Resting heart rate and incident atrial fibrillation: A stratified Mendelian randomization in the AFGen consortium

J. E. Siland; B. Geelhoed; C. Roselli; B. Wang; H. Lin; S. Weiss; S. Trompet; M. E. van den Berg; E. Z. Soliman; L. Y. Chen; I. Ford; J. W. Jukema; P. W. Macfarlane; J. Kornej; H. Lin; K. L. Lunetta; M. Kavousi; J. A. Kors; M. A. Ikram; X. Guo; J. Yao; M. Dörr; S. B. Felix; U. Völker; N. Sotoodehnia; D. E. Arking; B. H. Stricker; S. R. Heckbert; E. J. Benjamin; S. A. Lubitz; A. Alonso; P. T. Ellinor; P. van der Harst; M. Rienstra

doi:10.1371/journal.pone.0268768

Resting heart rate and incident atrial fibrillation: A stratified Mendelian randomization in the AFGen consortium

J. E. Siland, B. Geelhoed, C. Roselli, B. Wang, H. Lin, S. Weiss, S. Trompet, M. E. van den Berg, E. Z. Soliman, L. Y. Chen, I. Ford, J. W. Jukema, P. W. Macfarlane, J. Kornej, H. Lin, K. L. Lunetta, M. Kavousi, J. A. Kors, M. A. Ikram, X. GuoJ. Yao, M. Dörr, S. B. Felix, U. Völker, N. Sotoodehnia, D. E. Arking, B. H. Stricker, S. R. Heckbert, E. J. Benjamin, S. A. Lubitz, A. Alonso, P. T. Ellinor, P. van der Harst, M. Rienstra^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

Background Both elevated and low resting heart rates are associated with atrial fibrillation (AF), suggesting a U-shaped relationship. However, evidence for a U-shaped causal association between genetically-determined resting heart rate and incident AF is limited. We investigated potential directional changes of the causal association between genetically-determined resting heart rate and incident AF. Method and results Seven cohorts of the AFGen consortium contributed data to this meta-analysis. All participants were of European ancestry with known AF status, genotype information, and a heart rate measurement from a baseline electrocardiogram (ECG). Three strata of instrumental variable-free resting heart rate were used to assess possible non-linear associations between genetically-determined resting heart rate and the logarithm of the incident AF hazard rate: <65; 65–75; and >75 beats per minute (bpm). Mendelian randomization analyses using a weighted resting heart rate polygenic risk score were performed for each stratum. We studied 38,981 individuals (mean age 59±10 years, 54% women) with a mean resting heart rate of 67±11 bpm. During a mean follow-up of 13±5 years, 4,779 (12%) individuals developed AF. A U-shaped association between the resting heart rate and the incident AF-hazard ratio was observed. Genetically-determined resting heart rate was inversely associated with incident AF for instrumental variable-free resting heart rates below 65 bpm (hazard ratio for genetically-determined resting heart rate, 0.96; 95% confidence interval, 0.94–0.99; p = 0.01). Genetically-determined resting heart rate was not associated with incident AF in the other two strata. Conclusions For resting heart rates below 65 bpm, our results support an inverse causal association between genetically-determined resting heart rate and incident AF.

Original language	English
Article number	e0268768
Journal	PLoS ONE
Volume	17
DOIs	https://doi.org/10.1371/journal.pone.0268768
Publication status	Published - 20 May 2022

