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

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 W. Montgomery(The University of Queensland), Yu‐Hsuan Chuang, Steve Horvath(University of California, Los Angeles), Beate Ritz(University of California, Los Angeles), Glenda M. Halliday(The University of Sydney), Ian B. Hickie(The University of Sydney), John B. Kwok(The University of Sydney), John F. Pearson(University of Otago), Toni L. Pitcher(New Zealand Brain Research Institute), Martin A. 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 C. Dalrymple‐Alford(University of Canterbury), George D. Mellick(Griffith University), Peter M. Visscher(The University of Queensland), Jacob Gratten(The University of Queensland)
Nature Communications
March 6, 2020
10.1038/s41467-020-15065-7
Cited by 148Open Access
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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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