Age at Menopause and the Risk of Stroke: Observational and Mendelian Randomization Analysis in 204 244 Postmenopausal Women

Lena Tschiderer; Sanne A E Peters; Yvonne T van der Schouw; Anniek C van Westing; Tammy Y N Tong; Peter Willeit; Lisa Seekircher; Conchi Moreno-Iribas; José María Huerta; Marta Crous-Bou; Martin Söderholm; Matthias B Schulze; Cecilia Johansson; Sara Själander; Alicia K Heath; Alessandra Macciotta; Christina C Dahm; Daniel B Ibsen; Valeria Pala; Lene Mellemkjær; Stephen Burgess; Angela Wood; Rudolf Kaaks; Verena Katzke; Pilar Amiano; Miguel Rodriguez-Barranco; Gunnar Engström; Elisabete Weiderpass; Anne Tjønneland; Jytte Halkjær; Salvatore Panico; John Danesh; Adam Butterworth; N Charlotte Onland-Moret

doi:10.1161/JAHA.123.030280

Age at Menopause and the Risk of Stroke: Observational and Mendelian Randomization Analysis in 204 244 Postmenopausal Women

Lena Tschiderer, Sanne A E Peters, Yvonne T van der Schouw^*, Anniek C van Westing, Tammy Y N Tong, Peter Willeit, Lisa Seekircher, Conchi Moreno-Iribas, José María Huerta, Marta Crous-Bou, Martin Söderholm, Matthias B Schulze, Cecilia Johansson, Sara Själander, Alicia K Heath, Alessandra Macciotta, Christina C Dahm, Daniel B Ibsen, Valeria Pala, Lene MellemkjærStephen Burgess, Angela Wood, Rudolf Kaaks, Verena Katzke, Pilar Amiano, Miguel Rodriguez-Barranco, Gunnar Engström, Elisabete Weiderpass, Anne Tjønneland, Jytte Halkjær, Salvatore Panico, John Danesh, Adam Butterworth, N Charlotte Onland-Moret

^*Corresponding author for this work

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3 Citations (Scopus)

Abstract

Background Observational studies have shown that women with an early menopause are at higher risk of stroke compared with women with a later menopause. However, associations with stroke subtypes are inconsistent, and the causality is unclear. Methods and Results We analyzed data of the UK Biobank and EPIC-CVD (European Prospective Investigation Into Cancer and Nutrition-Cardiovascular Diseases) study. A total of 204 244 postmenopausal women without a history of stroke at baseline were included (7883 from EPIC-CVD [5292 from the subcohort], 196 361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD, 5.8), and pooled mean age at menopause was 47.8 years (SD, 6.2). Over a median follow-up of 12.6 years (interquartile range, 11.8-13.3), 6770 women experienced a stroke (5155 ischemic strokes, 1615 hemorrhagic strokes, 976 intracerebral hemorrhages, and 639 subarachnoid hemorrhages). In multivariable adjusted observational Cox regression analyses, the pooled hazard ratios per 5 years younger age at menopause were 1.09 (95% CI, 1.07-1.12) for stroke, 1.09 (95% CI, 1.06-1.13) for ischemic stroke, 1.10 (95% CI, 1.04-1.16) for hemorrhagic stroke, 1.14 (95% CI, 1.08-1.20) for intracerebral hemorrhage, and 1.00 (95% CI, 0.84-1.20) for subarachnoid hemorrhage. When using 2-sample Mendelian randomization analysis, we found no statistically significant association between genetically proxied age at menopause and risk of any type of stroke. Conclusions In our study, earlier age at menopause was related to a higher risk of stroke. We found no statistically significant association between genetically proxied age at menopause and risk of stroke, suggesting no causal relationship.

Original language	English
Article number	e030280
Journal	Journal of the American Heart Association
Volume	12
Issue	18
Number of pages	14
ISSN	2047-9980
DOIs	https://doi.org/10.1161/JAHA.123.030280
Publication status	Published - Sept 2023

Keywords

Mendelian randomization analysis
age at menopause
observational analysis
stroke

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10.1161/JAHA.123.030280Licence: CC BY

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Tschiderer, L., Peters, S. A. E., van der Schouw, Y. T., van Westing, A. C., Tong, T. Y. N., Willeit, P., Seekircher, L., Moreno-Iribas, C., Huerta, J. M., Crous-Bou, M., Söderholm, M., Schulze, M. B., Johansson, C., Själander, S., Heath, A. K., Macciotta, A., Dahm, C. C., Ibsen, D. B., Pala, V., ... Onland-Moret, N. C. (2023). Age at Menopause and the Risk of Stroke: Observational and Mendelian Randomization Analysis in 204 244 Postmenopausal Women. Journal of the American Heart Association, 12(18), Article e030280. https://doi.org/10.1161/JAHA.123.030280