Bibliographical note

Funding: The Atherosclerosis Risk in Communities study has been funded in whole or in part with funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Service (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, and HHSN268201700004I, R01HL087641, R01HL059367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C). Additional support for this analysis was provided by NHLBI grant K24HL148521 and American Heart Association grant 16EIA26410001. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (contract nos. N01-HC-25195, HHSN268201500001I, and 75N92019D00031). Dr. Kornej was supported by Marie Sklodowska-Curie Actions under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 838259). Dr. Benjamin is supported by NIH NHLBI grants R01HL092577 and 1R01HL128914 and American Heart Association 18SFRN34110082. Dr. Lubitz is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. Dr. Lubitz receives sponsored research support from Bristol Myers Squibb / Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, and IBM, and has consulted for Bristol Myers Squibb / Pfizer, Bayer AG, and Blackstone Life Sciences. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. PREVEND is supported by the Dutch Kidney Foundation (grant E0.13) and the Netherlands Heart Foundation (grant NHS2010B280). The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. Prof. Dr. J. W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). The Rotterdam Study is supported by the Erasmus University Medical Center and Erasmus University, Rotterdam; The Netherlands Organisation for Scientific Research (NWO); The Netherlands Organisation for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); The Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The contribution of inhabitants, general practitioners and pharmacists of the Ommoord district to the Rotterdam Study is gratefully acknowledged. The Study of Health in Pomerania (SHIP) is supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung (BMBF); grants 01ZZ9603, 01ZZ0103, and 01ZZ0403) and the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG); grant GR 1912/5-1). SHIP is part of the Community Medicine Research net (CMR) of the University of Greifswald which is funded by the BMBF as well as the Ministry for Education, Science and Culture and the Ministry of Labor, Equal Opportunities, and Social Affairs of the Federal State of Mecklenburg-West Pomerania. The CMR encompasses several research projects that share data from SHIP. Genome-wide data have been supported by a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The AFGen consortium is supported by R01HL128914 and 2R01 HL092577 and American Heart Association grant 18SFRN34110082. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Copyright: © 2022 Siland et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Cite this

Siland, J. E., Geelhoed, B., Roselli, C., Wang, B., Lin, H., Weiss, S., Trompet, S., van den Berg, M. E., Soliman, E. Z., Chen, L. Y., Ford, I., Jukema, J. W., Macfarlane, P. W., Kornej, J., Lin, H., Lunetta, K. L., Kavousi, M., Kors, J. A., Ikram, M. A., ... Rienstra, M. (2022). Resting heart rate and incident atrial fibrillation: A stratified Mendelian randomization in the AFGen consortium. PLoS ONE, 17, Article e0268768. https://doi.org/10.1371/journal.pone.0268768

@article{6f608f8a1cde43f2bb8bf8eb53b8b12e,

title = "Resting heart rate and incident atrial fibrillation: A stratified Mendelian randomization in the AFGen consortium",

abstract = "Background Both elevated and low resting heart rates are associated with atrial fibrillation (AF), suggesting a U-shaped relationship. However, evidence for a U-shaped causal association between genetically-determined resting heart rate and incident AF is limited. We investigated potential directional changes of the causal association between genetically-determined resting heart rate and incident AF. Method and results Seven cohorts of the AFGen consortium contributed data to this meta-analysis. All participants were of European ancestry with known AF status, genotype information, and a heart rate measurement from a baseline electrocardiogram (ECG). Three strata of instrumental variable-free resting heart rate were used to assess possible non-linear associations between genetically-determined resting heart rate and the logarithm of the incident AF hazard rate: <65; 65–75; and >75 beats per minute (bpm). Mendelian randomization analyses using a weighted resting heart rate polygenic risk score were performed for each stratum. We studied 38,981 individuals (mean age 59±10 years, 54% women) with a mean resting heart rate of 67±11 bpm. During a mean follow-up of 13±5 years, 4,779 (12%) individuals developed AF. A U-shaped association between the resting heart rate and the incident AF-hazard ratio was observed. Genetically-determined resting heart rate was inversely associated with incident AF for instrumental variable-free resting heart rates below 65 bpm (hazard ratio for genetically-determined resting heart rate, 0.96; 95% confidence interval, 0.94–0.99; p = 0.01). Genetically-determined resting heart rate was not associated with incident AF in the other two strata. Conclusions For resting heart rates below 65 bpm, our results support an inverse causal association between genetically-determined resting heart rate and incident AF.",

