Genetically Determined Reproductive Aging and Coronary Heart Disease: A Bidirectional 2-sample Mendelian Randomization

Veerle Dam; N Charlotte Onland-Moret; Stephen Burgess; Maria-Dolores Chirlaque; Sanne A E Peters; Ewoud Schuit; Kaja Tikk; Elisabete Weiderpass; Clare Oliver-Williams; Angela M Wood; Anne Tjønneland; Christina C Dahm; Kim Overvad; Marie-Christine Boutron-Ruault; Matthias B Schulze; Antonia Trichopoulou; Pietro Ferrari; Giovanna Masala; Vittorio Krogh; Rosario Tumino; Giuseppe Matullo; Salvatore Panico; Jolanda M A Boer; W M Monique Verschuren; Marit Waaseth; Maria José Sánchez Pérez; Pilar Amiano; Liher Imaz; Conchi Moreno-Iribas; Olle Melander; Sophia Harlid; Maria Nordendahl; Patrik Wennberg; Timothy J Key; Elio Riboli; Carmen Santiuste; Rudolf Kaaks; Verena Katzke; Claudia Langenberg; Nicholas J Wareham; Heribert Schunkert; Jeanette Erdmann; Christina Willenborg; Christian Hengstenberg; Marcus E Kleber; Graciela Delgado; Winfried März; Stavroula Kanoni; George Dedoussis; Panos Deloukas; Majid Nikpay; Ruth McPherson; Markus Scholz; Andrej Teren; Adam S Butterworth; Yvonne T van der Schouw

doi:10.1210/clinem/dgac171

Genetically Determined Reproductive Aging and Coronary Heart Disease: A Bidirectional 2-sample Mendelian Randomization

Veerle Dam, N Charlotte Onland-Moret, Stephen Burgess, Maria-Dolores Chirlaque, Sanne A E Peters, Ewoud Schuit, Kaja Tikk, Elisabete Weiderpass, Clare Oliver-Williams, Angela M Wood, Anne Tjønneland, Christina C Dahm, Kim Overvad, Marie-Christine Boutron-Ruault, Matthias B Schulze, Antonia Trichopoulou, Pietro Ferrari, Giovanna Masala, Vittorio Krogh, Rosario TuminoGiuseppe Matullo, Salvatore Panico, Jolanda M A Boer, W M Monique Verschuren, Marit Waaseth, Maria José Sánchez Pérez, Pilar Amiano, Liher Imaz, Conchi Moreno-Iribas, Olle Melander, Sophia Harlid, Maria Nordendahl, Patrik Wennberg, Timothy J Key, Elio Riboli, Carmen Santiuste, Rudolf Kaaks, Verena Katzke, Claudia Langenberg, Nicholas J Wareham, Heribert Schunkert, Jeanette Erdmann, Christina Willenborg, Christian Hengstenberg, Marcus E Kleber, Graciela Delgado, Winfried März, Stavroula Kanoni, George Dedoussis, Panos Deloukas, Majid Nikpay, Ruth McPherson, Markus Scholz, Andrej Teren, Adam S Butterworth, Yvonne T van der Schouw

Institute of Cardiogenetics

Abstract

BACKGROUND: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause.

OBJECTIVES: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian Randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men.

DESIGN: Two-sample MR, using both cohort data as well as summary statistics, with four methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression.

PARTICIPANTS: Data from EPIC-CVD and summary statistics from UK Biobank and publicly available GWAS were pooled for the different analyses.

MAIN OUTCOME MEASURES: CHD, CHD risk factors and ANM.

RESULTS: Across different methods of MR no association was found between genetically determined reproductive aging and CHD risk in women (Relative Risk Estimate (RRE)IVW=0.99, 95% confidence interval (CI):0.97;1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging.

CONCLUSION: Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men.

Original language	English
Journal	The Journal of clinical endocrinology and metabolism
Volume	107
Issue number	7
Pages (from-to)	E2952-E2961
ISSN	0021-972X
DOIs	https://doi.org/10.1210/clinem/dgac171
Publication status	Published - 16.06.2022

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Research Area: Medical Genetics

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10.1210/clinem/dgac171

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Dam, V., Onland-Moret, N. C., Burgess, S., Chirlaque, M.-D., Peters, S. A. E., Schuit, E., Tikk, K., Weiderpass, E., Oliver-Williams, C., Wood, A. M., Tjønneland, A., Dahm, C. C., Overvad, K., Boutron-Ruault, M.-C., Schulze, M. B., Trichopoulou, A., Ferrari, P., Masala, G., Krogh, V., ... van der Schouw, Y. T. (2022). Genetically Determined Reproductive Aging and Coronary Heart Disease: A Bidirectional 2-sample Mendelian Randomization. The Journal of clinical endocrinology and metabolism, 107(7), E2952-E2961. https://doi.org/10.1210/clinem/dgac171

