Vienna, Austria.
Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
University of Massachusetts, Boston, MA, USA.
School of Medicine, University of Utah, Salt Lake City, UT, USA.
VA Palo Alto Health Care System, Palo Alto, CA, USA.
School of Medicine, Stanford University, Stanford, CA, USA.
Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK.
Institute of Biomedicine, Medical Research Center Oulu, Oulu University, Oulu, Finland.
Oulu University Hospital, Oulu, Finland.
Institute of Pediatrics, Poznan University of Medical Sciences, Poznan, Poland.
Center for Life Course Health Research, Faculty of Medicine, Oulu University, Oulu, Finland.
Department of Life Sciences, College of Health and Life Sciences, Brunel University London, Uxbridge, UK.
Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
VA Boston Healthcare System, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Brigham Women's Hospital, Boston, MA, USA.
Departments of Medicine and Cardiology, Columbia University, New York City, NY, USA.
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Institute for Translational Medicine and Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
National Institute for Health Research, Imperial Biomedical Research Centre, Imperial College London, London, UK.
Health Data Research UK at Imperial College London, London, UK.

Serum concentration of hepatic enzymes are linked to liver dysfunction, metabolic and cardiovascular diseases. We perform genetic analysis on serum levels of alanine transaminase (ALT), alkaline phosphatase (ALP) and gamma-glutamyl transferase (GGT) using data on 437,438 UK Biobank participants. Replication in 315,572 individuals from European descent from the Million Veteran Program, Rotterdam Study and Lifeline study confirms 517 liver enzyme SNPs. Genetic risk score analysis using the identified SNPs is strongly associated with serum activity of liver enzymes in two independent European descent studies (The Airwave Health Monitoring study and the Northern Finland Birth Cohort 1966). Gene-set enrichment analysis using the identified SNPs highlights involvement in liver development and function, lipid metabolism, insulin resistance, and vascular formation. Mendelian randomization analysis shows association of liver enzyme variants with coronary heart disease and ischemic stroke. Genetic risk score for elevated serum activity of liver enzymes is associated with higher fat percentage of body, trunk, and liver and body mass index. Our study highlights the role of molecular pathways regulated by the liver in metabolic disorders and cardiovascular disease.

中文翻译：

欧洲血统个体的遗传分析确定了 517 个与肝酶相关的位点

肝酶的血清浓度与肝功能障碍、代谢和心血管疾病有关。我们使用 437,438 名英国生物银行参与者的数据对血清丙氨酸转氨酶 (ALT)、碱性磷酸酶 (ALP) 和γ-谷氨酰转移酶 (GGT) 水平进行遗传分析。来自百万退伍军人计划、鹿特丹研究和生命线研究的 315,572 名欧洲人后裔的复制证实了 517 个肝酶 SNP。在两项独立的欧洲血统研究（电波健康监测研究和芬兰北部出生队列 1966）中，使用已识别 SNP 的遗传风险评分分析与肝酶的血清活性密切相关。使用已识别的 SNP 的基因集富集分析突出了肝脏发育和功能、脂质代谢、胰岛素抵抗、和血管形成。孟德尔随机化分析显示肝酶变异与冠心病和缺血性中风相关。肝酶血清活性升高的遗传风险评分与较高的身体、躯干和肝脏脂肪百分比以及体重指数相关。我们的研究强调了肝脏调节的分子通路在代谢紊乱和心血管疾病中的作用。

更新日期：2021-05-10

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