Genome-wide association study of cardiac troponin I in the general population

Marta R Moksnes; Helge Røsjø; Anne Richmond; Magnus N Lyngbakken; Sarah E Graham; Ailin Falkmo Hansen; Brooke N Wolford; Sarah A Gagliano Taliun; Jonathon LeFaive; Humaira Rasheed; Laurent F Thomas; Wei Zhou; Nay Aung; Ida Surakka; Nicholas J Douville; Archie Campbell; David J Porteous; Steffen E Petersen; Patricia B Munroe; Paul Welsh; Naveed Sattar; George Davey Smith; Lars G Fritsche; Jonas B Nielsen; Bjørn Olav Åsvold; Kristian Hveem; Caroline Hayward; Cristen J Willer; Ben M Brumpton; Torbjørn Omland

doi:10.1093/hmg/ddab124

Genome-wide association study of cardiac troponin I in the general population

Hum Mol Genet. 2021 Oct 13;30(21):2027-2039. doi: 10.1093/hmg/ddab124.

Authors

Marta R Moksnes¹, Helge Røsjø^{2

3}, Anne Richmond⁴, Magnus N Lyngbakken^{3

5}, Sarah E Graham⁶, Ailin Falkmo Hansen¹, Brooke N Wolford⁷, Sarah A Gagliano Taliun^{8

9

10

11}, Jonathon LeFaive^{10

11}, Humaira Rasheed^{1

12}, Laurent F Thomas^{1

13

14

15}, Wei Zhou^{7

16

17

18}, Nay Aung^{19

20

21}, Ida Surakka⁶, Nicholas J Douville²², Archie Campbell²³, David J Porteous²³, Steffen E Petersen^{19

20

21}, Patricia B Munroe^{19

20}, Paul Welsh²⁴, Naveed Sattar²⁴, George Davey Smith¹², Lars G Fritsche^{10

11}, Jonas B Nielsen^{1

6

25

26}, Bjørn Olav Åsvold^{1

27

28}, Kristian Hveem^{1

27}, Caroline Hayward⁴, Cristen J Willer^{1

6

7

29}, Ben M Brumpton^{1

12

30}, Torbjørn Omland^{2

3

5}

Affiliations

¹ Department of Public Health and Nursing, K.G. Jebsen Center for Genetic Epidemiology, NTNU - Norwegian University of Science and Technology, 7491 Trondheim, Norway.
² Division of Research and Innovation, Akershus University Hospital, 1478 Lørenskog, Norway.
³ Faculty of Medicine, Institute of Clinical Medicine, University of Oslo, 0316 Oslo, Norway.
⁴ MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh EH4 2XU, UK.
⁵ Division of Medicine, Department of Cardiology, Akershus University Hospital, 1478 Lørenskog, Norway.
⁶ Division of Cardiovascular Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
⁷ Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA.
⁸ Faculty of Medicine, Université de Montréal, Montréal, QC H3T 1J4, Canada.
⁹ Montréal Heart Institute, Montréal, QC H1T 1C8, Canada.
¹⁰ Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
¹¹ Center for Statistical Genetics, University of Michigan School of Public Health, Ann Arbor, MI 48109, USA.
¹² MRC Integrative Epidemiology Unit, University of Bristol, Bristol BS8 2BN, UK.
¹³ Department of Clinical and Molecular Medicine, NTNU - Norwegian University of Science and Technology, 7491 Trondheim, Norway.
¹⁴ BioCore - Bioinformatics Core Facility, NTNU - Norwegian University of Science and Technology, 7491 Trondheim. Norway.
¹⁵ Clinic of Laboratory Medicine, St. Olavs Hospital, Trondheim University Hospital, 7491 Trondheim, Norway.
¹⁶ Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA.
¹⁷ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
¹⁸ Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
¹⁹ William Harvey Research Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
²⁰ National Institute for Health Research Barts Cardiovascular Biomedical Research Centre, Queen Mary University of London, London E1 4NS, UK.
²¹ Barts Heart Centre, St. Bartholomew's Hospital, Barts Health NHS Trust, London EC1A 7BE, UK.
²² Department of Anesthesiology, University of Michigan, Ann Arbor, MI 48109, USA.
²³ Medical Genetics Section, CGEM, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh EH4 2XU, UK.
²⁴ Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow G12 8TA, UK.
²⁵ Department of Epidemiology Research, Statens Serum Institute, 2300 Copenhagen, Denmark.
²⁶ Department of Cardiology, Copenhagen University Hospital, 2100 Copenhagen, Denmark.
²⁷ Department of Public Health and Nursing, HUNT Research Centre, NTNU - Norwegian University of Science and Technology, 7600 Levanger, Norway.
²⁸ Department of Endocrinology, St. Olavs Hospital, Trondheim University Hospital, 7006 Trondheim, Norway.
²⁹ Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
³⁰ Clinic of Thoracic and Occupational Medicine, St. Olavs Hospital, Trondheim University Hospital, 7006 Trondheim, Norway.

Abstract

Circulating cardiac troponin proteins are associated with structural heart disease and predict incident cardiovascular disease in the general population. However, the genetic contribution to cardiac troponin I (cTnI) concentrations and its causal effect on cardiovascular phenotypes are unclear. We combine data from two large population-based studies, the Trøndelag Health Study and the Generation Scotland Scottish Family Health Study, and perform a genome-wide association study of high-sensitivity cTnI concentrations with 48 115 individuals. We further use two-sample Mendelian randomization to investigate the causal effects of circulating cTnI on acute myocardial infarction (AMI) and heart failure (HF). We identified 12 genetic loci (8 novel) associated with cTnI concentrations. Associated protein-altering variants highlighted putative functional genes: CAND2, HABP2, ANO5, APOH, FHOD3, TNFAIP2, KLKB1 and LMAN1. Phenome-wide association tests in 1688 phecodes and 83 continuous traits in UK Biobank showed associations between a genetic risk score for cTnI and cardiac arrhythmias, metabolic and anthropometric measures. Using two-sample Mendelian randomization, we confirmed the non-causal role of cTnI in AMI (5948 cases, 355 246 controls). We found indications for a causal role of cTnI in HF (47 309 cases and 930 014 controls), but this was not supported by secondary analyses using left ventricular mass as outcome (18 257 individuals). Our findings clarify the biology underlying the heritable contribution to circulating cTnI and support cTnI as a non-causal biomarker for AMI in the general population. Using genetically informed methods for causal inference helps inform the role and value of measuring cTnI in the general population.

Publication types

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

MeSH terms

Alleles
Biomarkers*
Chromosome Mapping
Gene Expression
Genetic Variation
Genetics, Population*
Genome-Wide Association Study*
Mendelian Randomization Analysis
Organ Specificity
Quantitative Trait Loci
Troponin I / genetics*
Troponin T / genetics

Substances

Biomarkers
Troponin I
Troponin T

Abstract

Publication types

MeSH terms

Substances

Grants and funding