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

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

doi:10.1038/s41467-020-15065-7

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

Costanza L. Vallerga, Futao Zhang, Javed Fowdar, Allan F. McRae, Ting Qi, Marta F. Nabais, Qian Zhang, Irfahan Kassam, Anjali 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 KennedySteven R. Bentley, Peter A. Silburn, Jian Yang, Naomi R. Wray, Simon J. G. Lewis, Tim Anderson, John Dalrymple-Alford, George D. Mellick, Peter M. Visscher^*, Jacob Gratten

^*Corresponding author for this work

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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.

Original language	English
Article number	1238
Pages (from-to)	1-10
Number of pages	10
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-15065-7
Publication status	Published - 6 Mar 2020
Externally published	Yes

Bibliographical note

Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

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Vallerga, C. L., Zhang, F., Fowdar, J., McRae, A. F., Qi, T., Nabais, M. F., Zhang, Q., Kassam, I., Henders, A. K., Wallace, L., Montgomery, G., Chuang, Y. H., Horvath, S., Ritz, B., Halliday, G., Hickie, I., Kwok, J. B., Pearson, J., Pitcher, T., ... Gratten, J. (2020). Analysis of DNA methylation associates the cystine–glutamate antiporter SLC7A11 with risk of Parkinson’s disease. Nature Communications, 11(1), 1-10. Article 1238. https://doi.org/10.1038/s41467-020-15065-7

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title = "Analysis of DNA methylation associates the cystine–glutamate antiporter SLC7A11 with risk of Parkinson{\textquoteright}s disease",

abstract = "An improved understanding of etiological mechanisms in Parkinson{\textquoteright}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.",

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

note = "Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.",

year = "2020",

month = mar,

day = "6",

doi = "10.1038/s41467-020-15065-7",

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Vallerga, CL, Zhang, F, Fowdar, J, McRae, AF, Qi, T, Nabais, MF, Zhang, Q, Kassam, I, Henders, AK, Wallace, L, Montgomery, G, Chuang, YH, Horvath, S, Ritz, B, Halliday, G, Hickie, I, Kwok, JB, Pearson, J, Pitcher, T, Kennedy, M, Bentley, SR, Silburn, PA, Yang, J, Wray, NR, Lewis, SJG, Anderson, T, Dalrymple-Alford, J, Mellick, GD, Visscher, PM & Gratten, J 2020, 'Analysis of DNA methylation associates the cystine–glutamate antiporter SLC7A11 with risk of Parkinson’s disease', Nature Communications, vol. 11, no. 1, 1238, pp. 1-10. https://doi.org/10.1038/s41467-020-15065-7

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AU - Vallerga, Costanza L.

AU - Zhang, Futao

AU - Fowdar, Javed

AU - McRae, Allan F.

AU - Qi, Ting

AU - Nabais, Marta F.

AU - Zhang, Qian

AU - Kassam, Irfahan

AU - Henders, Anjali K.

AU - Wallace, Leanne

AU - Montgomery, Grant

AU - Chuang, Yu Hsuan

AU - Horvath, Steve

AU - Ritz, Beate

AU - Halliday, Glenda

AU - Hickie, Ian

AU - Kwok, John B.

AU - Pearson, John

AU - Pitcher, Toni

AU - Kennedy, Martin

AU - Bentley, Steven R.

AU - Silburn, Peter A.

AU - Yang, Jian

AU - Wray, Naomi R.

AU - Lewis, Simon J. G.

AU - Anderson, Tim

AU - Dalrymple-Alford, John

AU - Mellick, George D.

AU - Visscher, Peter M.

AU - Gratten, Jacob

N1 - Copyright the Author(s) 2020. Version archived for private and non-commercial use with the permission of the author/s and according to publisher conditions. For further rights please contact the publisher.

PY - 2020/3/6

Y1 - 2020/3/6

N2 - 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.

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

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