Analysis of DNA methylation associates the cystine-glutamate antiporter SLC7A11 with risk of Parkinson's disease.

Vallerga, Costanza L; 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 J G; Anderson, Tim; Dalrymple-Alford, John; Mellick, George D; Visscher, Peter M^*

PubMed

The University of Queensland; The University of New South Wales; The University of Sydney; GRIFFITH UNIVERSITY; the University of Canterbury; University of California,Los Angeles; University of California Los Angeles; university of Canterbury; David Geffen School of Medicine UCLA; 2; University of California-Los Angeles; the University of California, Los Angeles.; David Geffen School of Medicine, UCLA; Griffith university; University of California - Los Angeles; the University of New South Wales; university of new south wales; The university of Queensland; university of Queensland; griffith university; 5

摘要

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 beta-methylamino-L-alanine (BMAA). Our study identifies the SLC7A11 gene as a plausible biological target in PD.

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