Abstract
Background: Studies of Parkinson's disease (PD) and the association with age at menarche or menopause have reported inconsistent findings. Mendelian randomization (MR) may address measurement errors because of difficulties accurately reporting the age these life events occur. Objective: We used MR to assess the association between age at menopause and age at menarche with PD risk. Methods: We performed inverse variant-weighted (IVW) MR analysis using external genome-wide association study (GWAS) summary data from the United Kingdom biobank, and the effect estimates between genetic variants and PD among two population-based studies (Parkinson's disease in Denmark (PASIDA) study, Denmark, and Parkinson's Environment and Gene study [PEG], United States) that enrolled 1737 female and 2430 male subjects of European ancestry. We, then, replicated our findings for age at menopause using summary statistics from the PD consortium (19 773 women), followed by a meta-analysis combining all summary statistics. Results: For each year increase in age at menopause, the risk for PD decreased (odds ration [OR], 0.84; 95% confidence interval [CI], 0.73–0.98; P = 0.03) among women in our study, whereas there was no association among men (OR, 0.98; 95% CI, 0.85–1.11; P = 0.71). A replication using summary statistics from the PD consortium estimated an OR of 0.94 (95% CI, 0.90–0.99; P = 0.01), and we calculated a meta-analytic OR of 0.93 (95% CI, 0.89–0.98; P = 0.003). There was no indication for an association between age at menarche and PD (OR, 0.75; 95% CI, 0.44–1.29; P = 0.29). Conclusions: A later age at menopause was associated with a decreased risk of PD in women, supporting the hypothesis that sex hormones or other factors related to late menopause may be neuroprotective in PD.
Original language | English |
---|---|
Journal | Movement Disorders |
Volume | 36 |
Issue number | 10 |
Pages (from-to) | 2264-2272 |
Number of pages | 9 |
ISSN | 0885-3185 |
DOIs | |
Publication status | Published - 10.2021 |
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In: Movement Disorders, Vol. 36, No. 10, 10.2021, p. 2264-2272.
Research output: Journal Articles › Journal articles › Research › peer-review
TY - JOUR
T1 - Increased Menopausal Age Reduces the Risk of Parkinson's Disease
T2 - A Mendelian Randomization Approach
AU - Kusters, Cynthia D.J.
AU - Paul, Kimberly C.
AU - Duarte Folle, Aline
AU - Keener, Adrienne M.
AU - Bronstein, Jeff M.
AU - Bertram, Lars
AU - Hansen, Johnni
AU - Horvath, Steve
AU - Sinsheimer, Janet S.
AU - Lill, Christina M.
AU - Ritz, Beate R.
N1 - Funding Information: : C.M.L. and L.B. received funding from the German Research Foundation for the genome‐wide SNP data generation and processing of the PEG and PASIDA GWAS data (DFG; FOR2488/1: LI 2654/2‐1 and BE 2287/5‐1). C.M.L. received support by a “habilitation grant” (H01‐2019) from the University of Lübeck. J.S.S. was partially funded by NIH/NHGRI grant HG009120. This project has been made available with funding from National Institutes of Health (NIH) grants R01‐ES010544, R01‐ES013717, U54‐ES012078, P01‐ES016732, and P50‐NS038367; initial pilot funding from NIH P30‐ES07048; a Community Fast Track grant by the MJFox Foundation; a pilot grant by the American Parkinson Disease Association; and from the Parkinson’s Alliance. C.K. is supported by the NIH grant F32AG063442. Funding sources Funding Information: C.D.J.K. is supported by the NIH grant F32AG063442, and employed in the department of Human Genetics as a Ruth Kirchstein postdoctoral fellow (under the NIH F32 grant) at the University of California, Los Angeles. K.C.P. is supported by the NIH grant R21ES030175 and the Department of Defense grant W81XWH1910697. She was employed in the department of Epidemiology as a postdoctoral fellow at the University of California, Los Angeles, and has recently started a position as an assistant professor in the department of Neurology at the University of California, Los Angeles. A.D.F. was employed in the UCLA Department of Epidemiology as a Graduate Student Researcher and Public Administration Analyst, paid B.R.R.'s general funds and a grant by NIH (R01AG063969). She is currently a postdoctoral employee, funded by a Multiple System Atrophy Coalition grant CoreE‐2020‐08‐001 and by NIH R01 ES31106‐01A1. A.M.K. is employed by the Greater Los Angeles Veterans Affairs Medical Center, Los Angeles, and department of Neurology at the University of California, Los Angeles. She is on the Medical Advisory Board for two non‐profit patient groups: Parkinson's