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

被引：102

作者：

Vallerga, Costanza L. ^{[1
]}

Zhang, Futao ^{[1
]}

Fowdar, Javed ^{[2
]}

McRae, Allan F. ^{[1
]}

Qi, Ting ^{[1
]}

Nabais, Marta F. ^{[1
,3
]}

Zhang, Qian ^{[1
]}

Kassam, Irfahan ^{[1
]}

Henders, Anjali K. ^{[1
]}

Wallace, Leanne ^{[1
]}

Montgomery, Grant ^{[1
]}

Chuang, Yu-Hsuan ^{[4
]}

Horvath, Steve ^{[5
,6
]}

Ritz, Beate ^{[4
,7
,8
]}

Halliday, Glenda ^{[9
,10
]}

Hickie, Ian ^{[9
,10
]}

Kwok, John B. ^{[9
,10
,11
]}

Pearson, John ^{[12
]}

Pitcher, Toni ^{[13
,14
]}

Kennedy, Martin ^{[12
]}

Bentley, Steven R. ^{[2
]}

Silburn, Peter A. ^{[15
]}

Yang, Jian ^{[1
]}

Wray, Naomi R. ^{[1
,15
]}

Lewis, Simon J. G. ^{[9
,10
]}

Anderson, Tim ^{[13
,14
]}

Dalrymple-Alford, John ^{[13
,16
]}

Mellick, George D. ^{[2
]}

Visscher, Peter M. ^{[1
,15
]}

Gratten, Jacob ^{[1
,17
]}

机构：

[1] Univ Queensland, Inst Mol Biosci, Brisbane, Qld, Australia

[2] Griffith Univ, Griffith Inst Drug Discovery GRIDD, Brisbane, Qld, Australia

[3] Univ Exeter, Med Sch, Exeter EX2 5DW, Devon, England

[4] Univ Calif Los Angeles, Dept Epidemiol, Fielding Sch Publ Hlth, Los Angeles, CA USA

[5] Univ Calif Los Angeles, David Geffen Sch Med, Dept Human Genet, Los Angeles, CA 90095 USA

[6] Univ Calif Los Angeles, Dept Biostat, Fielding Sch Publ Hlth, Los Angeles, CA USA

[7] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Los Angeles, CA 90095 USA

[8] Univ Calif Los Angeles, Dept Environm Hlth, Fielding Sch Publ Hlth, Los Angeles, CA USA

[9] Univ Sydney, Brain & Mind Ctr, Sydney, NSW, Australia

[10] Univ Sydney, Fac Med & Hlth, Sydney, NSW, Australia

[11] Univ New South Wales, Sch Med Sci, Sydney, NSW, Australia

[12] Univ Otago, Dept Pathol, Christchurch, New Zealand

[13] New Zealand Brain Res Inst, Christchurch, New Zealand

[14] Univ Otago, Dept Med, Christchurch, New Zealand

[15] Univ Queensland, Queensland Brain Inst, Brisbane, Qld, Australia

[16] Univ Canterbury, Dept Psychol, Christchurch, New Zealand

[17] Univ Queensland, Mater Res Inst, Brisbane, Qld, Australia

来源：

NATURE COMMUNICATIONS | 2020年 / 11卷 / 01期

基金：

澳大利亚国家健康与医学研究理事会; 澳大利亚研究理事会; 英国医学研究理事会;

关键词：

EPIDERMOLYSIS-BULLOSA SIMPLEX; AMYOTROPHIC-LATERAL-SCLEROSIS; DIAGNOSTIC-CRITERIA; CYCAD NEUROTOXINS; SYSTEM X(C)(-); UNLIKELY CAUSE; FLYING FOXES; ALS-PDC; ACID; GENE;

D O I：

10.1038/s41467-020-15065-7

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

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.

引用

页数：10

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