TY - JOUR
T1 - Genome-wide association study of cardiac troponin i in the general population
AU - Moksnes, Marta R.
AU - Røsjø, Helge
AU - Richmond, Anne
AU - Lyngbakken, Magnus N.
AU - Graham, Sarah E.
AU - Hansen, Ailin Falkmo
AU - Wolford, Brooke N.
AU - Gagliano Taliun, Sarah A.
AU - Lefaive, Jonathon
AU - Rasheed, Humaira
AU - Thomas, Laurent F.
AU - Zhou, Wei
AU - Aung, Nay
AU - Surakka, Ida
AU - Douville, Nicholas J.
AU - Campbell, Archie
AU - Porteous, David J.
AU - Petersen, Steffen E.
AU - Munroe, Patricia B.
AU - Welsh, Paul
AU - Sattar, Naveed
AU - Smith, George Davey
AU - Fritsche, Lars G.
AU - Nielsen, Jonas B.
AU - Åsvold, Bjørn Olav
AU - Hveem, Kristian
AU - Hayward, Caroline
AU - Willer, Cristen J.
AU - Brumpton, Ben M.
AU - Omland, Torbjørn
N1 - Publisher Copyright:
© 2021 The Author(s) 2021. Published by Oxford University Press.
PY - 2021/11/1
Y1 - 2021/11/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85119059104&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddab124
DO - 10.1093/hmg/ddab124
M3 - Article
C2 - 33961016
AN - SCOPUS:85119059104
SN - 0964-6906
VL - 30
SP - 2027
EP - 2039
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 21
ER -