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title = "Age at Menopause and the Risk of Stroke: Observational and Mendelian Randomization Analysis in 204 244 Postmenopausal Women",

abstract = "Background Observational studies have shown that women with an early menopause are at higher risk of stroke compared with women with a later menopause. However, associations with stroke subtypes are inconsistent, and the causality is unclear. Methods and Results We analyzed data of the UK Biobank and EPIC-CVD (European Prospective Investigation Into Cancer and Nutrition-Cardiovascular Diseases) study. A total of 204 244 postmenopausal women without a history of stroke at baseline were included (7883 from EPIC-CVD [5292 from the subcohort], 196 361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD, 5.8), and pooled mean age at menopause was 47.8 years (SD, 6.2). Over a median follow-up of 12.6 years (interquartile range, 11.8-13.3), 6770 women experienced a stroke (5155 ischemic strokes, 1615 hemorrhagic strokes, 976 intracerebral hemorrhages, and 639 subarachnoid hemorrhages). In multivariable adjusted observational Cox regression analyses, the pooled hazard ratios per 5 years younger age at menopause were 1.09 (95% CI, 1.07-1.12) for stroke, 1.09 (95% CI, 1.06-1.13) for ischemic stroke, 1.10 (95% CI, 1.04-1.16) for hemorrhagic stroke, 1.14 (95% CI, 1.08-1.20) for intracerebral hemorrhage, and 1.00 (95% CI, 0.84-1.20) for subarachnoid hemorrhage. When using 2-sample Mendelian randomization analysis, we found no statistically significant association between genetically proxied age at menopause and risk of any type of stroke. Conclusions In our study, earlier age at menopause was related to a higher risk of stroke. We found no statistically significant association between genetically proxied age at menopause and risk of stroke, suggesting no causal relationship.",

keywords = "Mendelian randomization analysis, age at menopause, observational analysis, stroke",

author = "Lena Tschiderer and Peters, {Sanne A E} and {van der Schouw}, {Yvonne T} and {van Westing}, {Anniek C} and Tong, {Tammy Y N} and Peter Willeit and Lisa Seekircher and Conchi Moreno-Iribas and Huerta, {Jos{\'e} Mar{\'i}a} and Marta Crous-Bou and Martin S{\"o}derholm and Schulze, {Matthias B} and Cecilia Johansson and Sara Sj{\"a}lander and Heath, {Alicia K} and Alessandra Macciotta and Dahm, {Christina C} and Ibsen, {Daniel B} and Valeria Pala and Lene Mellemkj{\ae}r and Stephen Burgess and Angela Wood and Rudolf Kaaks and Verena Katzke and Pilar Amiano and Miguel Rodriguez-Barranco and Gunnar Engstr{\"o}m and Elisabete Weiderpass and Anne Tj{\o}nneland and Jytte Halkj{\ae}r and Salvatore Panico and John Danesh and Adam Butterworth and Onland-Moret, {N Charlotte}",

year = "2023",

month = sep,

doi = "10.1161/JAHA.123.030280",

language = "English",

volume = "12",

journal = "Journal of the American Heart Association",

issn = "2047-9980",

publisher = "American Heart Association Inc.",

number = "18",

}

Tschiderer, L, Peters, SAE, van der Schouw, YT, van Westing, AC, Tong, TYN, Willeit, P, Seekircher, L, Moreno-Iribas, C, Huerta, JM, Crous-Bou, M, Söderholm, M, Schulze, MB, Johansson, C, Själander, S, Heath, AK, Macciotta, A, Dahm, CC , Ibsen, DB, Pala, V, Mellemkjær, L, Burgess, S, Wood, A, Kaaks, R, Katzke, V, Amiano, P, Rodriguez-Barranco, M, Engström, G, Weiderpass, E, Tjønneland, A, Halkjær, J, Panico, S, Danesh, J, Butterworth, A & Onland-Moret, NC 2023, 'Age at Menopause and the Risk of Stroke: Observational and Mendelian Randomization Analysis in 204 244 Postmenopausal Women', Journal of the American Heart Association, vol. 12, no. 18, e030280. https://doi.org/10.1161/JAHA.123.030280

Age at Menopause and the Risk of Stroke: Observational and Mendelian Randomization Analysis in 204 244 Postmenopausal Women. / Tschiderer, Lena; Peters, Sanne A E; van der Schouw, Yvonne T et al.
In: Journal of the American Heart Association, Vol. 12, No. 18, e030280, 09.2023.