author = "Siland, {J. E.} and B. Geelhoed and C. Roselli and B. Wang and H. Lin and S. Weiss and S. Trompet and {van den Berg}, {M. E.} and Soliman, {E. Z.} and Chen, {L. Y.} and I. Ford and Jukema, {J. W.} and Macfarlane, {P. W.} and J. Kornej and H. Lin and Lunetta, {K. L.} and M. Kavousi and Kors, {J. A.} and Ikram, {M. A.} and X. Guo and J. Yao and M. D{\"o}rr and Felix, {S. B.} and U. V{\"o}lker and N. Sotoodehnia and Arking, {D. E.} and Stricker, {B. H.} and Heckbert, {S. R.} and Benjamin, {E. J.} and Lubitz, {S. A.} and A. Alonso and Ellinor, {P. T.} and {van der Harst}, P. and M. Rienstra",

note = "Funding: The Atherosclerosis Risk in Communities study has been funded in whole or in part with funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Service (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, and HHSN268201700004I, R01HL087641, R01HL059367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C). Additional support for this analysis was provided by NHLBI grant K24HL148521 and American Heart Association grant 16EIA26410001. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (contract nos. N01-HC-25195, HHSN268201500001I, and 75N92019D00031). Dr. Kornej was supported by Marie Sklodowska-Curie Actions under the European Union{\textquoteright}s Horizon 2020 research and innovation programme (grant agreement no. 838259). Dr. Benjamin is supported by NIH NHLBI grants R01HL092577 and 1R01HL128914 and American Heart Association 18SFRN34110082. Dr. Lubitz is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. Dr. Lubitz receives sponsored research support from Bristol Myers Squibb / Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, and IBM, and has consulted for Bristol Myers Squibb / Pfizer, Bayer AG, and Blackstone Life Sciences. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. PREVEND is supported by the Dutch Kidney Foundation (grant E0.13) and the Netherlands Heart Foundation (grant NHS2010B280). The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. Prof. Dr. J. W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). The Rotterdam Study is supported by the Erasmus University Medical Center and Erasmus University, Rotterdam; The Netherlands Organisation for Scientific Research (NWO); The Netherlands Organisation for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); The Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The contribution of inhabitants, general practitioners and pharmacists of the Ommoord district to the Rotterdam Study is gratefully acknowledged. The Study of Health in Pomerania (SHIP) is supported by the German Federal Ministry of Education and Research (Bundesministerium f{\"u}r Bildung und Forschung (BMBF); grants 01ZZ9603, 01ZZ0103, and 01ZZ0403) and the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG); grant GR 1912/5-1). SHIP is part of the Community Medicine Research net (CMR) of the University of Greifswald which is funded by the BMBF as well as the Ministry for Education, Science and Culture and the Ministry of Labor, Equal Opportunities, and Social Affairs of the Federal State of Mecklenburg-West Pomerania. The CMR encompasses several research projects that share data from SHIP. Genome-wide data have been supported by a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The AFGen consortium is supported by R01HL128914 and 2R01 HL092577 and American Heart Association grant 18SFRN34110082. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: Copyright: {\textcopyright} 2022 Siland et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.",

year = "2022",

month = may,

day = "20",

doi = "10.1371/journal.pone.0268768",

language = "English",

volume = "17",

journal = "PLoS ONE",

issn = "1932-6203",

publisher = "Public Library of Science",

}

Siland, JE, Geelhoed, B, Roselli, C, Wang, B, Lin, H, Weiss, S, Trompet, S, van den Berg, ME, Soliman, EZ, Chen, LY, Ford, I, Jukema, JW, Macfarlane, PW, Kornej, J, Lin, H, Lunetta, KL, Kavousi, M , Kors, JA , Ikram, MA, Guo, X, Yao, J, Dörr, M, Felix, SB, Völker, U, Sotoodehnia, N, Arking, DE, Stricker, BH, Heckbert, SR, Benjamin, EJ, Lubitz, SA, Alonso, A, Ellinor, PT, van der Harst, P & Rienstra, M 2022, 'Resting heart rate and incident atrial fibrillation: A stratified Mendelian randomization in the AFGen consortium', PLoS ONE, vol. 17, e0268768. https://doi.org/10.1371/journal.pone.0268768

TY - JOUR

T1 - Resting heart rate and incident atrial fibrillation

T2 - A stratified Mendelian randomization in the AFGen consortium

AU - Siland, J. E.