Community Los Angeles and Down with Dystonia. L.B. is employed by the University of Lübeck, Lübeck, Germany; and the University of Oslo, Oslo, Norway. He is funded by the following grants: Deutsche Forschungsgemeinschaft, Cure Alzheimer's Fund, and the European Research Council. He has given expert testimony for the Research Council of Norway. He also has a contract with Massachusetts General Hospital / Harvard Medical School. J.H. is supported by the following grants: NORDFORSK, RT‐10; Nordic Cancer Union. No number; NIEHS 1 R21 NS099910; NIEHS 1 R21 ES028472‐01A1; UCLA, Alpha‐1 Foundation, 611,519. He is employed by the Danish Cancer Society. S.H.is employed as a Professor by the Department of Human Genetics at the University of California, Los Angeles. He has patents for “DNA METHYLATION BASED BIOMARKERS FOR LIFE EXPECTANCY AND MORBIDITY”; U.S. Provisional Patent Application Serial Number 62/744,010 (reference: G&C 30435.361‐US‐P1), and for “DNA METHYLATION BASED ESTIMATOR OF TELOMERE LENGTH” (reference: 30435.0374WOU1). He consults for Iduna Inc; is on the advisory board of the Epigenetic Clock Development Foundation—founder of non‐profit foundation, and is supported by the NIH 1U01AG060908–01 grant. J.M.B. is employed as a Professor by the Department of Neurology at the University of California, Los Angeles. He performs Ultragenyx pre‐clinical consultations, and is an advisor to the internal education program of Alexion. He is supported by the following grants: Levine Foundation. Clinical Trials Site PI for these trials: Alexion (Wilson's disease trial); United States (US) World Meds (apomorphine infusion for treatment of PD; AbbVie, levodopa infusion for the treatment of PD. J.S.S. has been or is supported by NIH grants HG007703, HG009120, GM053275, and ES023451 and employed as a Professor by the Department of Human Genetics, David Geffen School of Medicine at the University of California, Los Angeles. She is a member of the Data Safety and Monitoring Board for the MPS 1 Intrathecal Research Collaborative Project. She has received royalties from US Patent App. 14/119,145. J.S.S. was partially funded by NIH/NHGRI grant HG009120. C.M.L. is employed by the University Hospital Schleswig‐Holstein, Lübeck, Germany; and the Imperial College London, London, United Kingdom. She is supported by grants from the Michael J. Fox Foundation, Deutsche Forschungsgemeinschaft, Cure Alzheimer's Fund, and the European Research Council. B.R.R. is employed as a professor in the departments of Epidemiology, Environmental Health Sciences, and Neurology at the University of California, Los Angeles. She is being supported by NIH grants (U01AG060908, R21ES030175, R01ES023451, and R01ES031106), and by grants from the Department of Defense (W81XWH1910697), the Michael J. Fox Foundation, the California State Air Resources Board, a contract from NASA (NNH12ZDA006O‐EVI3), and a training grant by the BURROUGHS WELLCOME FUND. She also has been an expert witness for plaintiffs (farmers) in law suits linking pesticide exposures to health outcomes. Funding Information: We thank all the participants in this study. We thank Dr. Valerija Dobricic and Fabian Kilpert, L?beck Interdisciplinary Platform for Genome Analytics (LIGA), University of L?beck, for sample processing and GWAS data pre-processing, quality control, and imputation, respectively, and Mrs. Tanja Wesse, Mrs. Sanaz Sedghpour Sabet, Dr. Michael Wittig, and Dr. Andre Franke at the Institute of Clinical Molecular Biology, Christian-Albrechts-University of Kiel, Kiel, Germany for assistance with GSA genotyping. The LIGA team acknowledges computational support from the OMICS compute cluster at the University of L?beck. This project has been made available with funding from National Institutes of Health (NIH) (R01-ES010544, R01-ES013717, U54-ES012078, P01-ES016732, and P50-NS03836)7; initial pilot funding from NIH (P30-ES07048); a Community Fast Track grant by the Michael J. Fox Foundation; a pilot grant by the American Parkinson Disease Association; and from the Parkinson's Alliance. C.K. is supported by the NIH (F32AG063442). Funding Information: We thank all the participants in this study. We thank Dr. Valerija Dobricic and Fabian Kilpert, Lübeck Interdisciplinary Platform for Genome Analytics (LIGA), University of Lübeck, for sample processing and GWAS data pre‐processing, quality control, and imputation, respectively, and Mrs. Tanja Wesse, Mrs. Sanaz Sedghpour Sabet, Dr. Michael Wittig, and Dr. Andre Franke at the Institute of Clinical Molecular Biology, Christian‐Albrechts‐University of Kiel, Kiel, Germany for assistance with GSA genotyping. The LIGA team acknowledges computational support from the OMICS compute cluster at the University of Lübeck. This project has been made available with funding from National Institutes of Health (NIH) (R01‐ES010544, R01‐ES013717, U54‐ES012078, P01‐ES016732, and P50‐NS03836)7; initial pilot funding from NIH (P30‐ES07048); a Community Fast Track grant by the Michael J. Fox Foundation; a pilot grant by the American Parkinson Disease Association; and from the Parkinson's Alliance. C.K. is supported by the NIH (F32AG063442). Publisher Copyright: © 2021 International Parkinson and Movement Disorder Society
