Genetic analysis in European ancestry individuals identifies 517 loci associated with liver enzymes.

Aged Alanine Transaminase / blood Alkaline Phosphatase / blood Cardiovascular Diseases / enzymology Cohort Studies Databases, Genetic Female Gene Expression Regulation, Enzymologic / genetics Genetic Predisposition to Disease Genetic Testing Genome-Wide Association Study Humans Insulin Resistance / genetics Lipid Metabolism / genetics Liver / enzymology Male Mendelian Randomization Analysis Metabolic Diseases / enzymology Middle Aged Polymorphism, Single Nucleotide Risk Factors White People gamma-Glutamyltransferase / blood

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
10 05 2021
Historique:
received: 13 07 2020
accepted: 05 02 2021
entrez: 11 5 2021
pubmed: 12 5 2021
medline: 3 6 2021
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-021-22338-2 PMID: 33972514 PMC: PMC8110798
pubmed: 33972514
doi: 10.1038/s41467-021-22338-2
pii: 10.1038/s41467-021-22338-2
pmc: PMC8110798
doi:

Substances chimiques

gamma-Glutamyltransferase EC 2.3.2.2
Alanine Transaminase EC 2.6.1.2
Alkaline Phosphatase EC 3.1.3.1

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

Langues

eng

Sous-ensembles de citation

IM

Pagination

2579

Subventions

Organisme : NIDDK NIH HHS
ID : R56 DK101478
Pays : United States
Organisme : Medical Research Council
ID : MR/R0265051/1
Pays : United Kingdom
Organisme : NIDDK NIH HHS
ID : K23 DK115897
Pays : United States
Organisme : Department of Health
Pays : United Kingdom
Organisme : British Heart Foundation
ID : SP/13/2/30111
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S019669/1
Pays : United Kingdom
Organisme : NHLBI NIH HHS
ID : R01 HL087679
Pays : United States
Organisme : Medical Research Council
ID : MR/R023484/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : NIMH NIH HHS
ID : RL1 MH083268
Pays : United States
Organisme : Medical Research Council
ID : MR/L01341X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/R026505/2
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/S03658X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L01632X/1
Pays : United Kingdom

Investigateurs

H Marike Boezen (HM)
Lude Franke (L)
Pim van der Harst (P)
Gerjan Navis (G)
Marianne Rots (M)
Morris Swertz (M)
Bruce H R Wolffenbuttel (BHR)
Cisca Wijmenga (C)
Zuhair K Ballas (ZK)
Sujata Bhushan (S)
Edward J Boyko (EJ)
David M Cohen (DM)
John Concato (J)
Michaela Aslan (M)
Hongyu Zhao (H)
Joseph I Constans (JI)
Louis J Dellitalia (LJ)
Joseph M Fayad (JM)
Ronald S Fernando (RS)
Hermes J Florez (HJ)
Melinda A Gaddy (MA)
Saib S Gappy (SS)
Gretchen Gibson (G)
Michael Godschalk (M)
Jennifer A Greco (JA)
Samir Gupta (S)
Salvador Gutierrez (S)
Kimberly D Hammer (KD)
Mark B Hamner (MB)
John B Harley (JB)
Adriana M Hung (AM)
Mostaqul Huq (M)
Robin A Hurley (RA)
Pran R Iruvanti (PR)
Douglas J Ivins (DJ)
Frank J Jacono (FJ)
Darshana N Jhala (DN)
Laurence S Kaminsky (LS)
Jon B Klein (JB)
Suthat Liangpunsakul (S)
Jack H Lichy (JH)
Jennifer Moser (J)
Grant D Huang (GD)
Sumitra Muralidhar (S)
Stephen M Mastorides (SM)
Roy O Mathew (RO)
Kristin M Mattocks (KM)
Rachel McArdle (R)
Paul N Meyer (PN)
Laurence J Meyer (LJ)
Jonathan P Moorman (JP)
Timothy R Morgan (TR)
Maureen Murdoch (M)
Olaoluwa O Okusaga (OO)
Kris-Ann K Oursler (KK)
Nora R Ratcliffe (NR)
Michael I Rauchman (MI)
R Brooks Robey (RB)
George W Ross (GW)
Richard J Servatius (RJ)
Satish C Sharma (SC)
Scott E Sherman (SE)
Elif Sonel (E)
Peruvemba Sriram (P)
Todd Stapley (T)
Robert T Striker (RT)
Neeraj Tandon (N)
Gerardo Villareal (G)
Agnes S Wallbom (AS)
John M Wells (JM)
Jeffrey C Whittle (JC)
Mary A Whooley (MA)
Peter W Wilson (PW)
Yan V Sun (YV)
Junzhe Xu (J)
Shing-Shing Yeh (SS)
Todd Connor (T)
Dean P Argyres (DP)
Elizabeth R Hauser (ER)
Jean C Beckham (JC)
Brady Stephens (B)
Samuel M Aguayo (SM)
Sunil K Ahuja (SK)
Saiju Pyarajan (S)
Kelly Cho (K)
J Michael Gaziano (JM)
Scott Kinlay (S)
Xuan-Mai T Nguyen (XT)
Jessica V Brewer (JV)
Mary T Brophy (MT)
Nhan V Do (NV)
Donald E Humphries (DE)
Luis E Selva (LE)
Shahpoor Shayan (S)
Stacey B Whitbourne (SB)
Jim L Breeling (JL)
J P Casas Romero (JPC)
Rachel B Ramoni (RB)

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Auteurs

Raha Pazoki (R)

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, London, UK. raha.pazoki@brunel.ac.uk.
Division of Biomedical Sciences, Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK. raha.pazoki@brunel.ac.uk.
ORCID: 0000-0002-5142-2348

Marijana Vujkovic (M)

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
ORCID: 0000-0003-4924-5714

Joshua Elliott (J)

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, London, UK.
Royal Surrey County Hospital, Guildford, Surrey, UK.