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

TY - JOUR

T1 - Age at Menopause and the Risk of Stroke

T2 - Observational and Mendelian Randomization Analysis in 204 244 Postmenopausal Women

AU - Tschiderer, Lena

AU - Peters, Sanne A E

AU - van der Schouw, Yvonne T

AU - van Westing, Anniek C

AU - Tong, Tammy Y N

AU - Willeit, Peter

AU - Seekircher, Lisa

AU - Moreno-Iribas, Conchi

AU - Huerta, José María

AU - Crous-Bou, Marta

AU - Söderholm, Martin

AU - Schulze, Matthias B

AU - Johansson, Cecilia

AU - Själander, Sara

AU - Heath, Alicia K

AU - Macciotta, Alessandra

AU - Dahm, Christina C

AU - Ibsen, Daniel B

AU - Pala, Valeria

AU - Mellemkjær, Lene

AU - Burgess, Stephen

AU - Wood, Angela

AU - Kaaks, Rudolf

AU - Katzke, Verena

AU - Amiano, Pilar

AU - Rodriguez-Barranco, Miguel

AU - Engström, Gunnar

AU - Weiderpass, Elisabete

AU - Tjønneland, Anne

AU - Halkjær, Jytte

AU - Panico, Salvatore

AU - Danesh, John

AU - Butterworth, Adam

AU - Onland-Moret, N Charlotte

PY - 2023/9

Y1 - 2023/9

N2 - Background Observational studies have shown that women with an early menopause are at higher risk of stroke compared with women with a later menopause. However, associations with stroke subtypes are inconsistent, and the causality is unclear. Methods and Results We analyzed data of the UK Biobank and EPIC-CVD (European Prospective Investigation Into Cancer and Nutrition-Cardiovascular Diseases) study. A total of 204 244 postmenopausal women without a history of stroke at baseline were included (7883 from EPIC-CVD [5292 from the subcohort], 196 361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD, 5.8), and pooled mean age at menopause was 47.8 years (SD, 6.2). Over a median follow-up of 12.6 years (interquartile range, 11.8-13.3), 6770 women experienced a stroke (5155 ischemic strokes, 1615 hemorrhagic strokes, 976 intracerebral hemorrhages, and 639 subarachnoid hemorrhages). In multivariable adjusted observational Cox regression analyses, the pooled hazard ratios per 5 years younger age at menopause were 1.09 (95% CI, 1.07-1.12) for stroke, 1.09 (95% CI, 1.06-1.13) for ischemic stroke, 1.10 (95% CI, 1.04-1.16) for hemorrhagic stroke, 1.14 (95% CI, 1.08-1.20) for intracerebral hemorrhage, and 1.00 (95% CI, 0.84-1.20) for subarachnoid hemorrhage. When using 2-sample Mendelian randomization analysis, we found no statistically significant association between genetically proxied age at menopause and risk of any type of stroke. Conclusions In our study, earlier age at menopause was related to a higher risk of stroke. We found no statistically significant association between genetically proxied age at menopause and risk of stroke, suggesting no causal relationship.

AB - Background Observational studies have shown that women with an early menopause are at higher risk of stroke compared with women with a later menopause. However, associations with stroke subtypes are inconsistent, and the causality is unclear. Methods and Results We analyzed data of the UK Biobank and EPIC-CVD (European Prospective Investigation Into Cancer and Nutrition-Cardiovascular Diseases) study. A total of 204 244 postmenopausal women without a history of stroke at baseline were included (7883 from EPIC-CVD [5292 from the subcohort], 196 361 from the UK Biobank). Pooled mean baseline age was 58.9 years (SD, 5.8), and pooled mean age at menopause was 47.8 years (SD, 6.2). Over a median follow-up of 12.6 years (interquartile range, 11.8-13.3), 6770 women experienced a stroke (5155 ischemic strokes, 1615 hemorrhagic strokes, 976 intracerebral hemorrhages, and 639 subarachnoid hemorrhages). In multivariable adjusted observational Cox regression analyses, the pooled hazard ratios per 5 years younger age at menopause were 1.09 (95% CI, 1.07-1.12) for stroke, 1.09 (95% CI, 1.06-1.13) for ischemic stroke, 1.10 (95% CI, 1.04-1.16) for hemorrhagic stroke, 1.14 (95% CI, 1.08-1.20) for intracerebral hemorrhage, and 1.00 (95% CI, 0.84-1.20) for subarachnoid hemorrhage. When using 2-sample Mendelian randomization analysis, we found no statistically significant association between genetically proxied age at menopause and risk of any type of stroke. Conclusions In our study, earlier age at menopause was related to a higher risk of stroke. We found no statistically significant association between genetically proxied age at menopause and risk of stroke, suggesting no causal relationship.

KW - Mendelian randomization analysis

KW - age at menopause

KW - observational analysis

KW - stroke

UR - http://www.scopus.com/inward/record.url?scp=85171770875&partnerID=8YFLogxK

U2 - 10.1161/JAHA.123.030280

DO - 10.1161/JAHA.123.030280

M3 - Journal article

C2 - 37681566

SN - 2047-9980

VL - 12

JO - Journal of the American Heart Association

JF - Journal of the American Heart Association

IS - 18

M1 - e030280

ER -

Age at Menopause and the Risk of Stroke: Observational and Mendelian Randomization Analysis in 204 244 Postmenopausal Women

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