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

An improved understanding of etiological mechanisms in Parkinson’s disease (PD) is urgently needed because the number of affected individuals is predicted 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 cg068690548 on chromosome 4. We demonstrate that cg068690548 hypermethylation in PD is associated with down-regulation of the SLC7A11 gene and show this is consistent with an environmental exposure, as opposed to moderates genetic factors with effects on DNA methylation or gene expression. These findings are notable because SLC7A11 codes for a cystine-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.

Costanza L. Vallerga, Futao Zhang, Javed Fowdar, Allan F. McRae, Ting Qi, Marta F. Nabais, Qian Zhang, Irfahan Kassam, Anjalk 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, John Dalrymple-Alford, George D. Mellick, Peter M. Visscher, Jacob Gratten