AU - Geelhoed, B.

AU - Roselli, C.

AU - Wang, B.

AU - Lin, H.

AU - Weiss, S.

AU - Trompet, S.

AU - van den Berg, M. E.

AU - Soliman, E. Z.

AU - Chen, L. Y.

AU - Ford, I.

AU - Jukema, J. W.

AU - Macfarlane, P. W.

AU - Kornej, J.

AU - Lin, H.

AU - Lunetta, K. L.

AU - Kavousi, M.

AU - Kors, J. A.

AU - Ikram, M. A.

AU - Guo, X.

AU - Yao, J.

AU - Dörr, M.

AU - Felix, S. B.

AU - Völker, U.

AU - Sotoodehnia, N.

AU - Arking, D. E.

AU - Stricker, B. H.

AU - Heckbert, S. R.

AU - Benjamin, E. J.

AU - Lubitz, S. A.

AU - Alonso, A.

AU - Ellinor, P. T.

AU - van der Harst, P.

AU - Rienstra, M.

N1 - Funding: The Atherosclerosis Risk in Communities study has been funded in whole or in part with funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Service (contract numbers HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, and HHSN268201700004I, R01HL087641, R01HL059367, and R01HL086694; National Human Genome Research Institute contract U01HG004402; and National Institutes of Health contract HHSN268200625226C). Additional support for this analysis was provided by NHLBI grant K24HL148521 and American Heart Association grant 16EIA26410001. The Framingham Heart Study is conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with Boston University (contract nos. N01-HC-25195, HHSN268201500001I, and 75N92019D00031). Dr. Kornej was supported by Marie Sklodowska-Curie Actions under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 838259). Dr. Benjamin is supported by NIH NHLBI grants R01HL092577 and 1R01HL128914 and American Heart Association 18SFRN34110082. Dr. Lubitz is supported by NIH grant 1R01HL139731 and American Heart Association 18SFRN34250007. Dr. Lubitz receives sponsored research support from Bristol Myers Squibb / Pfizer, Bayer AG, Boehringer Ingelheim, Fitbit, and IBM, and has consulted for Bristol Myers Squibb / Pfizer, Bayer AG, and Blackstone Life Sciences. MESA and the MESA SHARe project are conducted and supported by the National Heart, Lung, and Blood Institute (NHLBI) in collaboration with MESA investigators. Support for MESA is provided by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, UL1-TR-000040, UL1-TR-001079, UL1-TR-001420, UL1-TR-001881, and DK063491. Funding for SHARe genotyping was provided by NHLBI contract N02-HL-64278. Genotyping was performed at Affymetrix (Santa Clara, California, USA) and the Broad Institute of Harvard and MIT (Boston, Massachusetts, USA) using the Affymetrix Genome-Wide Human SNP Array 6.0. PREVEND is supported by the Dutch Kidney Foundation (grant E0.13) and the Netherlands Heart Foundation (grant NHS2010B280). The PROSPER study was supported by an investigator-initiated grant obtained from Bristol-Myers Squibb. Prof. Dr. J. W. Jukema is an Established Clinical Investigator of the Netherlands Heart Foundation (grant 2001 D 032). Support for genotyping was provided by the seventh framework program of the European commission (grant 223004) and by the Netherlands Genomics Initiative (Netherlands Consortium for Healthy Aging grant 050-060-810). The Rotterdam Study is supported by the Erasmus University Medical Center and Erasmus University, Rotterdam; The Netherlands Organisation for Scientific Research (NWO); The Netherlands Organisation for Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); The Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. The contribution of inhabitants, general practitioners and pharmacists of the Ommoord district to the Rotterdam Study is gratefully acknowledged. The Study of Health in Pomerania (SHIP) is supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung (BMBF); grants 01ZZ9603, 01ZZ0103, and 01ZZ0403) and the German Research Foundation (Deutsche Forschungsgemeinschaft (DFG); grant GR 1912/5-1). SHIP is part of the Community Medicine Research net (CMR) of the University of Greifswald which is funded by the BMBF as well as the Ministry for Education, Science and Culture and the Ministry of Labor, Equal Opportunities, and Social Affairs of the Federal State of Mecklenburg-West Pomerania. The CMR encompasses several research projects that share data from SHIP. Genome-wide data have been supported by a joint grant from Siemens Healthcare, Erlangen, Germany and the Federal State of Mecklenburg-West Pomerania. The AFGen consortium is supported by R01HL128914 and 2R01 HL092577 and American Heart Association grant 18SFRN34110082. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Publisher Copyright: Copyright: © 2022 Siland et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

