University of Oulu

Blauwendraat, C., Iwaki, H., Makarious, M.B., Bandres-Ciga, S., Leonard, H.L., Grenn, F.P., Lake, J., Krohn, L., Tan, M., Kim, J.J., Gibbs, J.R., Hernandez, D.G., Ruskey, J.A., Pihlstrøm, L., Toft, M., van Hilten, J.J., Marinus, J., Schulte, C., Brockmann, K., Sharma, M., Siitonen, A., Majamaa, K., Eerola-Rautio, J., Tienari, P.J., Grosset, D.G., Lesage, S., Corvol, J.-C., Brice, A., Wood, N., Hardy, J., Gan-Or, Z., Heutink, P., Gasser, T., Morris, H.R., Noyce, A.J., Nalls, M.A., Singleton, A.B. and (2021), Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease. Ann Neurol, 90: 35-42. https://doi.org/10.1002/ana.26090

Investigation of autosomal genetic sex differences in Parkinson’s disease

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Author: Blauwendraat, Cornelis1; Iwaki, Hirotaka1,2,3; Makarious, Mary B.1,4;
Organizations: 1NIH, Lab Neurogenet, NIA, Bldg 35,35 Convent Dr, Bethesda, MD 20892 USA.
2NIH, Ctr Alzheimers & Related Dementias, Bethesda, MD 20892 USA.
3Data Tecn Int, Glen Echo, MD USA.
4UCL Queen Sq Inst Neurol, Dept Clin & Movement Neurosci, London, England.
5McGill Univ, Dept Human Genet, Montreal, PQ, Canada.
6McGill Univ, Neuro Montreal Neurol Inst Hosp, Montreal, PQ, Canada.
7Oslo Univ Hosp, Dept Neurol, Oslo, Norway.
8Queen Mary Univ London, Wolfson Inst Prevent Med, Prevent Neurol Unit, London, England.
9Leiden Univ, Med Ctr, Dept Neurol, Leiden, Netherlands.
10Univ Tubingen, Hertie Inst Clin Brain Res, Tubingen, Germany.
11German Ctr Neurodegenerat Dis DZNE, Tubingen, Germany.
12Univ Tubingen, Inst Clin Epidemiol & Appl Biometry, Ctr Genet Epidemiol, Tubingen, Germany.
13Univ Oulu, Res Unit Clin Neurosci, Oulu, Finland.
14Oulu Univ Hosp, Dept Neurol, Oulu, Finland.
15Oulu Univ Hosp, Med Res Ctr, Oulu, Finland.
16Helsinki Univ Hosp, Dept Neurol, Helsinki, Finland.
17Univ Helsinki, Biomedicum, Res Programs Unit, Mol Neurol, Helsinki, Finland.
18Queen Elizabeth Univ Hosp, Inst Neurol Sci, Dept Neurol, Glasgow, Lanark, Scotland.
19Sorbonne Univ, AP HP, Paris Brain Inst Inst Cerveau ICM, INSERM,CNRS,Dept Neurol & Genet, Paris, France.
20McGill Univ, Dept Neurol & Neurosurg, Montreal, PQ, Canada.
Format: article
Version: published version
Access: open
Online Access: PDF Full Text (PDF, 0.7 MB)
Persistent link: http://urn.fi/urn:nbn:fi-fe2021071441461
Language: English
Published: John Wiley & Sons, 2021
Publish Date: 2021-07-14
Description:

Abstract

Objective: Parkinson’s disease (PD) is a complex neurodegenerative disorder. Men are on average similar to 1.5 times more likely to develop PD compared to women with European ancestry. Over the years, genomewide association studies (GWAS) have identified numerous genetic risk factors for PD, however, it is unclear whether genetics contribute to disease etiology in a sex-specific manner.

Methods: In an effort to study sex-specific genetic factors associated with PD, we explored 2 large genetic datasets from the International Parkinson’s Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases, and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases.

Results: In total, 19 genomewide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWAS were identified (rg = 0.877) and heritability estimates were identical between male and female PD cases (similar to 20%).

Interpretation: We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females cases at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus female patients.

