Investigation of Autosomal Genetic Sex Differences in Parkinson's Disease

Cornelis Blauwendraat, Hirotaka Iwaki, Mary B Makarious, Sara Bandres-Ciga, Hampton L Leonard, Francis P Grenn, Julie Lake, Lynne Krohn, Manuela Tan, Jonggeol J Kim, Jesse R Gibbs, Dena G Hernandez, Jennifer A Ruskey, Lasse Pihlstrøm, Mathias Toft, Jacobus J van Hilten, Johan Marinus, Claudia Schulte, Kathrin Brockmann, Manu SharmaAri Siitonen, Kari Majamaa, Johanna Eerola-Rautio, Pentti J Tienari, Donald G Grosset, Suzanne Lesage, Jean-Christophe Corvol, Alexis Brice, Nick Wood, John Hardy, Ziv Gan-Or, Peter Heutink, Thomas Gasser, Huw R Morris, Alastair J Noyce, Mike A Nalls, Andrew B Singleton, Karen Morrison

Research output: Contribution to journalArticlepeer-review

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Abstract

OBJECTIVE: Parkinson's disease (PD) is a complex neurodegenerative disorder. Men are on average ~ 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 (~ 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. 

Original languageEnglish
Pages (from-to)35-42
Number of pages8
JournalAnnals of neurology
Volume90
Issue number1
Early online date24 May 2021
DOIs
Publication statusPublished - Jul 2021

Bibliographical note

© 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.

Keywords

  • Aged
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Genotype
  • Humans
  • Male
  • Middle Aged
  • Parkinson Disease/genetics
  • Sex Characteristics

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