Cornish Kim M, Kraan Claudine M, Bui Quang Minh, Bellgrove Mark A, Metcalfe Sylvia A, Trollor Julian N, Hocking Darren R, Slater Howard R, Inaba Yoshimi, Li Xin, Archibald Alison D, Turbitt Erin, Cohen Jonathan, Godler David E
From the School of Psychological Sciences, Faculty of Medicine, Nursing and Health Sciences (K.M.C., C.M.K., M.A.B.), and the Centre for Developmental Disability Health Victoria (J.C.), Monash University, Clayton; the Centre for Epidemiology and Biostatistics (Q.M.B.), Melbourne School of Population and Global Health, University of Melbourne; Genetics Education and Health Research (S.A.M., A.D.A., E.T.), the Cytomolecular Diagnostic Research Laboratory (H.R.S., Y.I., X.L., D.E.G.) and Victorian Clinical Genetics Services (A.D.A.), Murdoch Childrens Research Institute, Royal Children's Hospital, Parkville, Melbourne; the Department of Paediatrics, Faculty of Medicine, Dentistry and Health Sciences (S.A.M., A.D.A., E.T.), The University of Melbourne, Parkville; the Department of Developmental Disability Neuropsychiatry and Centre for Healthy Brain Ageing (J.N.T.), UNSW Australia, Sydney; Olga Tennison Autism Research Centre (D.R.H.), School of Psychological Science, La Trobe, Bundoora; and Fragile X Alliance Inc. (Clinic) (J.C.), North Caufield, Australia.
Neurology. 2015 Apr 21;84(16):1631-8. doi: 10.1212/WNL.0000000000001496. Epub 2015 Mar 25.
To examine the epigenetic basis of psychiatric symptoms and dysexecutive impairments in FMR1 premutation (PM: 55 to 199 CGG repeats) women.
A total of 35 FMR1 PM women aged between 22 and 55 years and 35 age- and IQ-matched women controls (CGG <45) participated in this study. All participants completed a range of executive function tests and self-reported symptoms of psychiatric disorders. The molecular measures included DNA methylation of the FMR1 CpG island in blood, presented as FMR1 activation ratio (AR), and 9 CpG sites located at the FMR1 exon1/intron 1 boundary, CGG size, and FMR1 mRNA levels.
We show that FMR1 intron 1 methylation levels could be used to dichotomize PM women into greater and lower risk categories (p = 0.006 to 0.037; odds ratio = 14-24.8), with only FMR1 intron 1 methylation, and to a lesser extent AR, being significantly correlated with the likelihood of probable dysexecutive or psychiatric symptoms (p < 0.05). Furthermore, the significant relationships between methylation and social anxiety were found to be mediated by executive function performance, but only in PM women. FMR1 exon 1 methylation, CGG size, and FMR1 mRNA could not predict probable dysexecutive/psychiatric disorders in PM women.
This is the first study supporting presence of specific epigenetic etiology associated with increased risk of developing comorbid dysexecutive and social anxiety symptoms in PM women. These findings could have implications for early intervention and risk estimate recommendations aimed at improving the outcomes for PM women and their families.
研究脆性X智力低下1基因前突变（PM：55至199个CGG重复序列）女性精神症状和执行功能障碍的表观遗传基础。
本研究共纳入35名年龄在22至55岁之间的脆性X智力低下1基因前突变女性以及35名年龄和智商匹配的女性对照（CGG<45）。所有参与者均完成了一系列执行功能测试以及精神疾病的自我报告症状。分子检测指标包括血液中脆性X智力低下1基因启动子区的DNA甲基化，以脆性X智力低下1基因激活率（AR）表示，以及位于脆性X智力低下1基因外显子1/内含子1边界的9个CpG位点、CGG大小和脆性X智力低下1基因mRNA水平。
我们发现，脆性X智力低下1基因内含子1甲基化水平可将前突变女性分为高风险和低风险两类（p=0.006至0.037；优势比=14至24.8），只有脆性X智力低下1基因内含子1甲基化，以及在较小程度上的AR，与可能的执行功能障碍或精神症状可能性显著相关（p<0.05）。此外，甲基化与社交焦虑之间的显著关系被发现是由执行功能表现介导的，但仅在前突变女性中如此。脆性X智力低下1基因外显子1甲基化、CGG大小和脆性X智力低下1基因mRNA无法预测前突变女性可能的执行功能障碍/精神疾病。
这是第一项支持存在特定表观遗传病因与前突变女性发生共病性执行功能障碍和社交焦虑症状风险增加相关的研究。这些发现可能对旨在改善前突变女性及其家庭结局的早期干预和风险评估建议具有启示意义。