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Series: Annals of neurology
ISSN: 0364-5134
ISSN-E: 1531-8249
ISSN-L: 0364-5134
Volume: 90
Issue: 1
Pages: 35 - 42
DOI: 10.1002/ana.26090
OADOI: https://oadoi.org/10.1002/ana.26090
Type of Publication: A1 Journal article – refereed
Field of Science: 3124 Neurology and psychiatry
3112 Neurosciences
Subjects:
Funding: The authors would like to thank all of the subjects who donated their time and biological samples to be a part of this study. We also would like to thank all members of the International Parkinson Disease Genomics Consortium (IPDGC). See for a complete overview of members, acknowledgments, and funding . This work was supported in part by the Intramural Research Programs of the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), and the National Institute of Environmental Health Sciences both part of the National Institutes of Health, Department of Health and Human Services; project numbers 1ZIA-NS003154, Z01-AG000949-02, and Z01-ES101986. In addition, this work was supported by the Department of Defense (award W81XWH-09-2-0128), and The Michael J. Fox Foundation for Parkinson's Research. This work was supported by National Institutes of Health grants R01NS037167, R01CA141668, and P50NS071674, American Parkinson Disease Association (APDA); Barnes Jewish Hospital Foundation; Greater St Louis Chapter of the APDA. The KORA (Cooperative Research in the Region of Augsburg) research platform was started and financed by the Forschungszentrum fur Umwelt und Gesundheit, which is funded by the German Federal Ministry of Education, Science, Research, and Technology and by the State of Bavaria. This study was also funded by the German Federal Ministry of Education and Research (BMBF) under the funding code 031A430A, the EU Joint Programme - Neurodegenerative Diseases Research funding code 01ED1406 and iMed - the Helmholtz Initiative on Personalized Medicine. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, MD, USA (), and DNA panels, samples, and clinical data from the National Institute of Neurological Disorders and Stroke Human Genetics Resource Center DNA and Cell Line Repository. People who contributed samples are acknowledged in descriptions of every panel on the repository website. We thank P. Tienari (Molecular Neurology Programme, Biomedicum, University of Helsinki), T. Peuralinna Myllykangas (Folkhalsan Institute of Genetics and Department of Pathology, University of Helsinki), and R. Sulkava (Department of Public Health and General Practice Division of Geriatrics, University of Eastern Finland) for the Finnish controls (Vantaa85+ GWAS data). This study was also funded by the Sigrid Juselius Foundation (KM). We used genomewide association data generated by the Wellcome Trust Case-Control Consortium 2 (WTCCC2) from UK patients with Parkinson's disease and UK control individuals from the 1958 Birth Cohort and National Blood Service. UK population control data was made available through WTCCC1. As with previous IPDGC efforts, this study makes use of data generated by the Wellcome Trust Case-Control Consortium. A full list of the investigators who contributed to the generation of the data is available from . Funding for the project was provided by the Wellcome Trust under awards 076113, 085475, and 090355. This study was also supported by Parkinson's UK (grants 8047 and J-0804) and the Medical Research Council University was supported by grants from the Michael J.; Fox Foundation, the Canadian Consortium on Neurodegeneration in Aging (CCNA), the Canada First Research Excellence Fund (CFREF), awarded to McGill University for the Healthy Brains for Healthy Lives (HBHL) program and Parkinson's Society Canada. The access to part of the participants at McGill has been made possible thanks to the Quebec Parkinson's Network (). We thank the Quebec Parkinson's Network () and its members. Harvard NeuroDiscovery Biomarker Study (HBS) is a collaboration of HBS investigators and funded through philanthropy and NIH and Non-NIH funding sources. The HBS Investigators have not participated in reviewing the data analysis or content of the manuscript. PPMI - a public-private partnership - is funded by the Michael J. Fox Foundation for Parkinson's Research and funding partners, the full names of all of the PPMI funding partners can be found at . The PPMI Investigators have not participated in reviewing the data analysis or content of the manuscript. For up-to-date information on the study, visit . Parkinson's Disease Biomarker Program (PDBP) consortium is supported by the National Institute of Neurological Disorders and Stroke (NINDS) at the National Institutes of Health. A full list of PDBP investigators can be found at analysis or content of the manuscript.
Copyright information: © 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. This article has been contributed to by US Government employees and their work is in the public domain in the USA. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
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