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Analysis of DNA methylation associates the cystine–glutamate antiporter SLC7A11 with risk of Parkinson’s disease

Author

Listed:
  • Costanza L. Vallerga

    (The University of Queensland)

  • Futao Zhang

    (The University of Queensland)

  • Javed Fowdar

    (Griffith University)

  • Allan F. McRae

    (The University of Queensland)

  • Ting Qi

    (The University of Queensland)

  • Marta F. Nabais

    (The University of Queensland
    University of Exeter Medical School, Exeter EX2 5DW)

  • Qian Zhang

    (The University of Queensland)

  • Irfahan Kassam

    (The University of Queensland)

  • Anjali K. Henders

    (The University of Queensland)

  • Leanne Wallace

    (The University of Queensland)

  • Grant Montgomery

    (The University of Queensland)

  • Yu-Hsuan Chuang

    (Fielding School of Public Health, UCLA)

  • Steve Horvath

    (University of California Los Angeles (UCLA)
    Fielding School of Public Health, UCLA)

  • Beate Ritz

    (Fielding School of Public Health, UCLA
    David Geffen School of Medicine, UCLA
    Fielding School of Public Health, UCLA)

  • Glenda Halliday

    (The University of Sydney)

  • Ian Hickie

    (The University of Sydney)

  • John B. Kwok

    (The University of Sydney
    University of New South Wales)

  • John Pearson

    (University of Otago)

  • Toni Pitcher

    (New Zealand Brain Research Institute
    University of Otago)

  • Martin Kennedy

    (University of Otago)

  • Steven R. Bentley

    (Griffith University)

  • Peter A. Silburn

    (The University of Queensland)

  • Jian Yang

    (The University of Queensland)

  • Naomi R. Wray

    (The University of Queensland
    The University of Queensland)

  • Simon J. G. Lewis

    (The University of Sydney)

  • Tim Anderson

    (New Zealand Brain Research Institute
    University of Otago)

  • John Dalrymple-Alford

    (New Zealand Brain Research Institute
    University of Canterbury)

  • George D. Mellick

    (Griffith University)

  • Peter M. Visscher

    (The University of Queensland
    The University of Queensland)

  • Jacob Gratten

    (The University of Queensland
    The University of Queensland)

Abstract

An improved understanding of etiological mechanisms in Parkinson’s disease (PD) is urgently needed because the number of affected individuals is projected to increase rapidly as populations age. We present results from a blood-based methylome-wide association study of PD involving meta-analysis of 229 K CpG probes in 1,132 cases and 999 controls from two independent cohorts. We identify two previously unreported epigenome-wide significant associations with PD, including cg06690548 on chromosome 4. We demonstrate that cg06690548 hypermethylation in PD is associated with down-regulation of the SLC7A11 gene and show this is consistent with an environmental exposure, as opposed to medications or genetic factors with effects on DNA methylation or gene expression. These findings are notable because SLC7A11 codes for a cysteine-glutamate anti-porter regulating levels of the antioxidant glutathione, and it is a known target of the environmental neurotoxin β-methylamino-L-alanine (BMAA). Our study identifies the SLC7A11 gene as a plausible biological target in PD.

Suggested Citation

  • Costanza L. Vallerga & Futao Zhang & Javed Fowdar & Allan F. McRae & Ting Qi & Marta F. Nabais & Qian Zhang & Irfahan Kassam & Anjali K. Henders & Leanne Wallace & Grant Montgomery & Yu-Hsuan Chuang &, 2020. "Analysis of DNA methylation associates the cystine–glutamate antiporter SLC7A11 with risk of Parkinson’s disease," Nature Communications, Nature, vol. 11(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-15065-7
    DOI: 10.1038/s41467-020-15065-7
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    Cited by:

    1. Lasse Pihlstrøm & Gemma Shireby & Hanneke Geut & Sandra Pilar Henriksen & Annemieke J. M. Rozemuller & Jon-Anders Tunold & Eilis Hannon & Paul Francis & Alan J. Thomas & Seth Love & Jonathan Mill & Wi, 2022. "Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Danni A. Gadd & Robert F. Hillary & Daniel L. McCartney & Liu Shi & Aleks Stolicyn & Neil A. Robertson & Rosie M. Walker & Robert I. McGeachan & Archie Campbell & Shen Xueyi & Miruna C. Barbu & Claire, 2022. "Integrated methylome and phenome study of the circulating proteome reveals markers pertinent to brain health," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    3. Alesha A. Hatton & Fei-Fei Cheng & Tian Lin & Ren-Juan Shen & Jie Chen & Zhili Zheng & Jia Qu & Fan Lyu & Sarah E. Harris & Simon R. Cox & Zi-Bing Jin & Nicholas G. Martin & Dongsheng Fan & Grant W. M, 2024. "Genetic control of DNA methylation is largely shared across European and East Asian populations," Nature Communications, Nature, vol. 15(1), pages 1-12, December.

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