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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 is unclear. We combine data from two large population-based studies, the Trondelag 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 used two-sample Mendelian randomization to investigate the causal effects of circulating cTnI on acute myocardial infarction and heart failure. 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 1283 phecodes and 274 continuous traits in UK Biobank showed associations between a polygenic risk score for cTnI and cardiac arrhythmias, aspartate aminotransferase 1 and anthropometric measures. Excluding individuals with a known history of comorbidities did not materially change associations with cTnI. Using two-sample Mendelian randomization we confirmed the non-causal role of cTnI in acute myocardial infarction (5 948 cases, 355 246 controls). We found some indications for a causal role of cTnI in heart failure (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 acute myocardial infarction and heart failure development in the general population. Using genetically informed methods for causal inference of cTnI helps inform the role and value of measuring cTnI in the general population.

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