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

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, Steve Horvath, Beate Ritz, Glenda Halliday, Ian Hickie, John B. Kwok, John Pearson, Toni Pitcher, Martin Kennedy, Steven R. Bentley, Peter A. Silburn, Jian Yang, Naomi R. Wray, Simon J. G. Lewis, Tim Anderson, John Dalrymple-Alford, George D. Mellick, Peter M. Visscher () and Jacob Gratten ()
Additional contact information
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
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)
Beate Ritz: 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
John Pearson: University of Otago
Toni Pitcher: New Zealand Brain Research Institute
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
Simon J. G. Lewis: The University of Sydney
Tim Anderson: New Zealand Brain Research Institute
John Dalrymple-Alford: New Zealand Brain Research Institute
George D. Mellick: Griffith University
Peter M. Visscher: The University of Queensland
Jacob Gratten: The University of Queensland

Nature Communications, 2020, vol. 11, issue 1, 1-10

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-15065-7

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