PY - 2021/10
Y1 - 2021/10
N2 - Background: Studies of Parkinson's disease (PD) and the association with age at menarche or menopause have reported inconsistent findings. Mendelian randomization (MR) may address measurement errors because of difficulties accurately reporting the age these life events occur. Objective: We used MR to assess the association between age at menopause and age at menarche with PD risk. Methods: We performed inverse variant-weighted (IVW) MR analysis using external genome-wide association study (GWAS) summary data from the United Kingdom biobank, and the effect estimates between genetic variants and PD among two population-based studies (Parkinson's disease in Denmark (PASIDA) study, Denmark, and Parkinson's Environment and Gene study [PEG], United States) that enrolled 1737 female and 2430 male subjects of European ancestry. We, then, replicated our findings for age at menopause using summary statistics from the PD consortium (19 773 women), followed by a meta-analysis combining all summary statistics. Results: For each year increase in age at menopause, the risk for PD decreased (odds ration [OR], 0.84; 95% confidence interval [CI], 0.73–0.98; P = 0.03) among women in our study, whereas there was no association among men (OR, 0.98; 95% CI, 0.85–1.11; P = 0.71). A replication using summary statistics from the PD consortium estimated an OR of 0.94 (95% CI, 0.90–0.99; P = 0.01), and we calculated a meta-analytic OR of 0.93 (95% CI, 0.89–0.98; P = 0.003). There was no indication for an association between age at menarche and PD (OR, 0.75; 95% CI, 0.44–1.29; P = 0.29). Conclusions: A later age at menopause was associated with a decreased risk of PD in women, supporting the hypothesis that sex hormones or other factors related to late menopause may be neuroprotective in PD.
AB - Background: Studies of Parkinson's disease (PD) and the association with age at menarche or menopause have reported inconsistent findings. Mendelian randomization (MR) may address measurement errors because of difficulties accurately reporting the age these life events occur. Objective: We used MR to assess the association between age at menopause and age at menarche with PD risk. Methods: We performed inverse variant-weighted (IVW) MR analysis using external genome-wide association study (GWAS) summary data from the United Kingdom biobank, and the effect estimates between genetic variants and PD among two population-based studies (Parkinson's disease in Denmark (PASIDA) study, Denmark, and Parkinson's Environment and Gene study [PEG], United States) that enrolled 1737 female and 2430 male subjects of European ancestry. We, then, replicated our findings for age at menopause using summary statistics from the PD consortium (19 773 women), followed by a meta-analysis combining all summary statistics. Results: For each year increase in age at menopause, the risk for PD decreased (odds ration [OR], 0.84; 95% confidence interval [CI], 0.73–0.98; P = 0.03) among women in our study, whereas there was no association among men (OR, 0.98; 95% CI, 0.85–1.11; P = 0.71). A replication using summary statistics from the PD consortium estimated an OR of 0.94 (95% CI, 0.90–0.99; P = 0.01), and we calculated a meta-analytic OR of 0.93 (95% CI, 0.89–0.98; P = 0.003). There was no indication for an association between age at menarche and PD (OR, 0.75; 95% CI, 0.44–1.29; P = 0.29). Conclusions: A later age at menopause was associated with a decreased risk of PD in women, supporting the hypothesis that sex hormones or other factors related to late menopause may be neuroprotective in PD.
UR - http://www.scopus.com/inward/record.url?scp=85113810285&partnerID=8YFLogxK
U2 - 10.1002/mds.28760
DO - 10.1002/mds.28760
M3 - Journal articles
C2 - 34426982
AN - SCOPUS:85113810285
SN - 0885-3185
VL - 36
SP - 2264
EP - 2272
JO - Movement Disorders
JF - Movement Disorders
IS - 10
ER -