Analysis of DNA methylation associates the cystine-glutamate antiporter SLC7A11 with risk of Parkinson's disease
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Zhang, Futao
Fowdar, Javed
McRae, Allan F
Qi, Ting
Nabais, Marta F
Zhang, Qian
Kassam, Irfahan
Henders, Anjali K
Wallace, Leanne
Montgomery, Grant
Chuang, Yu-Hsuan
Horvath, Steve
Ritz, Beate
Halliday, Glenda
Hickie, Ian
Kwok, John B
Pearson, John
Pitcher, Toni
Kennedy, Martin
Bentley, Steven R
Silburn, Peter A
Yang, Jian
Wray, Naomi R
Lewis, Simon JG
Anderson, Tim
Dalrymple-Alford, John
Mellick, George D
Visscher, Peter M
Gratten, Jacob
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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.
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Nature Communications
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11
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1
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© The Author(s) 2020. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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Biomedical and clinical sciences
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Vallerga, CL; Zhang, F; Fowdar, J; McRae, AF; Qi, T; Nabais, MF; Zhang, Q; Kassam, I; Henders, AK; Wallace, L; Montgomery, G; Chuang, Y-H; Horvath, S; Ritz, B; Halliday, G; Hickie, I; Kwok, JB; Pearson, J; Pitcher, T; Kennedy, M; Bentley, SR; Silburn, PA; Yang, J; Wray, NR; Lewis, SJG; Anderson, T; Dalrymple-Alford, J; Mellick, GD; Visscher, PM; Gratten, J, Analysis of DNA methylation associates the cystine-glutamate antiporter SLC7A11 with risk of Parkinson's disease, Nature Communications, 2020, 11 (1), pp. 1238:1-1238:10