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title = "Genetically Determined Reproductive Aging and Coronary Heart Disease: A Bidirectional 2-sample Mendelian Randomization",

abstract = "BACKGROUND: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause.OBJECTIVES: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian Randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men.DESIGN: Two-sample MR, using both cohort data as well as summary statistics, with four methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression.PARTICIPANTS: Data from EPIC-CVD and summary statistics from UK Biobank and publicly available GWAS were pooled for the different analyses.MAIN OUTCOME MEASURES: CHD, CHD risk factors and ANM.RESULTS: Across different methods of MR no association was found between genetically determined reproductive aging and CHD risk in women (Relative Risk Estimate (RRE)IVW=0.99, 95% confidence interval (CI):0.97;1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging.CONCLUSION: Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men.",

author = "Veerle Dam and Onland-Moret, {N Charlotte} and Stephen Burgess and Maria-Dolores Chirlaque and Peters, {Sanne A E} and Ewoud Schuit and Kaja Tikk and Elisabete Weiderpass and Clare Oliver-Williams and Wood, {Angela M} and Anne Tj{\o}nneland and Dahm, {Christina C} and Kim Overvad and Marie-Christine Boutron-Ruault and Schulze, {Matthias B} and Antonia Trichopoulou and Pietro Ferrari and Giovanna Masala and Vittorio Krogh and Rosario Tumino and Giuseppe Matullo and Salvatore Panico and Boer, {Jolanda M A} and Verschuren, {W M Monique} and Marit Waaseth and {S{\'a}nchez P{\'e}rez}, {Maria Jos{\'e}} and Pilar Amiano and Liher Imaz and Conchi Moreno-Iribas and Olle Melander and Sophia Harlid and Maria Nordendahl and Patrik Wennberg and Key, {Timothy J} and Elio Riboli and Carmen Santiuste and Rudolf Kaaks and Verena Katzke and Claudia Langenberg and Wareham, {Nicholas J} and Heribert Schunkert and Jeanette Erdmann and Christina Willenborg and Christian Hengstenberg and Kleber, {Marcus E} and Graciela Delgado and Winfried M{\"a}rz and Stavroula Kanoni and George Dedoussis and Panos Deloukas and Majid Nikpay and Ruth McPherson and Markus Scholz and Andrej Teren and Butterworth, {Adam S} and {van der Schouw}, {Yvonne T}",

note = "Publisher Copyright: {\textcopyright} 2022 The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society.",

year = "2022",

month = jun,

day = "16",

doi = "10.1210/clinem/dgac171",

language = "English",

volume = "107",

pages = "E2952--E2961",

journal = "The Journal of clinical endocrinology and metabolism",

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Dam, V, Onland-Moret, NC, Burgess, S, Chirlaque, M-D, Peters, SAE, Schuit, E, Tikk, K, Weiderpass, E, Oliver-Williams, C, Wood, AM, Tjønneland, A, Dahm, CC, Overvad, K, Boutron-Ruault, M-C, Schulze, MB, Trichopoulou, A, Ferrari, P, Masala, G, Krogh, V, Tumino, R, Matullo, G, Panico, S, Boer, JMA, Verschuren, WMM, Waaseth, M, Sánchez Pérez, MJ, Amiano, P, Imaz, L, Moreno-Iribas, C, Melander, O, Harlid, S, Nordendahl, M, Wennberg, P, Key, TJ, Riboli, E, Santiuste, C, Kaaks, R, Katzke, V, Langenberg, C, Wareham, NJ, Schunkert, H, Erdmann, J, Willenborg, C, Hengstenberg, C, Kleber, ME, Delgado, G, März, W, Kanoni, S, Dedoussis, G, Deloukas, P, Nikpay, M, McPherson, R, Scholz, M, Teren, A, Butterworth, AS & van der Schouw, YT 2022, 'Genetically Determined Reproductive Aging and Coronary Heart Disease: A Bidirectional 2-sample Mendelian Randomization', The Journal of clinical endocrinology and metabolism, vol. 107, no. 7, pp. E2952-E2961. https://doi.org/10.1210/clinem/dgac171

Genetically Determined Reproductive Aging and Coronary Heart Disease: A Bidirectional 2-sample Mendelian Randomization. / Dam, Veerle; Onland-Moret, N Charlotte; Burgess, Stephen et al.
In: The Journal of clinical endocrinology and metabolism, Vol. 107, No. 7, 16.06.2022, p. E2952-E2961.

