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

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.

Peculiarities of Platelet Metabolism in Patients with Acute Coronary Syndrome with Anxiety–Depressive Disorders and Informativity of Enzymes in the Forecast of Development of Cardiovascular Complications

“…It is established that various intracellular metabolites affect epigenetic processes, being substrates or coenzymes of epigenetically modifying enzymes [ 34 , 35 , 36 ]. NAD + , glutamine, α-ketoglutarate, acetyl- coenzyme A and glutathione are identified as the most important metabolites that affect the activity of enzymes that change the structure of chromatin and, consequently, gene expression and cell activity [ 36 , 37 , 38 , 39 ].…”

Epigenetics in Lewy Body Diseases: Impact on Gene Expression, Utility as a Biomarker, and Possibilities for Therapy

“…Another alteration confounding the relationship between the disease and epigenetics is blood cell composition, which differs significantly between PD cases. Correspondingly, many of the genome wide significant CpGs correlate with changes in cell composition [ 122 , 133 , 142 , 143 ]. Cell composition in specific brain areas can differ between patients and controls due to degeneration and cell loss characteristic in neurodegenerative diseases [ 130 ].…”

“…As discussed above, DNA methylation in LBD has been primarily investigated within selected candidate genes [ 85 , 86 , 113 , 116 , 117 , 146 , 147 , 148 ]. However, global DNA methylation abnormalities in PD and DLB brains have been identified in several epigenome-wide studies (see Figure 2 ) [ 122 , 130 , 131 , 142 , 149 , 150 , 151 , 152 , 153 , 154 , 155 ].…”

“…However, this finding has not been replicated. The genome-wide DNA methylation profiling studies that revealed the hypermethylation of the solute carrier family 7-member 11 (SLC7A11) promoter in blood correlated with diminished SLC7A11 expression in a large PD cohort [ 142 ]. Only when gene/pathway functional enrichment analysis is performed, are the results revealed that the observed methylation changes may contribute to alterations in neurogenesis, neurodevelopment, neurodegeneration, immunity, and stress oxidation [ 122 , 131 , 147 ].…”

Review: In vitro Cell Platform for Understanding Developmental Toxicity

“…Furthermore, CpH hypomethylation is accelerated in AD brains compared to normal aging ones ( Li et al, 2019 ). Abnormal DNA methylation of ASCC1 and SLC7A11 has also been linked to PD ( Vallerga et al, 2020 ). Similar methylation features were also revealed in iPSC models reprogrammed from patients iPSCs ( Fetahu et al, 2019 ).…”