Evangelos Evangelou (E)

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, London, UK.
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
ORCID: 0000-0002-5488-2999

Dipender Gill (D)

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, London, UK.
British Heart Foundation Centre of Research Excellence, Imperial College London, London, UK.
ORCID: 0000-0001-7312-7078

Mohsen Ghanbari (M)

Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
Department of Genetics, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
ORCID: 0000-0002-9476-7143

Peter J van der Most (PJ)

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
ORCID: 0000-0001-8450-3518

Rui Climaco Pinto (RC)

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, London, UK.
UK Dementia Research Institute, Imperial College London, London, UK.

Matthias Wielscher (M)

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, London, UK.
Department of Dermatology, Medical University of Vienna, Vienna, Austria.

Matthias Farlik (M)

Department of Dermatology, Medical University of Vienna, Vienna, Austria.
ORCID: 0000-0003-0698-2992

Verena Zuber (V)

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, London, UK.
ORCID: 0000-0001-9827-1877

Robert J de Knegt (RJ)

Department of Gastroenterology and Hepatology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.

Harold Snieder (H)

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
ORCID: 0000-0003-1949-2298

André G Uitterlinden (AG)

Department of Internal Medicine, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
ORCID: 0000-0002-7276-3387

Julie A Lynch (JA)

VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
University of Massachusetts, Boston, MA, USA.
ORCID: 0000-0003-0108-2127

Xiyun Jiang (X)

Division of Biomedical Sciences, Department of Life Sciences, College of Health, Medicine and Life Sciences, Brunel University London, Uxbridge, UK.

Saredo Said (S)

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, London, UK.

David E Kaplan (DE)

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Kyung Min Lee (KM)

VA Salt Lake City Health Care System, Salt Lake City, UT, USA.
School of Medicine, University of Utah, Salt Lake City, UT, USA.
ORCID: 0000-0001-8995-0448

Marina Serper (M)

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.

Rotonya M Carr (RM)

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
ORCID: 0000-0003-0235-6994

Philip S Tsao (PS)

VA Palo Alto Health Care System, Palo Alto, CA, USA.
School of Medicine, Stanford University, Stanford, CA, USA.
ORCID: 0000-0001-7274-9318

Stephen R Atkinson (SR)

Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK.

Abbas Dehghan (A)

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, London, UK.
UK Dementia Research Institute, Imperial College London, London, UK.

Ioanna Tzoulaki (I)

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, London, UK.
Department of Hygiene and Epidemiology, University of Ioannina Medical School, Ioannina, Greece.
ORCID: 0000-0002-4275-9328

M Arfan Ikram (MA)

Department of Epidemiology, Erasmus University Medical Center Rotterdam, Rotterdam, The Netherlands.
ORCID: 0000-0003-0372-8585

Karl-Heinz Herzig (KH)

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.

Marjo-Riitta Järvelin (MR)

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, London, UK.
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.
ORCID: 0000-0002-2149-0630

Behrooz Z Alizadeh (BZ)

Department of Epidemiology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
ORCID: 0000-0002-1415-8007

Christopher J O'Donnell (CJ)

VA Boston Healthcare System, Boston, MA, USA.
Harvard Medical School, Boston, MA, USA.
Brigham Women's Hospital, Boston, MA, USA.
ORCID: 0000-0002-2667-8624

Danish Saleheen (D)

Departments of Medicine and Cardiology, Columbia University, New York City, NY, USA.
ORCID: 0000-0001-6193-020X

Benjamin F Voight (BF)

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, 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.
ORCID: 0000-0002-6205-9994

Kyong-Mi Chang (KM)

Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
ORCID: 0000-0001-6811-9364

Mark R Thursz (MR)

Division of Digestive Diseases, Department of Metabolism, Digestion & Reproduction, Imperial College London, London, UK.

Paul Elliott (P)

Department of Epidemiology and Biostatistics, MRC Centre for Environment and Health, School of Public Health, London, UK. p.elliott@imperial.ac.uk.
British Heart Foundation Centre of Research Excellence, Imperial College London, London, UK. p.elliott@imperial.ac.uk.
UK Dementia Research Institute, Imperial College London, London, UK. p.elliott@imperial.ac.uk.
National Institute for Health Research, Imperial Biomedical Research Centre, Imperial College London, London, UK. p.elliott@imperial.ac.uk.
Health Data Research UK at Imperial College London, London, UK. p.elliott@imperial.ac.uk.
ORCID: 0000-0002-7511-5684

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