Research output: Journal Articles › Journal articles › Research › peer-review

TY - JOUR

T1 - Genetically Determined Reproductive Aging and Coronary Heart Disease

T2 - A Bidirectional 2-sample Mendelian Randomization

AU - Dam, Veerle

AU - Onland-Moret, N Charlotte

AU - Burgess, Stephen

AU - Chirlaque, Maria-Dolores

AU - Peters, Sanne A E

AU - Schuit, Ewoud

AU - Tikk, Kaja

AU - Weiderpass, Elisabete

AU - Oliver-Williams, Clare

AU - Wood, Angela M

AU - Tjønneland, Anne

AU - Dahm, Christina C

AU - Overvad, Kim

AU - Boutron-Ruault, Marie-Christine

AU - Schulze, Matthias B

AU - Trichopoulou, Antonia

AU - Ferrari, Pietro

AU - Masala, Giovanna

AU - Krogh, Vittorio

AU - Tumino, Rosario

AU - Matullo, Giuseppe

AU - Panico, Salvatore

AU - Boer, Jolanda M A

AU - Verschuren, W M Monique

AU - Waaseth, Marit

AU - Sánchez Pérez, Maria José

AU - Amiano, Pilar

AU - Imaz, Liher

AU - Moreno-Iribas, Conchi

AU - Melander, Olle

AU - Harlid, Sophia

AU - Nordendahl, Maria

AU - Wennberg, Patrik

AU - Key, Timothy J

AU - Riboli, Elio

AU - Santiuste, Carmen

AU - Kaaks, Rudolf

AU - Katzke, Verena

AU - Langenberg, Claudia

AU - Wareham, Nicholas J

AU - Schunkert, Heribert

AU - Erdmann, Jeanette

AU - Willenborg, Christina

AU - Hengstenberg, Christian

AU - Kleber, Marcus E

AU - Delgado, Graciela

AU - März, Winfried

AU - Kanoni, Stavroula

AU - Dedoussis, George

AU - Deloukas, Panos

AU - Nikpay, Majid

AU - McPherson, Ruth

AU - Scholz, Markus

AU - Teren, Andrej

AU - Butterworth, Adam S

AU - van der Schouw, Yvonne T

PY - 2022/6/16

Y1 - 2022/6/16

N2 - BACKGROUND: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause.OBJECTIVES: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian Randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men.DESIGN: Two-sample MR, using both cohort data as well as summary statistics, with four methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression.PARTICIPANTS: Data from EPIC-CVD and summary statistics from UK Biobank and publicly available GWAS were pooled for the different analyses.MAIN OUTCOME MEASURES: CHD, CHD risk factors and ANM.RESULTS: Across different methods of MR no association was found between genetically determined reproductive aging and CHD risk in women (Relative Risk Estimate (RRE)IVW=0.99, 95% confidence interval (CI):0.97;1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging.CONCLUSION: Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men.

AB - BACKGROUND: Accelerated reproductive aging, in women indicated by early natural menopause, is associated with increased coronary heart disease (CHD) risk in observational studies. Conversely, an adverse CHD risk profile has been suggested to accelerate menopause.OBJECTIVES: To study the direction and evidence for causality of the relationship between reproductive aging and (non-)fatal CHD and CHD risk factors in a bidirectional Mendelian Randomization (MR) approach, using age at natural menopause (ANM) genetic variants as a measure for genetically determined reproductive aging in women. We also studied the association of these variants with CHD risk (factors) in men.DESIGN: Two-sample MR, using both cohort data as well as summary statistics, with four methods: simple and weighted median-based, standard inverse-variance weighted (IVW) regression, and MR-Egger regression.PARTICIPANTS: Data from EPIC-CVD and summary statistics from UK Biobank and publicly available GWAS were pooled for the different analyses.MAIN OUTCOME MEASURES: CHD, CHD risk factors and ANM.RESULTS: Across different methods of MR no association was found between genetically determined reproductive aging and CHD risk in women (Relative Risk Estimate (RRE)IVW=0.99, 95% confidence interval (CI):0.97;1.01), or any of the CHD risk factors. Similarly, no associations were found in men. Neither did the reversed analyses show evidence for an association between CHD (risk factors) and reproductive aging.CONCLUSION: Genetically determined reproductive aging is not causally associated with CHD risk (factors) in women, nor were the genetic variants associated in men. We found no evidence for a reverse association in a combined sample of women and men.

UR - https://www.mendeley.com/catalogue/297499b5-0042-3931-bb1b-9fda7888bf4d/

UR - http://www.scopus.com/inward/record.url?scp=85132454263&partnerID=8YFLogxK

U2 - 10.1210/clinem/dgac171

DO - 10.1210/clinem/dgac171

M3 - Journal articles

C2 - 35306566

SN - 0021-972X

VL - 107

SP - E2952-E2961

JO - The Journal of clinical endocrinology and metabolism

JF - The Journal of clinical endocrinology and metabolism

IS - 7

ER -

Genetically Determined Reproductive Aging and Coronary Heart Disease: A Bidirectional 2-sample Mendelian Randomization

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