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 WelshNaveed 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)2027-2039
Number of pages13
JournalHuman Molecular Genetics
Volume30
Issue number21
Early online date7 May 2021
DOIs
Publication statusPublished - 1 Nov 2021

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