Journal Article

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

Wallace, Leanne, Pearson, John, Dalrymple-Alford, John, Horvath, Steve, Bentley, Steven R., Henders, Anjali K., Wray, Naomi R., Silburn, Peter A., Gratten, Jacob, Kassam, Irfahan, Chuang, Yu-Hsuan, Kennedy, Martin, Qi, Ting, Pitcher, Toni, Fowdar, Javed, Anderson, Tim, Mellick, George D., McRae, Allan F., Nabais, Marta F., Visscher, Peter M., Zhang, Qian, Lewis, Simon J. G., Halliday, Glenda, Vallerga, Costanza L., Ritz, Beate, Montgomery, Grant, Hickie, Ian, Yang, Jian, Kwok, John B., Zhang, Futao

2020

Overview

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. Parkinson’s disease (PD) is a common neurodegenerative disorder with a complex etiology involving genetics and the environment. Here, Vallerga et al. identify two CpG probes associated with PD in a blood cell type-corrected epigenome-wide meta-analysis, implicating the SLC7A11 gene as a plausible biological target.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 45/61 / 631/208/176/1988 / 631/208/177 / 692/499 / 692/617/375/1718 / Adult / Aged / Aged, 80 and over / Alanine / Amino Acid Transport System y+ - genetics / Amino Acid Transport System y+ - metabolism / Antioxidants / Australia / Blood cells / Case-Control Studies / Chromosome 4 / Chromosomes / Chromosomes, Human, Pair 4 - genetics / CpG islands / CpG Islands - genetics / Cystine / Deoxyribonucleic acid / DNA / DNA Methylation / DNA probes / Down-Regulation / Epigenomics - methods / Etiology / Female / Gene expression / Genetic factors / Genetics / Glutathione / Glutathione - metabolism / Healthy Volunteers / Humanities and Social Sciences / Humans / L-Alanine / Male / Mendelian Randomization Analysis / Middle Aged / Movement disorders / multidisciplinary / Neurodegenerative diseases / Neurotoxins / New Zealand / Parkinson Disease - blood / Parkinson Disease - genetics / Parkinson Disease - pathology / Parkinson's disease / Probes / Science / Science (multidisciplinary) / Toxins