PY - 2022/5/20

Y1 - 2022/5/20

N2 - Background Both elevated and low resting heart rates are associated with atrial fibrillation (AF), suggesting a U-shaped relationship. However, evidence for a U-shaped causal association between genetically-determined resting heart rate and incident AF is limited. We investigated potential directional changes of the causal association between genetically-determined resting heart rate and incident AF. Method and results Seven cohorts of the AFGen consortium contributed data to this meta-analysis. All participants were of European ancestry with known AF status, genotype information, and a heart rate measurement from a baseline electrocardiogram (ECG). Three strata of instrumental variable-free resting heart rate were used to assess possible non-linear associations between genetically-determined resting heart rate and the logarithm of the incident AF hazard rate: <65; 65–75; and >75 beats per minute (bpm). Mendelian randomization analyses using a weighted resting heart rate polygenic risk score were performed for each stratum. We studied 38,981 individuals (mean age 59±10 years, 54% women) with a mean resting heart rate of 67±11 bpm. During a mean follow-up of 13±5 years, 4,779 (12%) individuals developed AF. A U-shaped association between the resting heart rate and the incident AF-hazard ratio was observed. Genetically-determined resting heart rate was inversely associated with incident AF for instrumental variable-free resting heart rates below 65 bpm (hazard ratio for genetically-determined resting heart rate, 0.96; 95% confidence interval, 0.94–0.99; p = 0.01). Genetically-determined resting heart rate was not associated with incident AF in the other two strata. Conclusions For resting heart rates below 65 bpm, our results support an inverse causal association between genetically-determined resting heart rate and incident AF.

AB - Background Both elevated and low resting heart rates are associated with atrial fibrillation (AF), suggesting a U-shaped relationship. However, evidence for a U-shaped causal association between genetically-determined resting heart rate and incident AF is limited. We investigated potential directional changes of the causal association between genetically-determined resting heart rate and incident AF. Method and results Seven cohorts of the AFGen consortium contributed data to this meta-analysis. All participants were of European ancestry with known AF status, genotype information, and a heart rate measurement from a baseline electrocardiogram (ECG). Three strata of instrumental variable-free resting heart rate were used to assess possible non-linear associations between genetically-determined resting heart rate and the logarithm of the incident AF hazard rate: <65; 65–75; and >75 beats per minute (bpm). Mendelian randomization analyses using a weighted resting heart rate polygenic risk score were performed for each stratum. We studied 38,981 individuals (mean age 59±10 years, 54% women) with a mean resting heart rate of 67±11 bpm. During a mean follow-up of 13±5 years, 4,779 (12%) individuals developed AF. A U-shaped association between the resting heart rate and the incident AF-hazard ratio was observed. Genetically-determined resting heart rate was inversely associated with incident AF for instrumental variable-free resting heart rates below 65 bpm (hazard ratio for genetically-determined resting heart rate, 0.96; 95% confidence interval, 0.94–0.99; p = 0.01). Genetically-determined resting heart rate was not associated with incident AF in the other two strata. Conclusions For resting heart rates below 65 bpm, our results support an inverse causal association between genetically-determined resting heart rate and incident AF.

UR - http://www.scopus.com/inward/record.url?scp=85130474405&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0268768

DO - 10.1371/journal.pone.0268768

M3 - Article

C2 - 35594314

AN - SCOPUS:85130474405

SN - 1932-6203

VL - 17

JO - PLoS ONE

JF - PLoS ONE

M1 - e0268768

ER -

Resting heart rate and incident atrial fibrillation: A stratified Mendelian randomization in the AFGen consortium

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