强迫症的表观遗传学研究进展

doi:10.3969/j.issn.1674-8115.2021.02.023

摘要/Abstract

摘要：

强迫症是一种致残率较高的精神疾病，其病因尚未明确。研究表明，强迫症的发生发展是基因与环境共同作用的结果。表观遗传学为解释环境因素对个体遗传的作用提供了途径及机制。目前已有报道，强迫症患者与健康人群之间存在DNA甲基化差异，而DNA甲基化水平可能与治疗效果存在密切关联。此外，研究发现强迫症患者微RNA表达丰度较健康对照上升。该文通过综述文献中关于强迫症表观遗传学的研究，总结强迫症可能的表观遗传修饰变化，有助于进一步理解强迫症发生发展的病理生理机制。

关键词: 强迫症, 表观遗传学, 遗传学, DNA甲基化, 微RNA

Abstract:

Obsessive-compulsive disorder is a high disabling psychiatric disease, with unknown etiology. Many studies have shown that the pathogenesis of obsessive-compulsive disorder is associated with both genes and the environment. Epigenetics has provided an approach to explaining the influence on individual inheritance caused by environmental factors. Nowadays, several types of research have proved that there are differences in DNA methylation between obsessive-compulsive disorder patients and healthy population, and the DNA methylation may be strongly related to treatment response. Additionally, an increased level of microRNA was found in patients with obsessive-compulsive disorder. This review summaries the studies of epigenetics of obsessive-compulsive disorder and concludes the possible changes in epigenetic modifications to further understand the pathophysiology of obsessive-compulsive disorder.

Key words: obsessive-compulsive disorder, epigenetics, genetics, DNA methylation, microRNA

中图分类号:

R749.7

林梁俊, 王卫娣, 王佩, 林关宁, 王振. 强迫症的表观遗传学研究进展[J]. 上海交通大学学报(医学版), 2021, 41(2): 267-272.

Liang-jun LIN, Wei-di WANG, Pei WANG, Guan-ning LIN, Zhen WANG. Research progress in epigenetics of obsessive-compulsive disorder[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(2): 267-272.

图/表 1

参考文献 60

1	Huang YQ, Wang Y, Wang H, et al. Prevalence of mental disorders in China: a cross-sectional epidemiological study[J]. Lancet Psychiatry, 2019, 6(3): 211-224.
2	Pauls DL, Abramovitch A, Rauch SL, et al. Obsessive-compulsive disorder: an integrative genetic and neurobiological perspective[J]. Nat Rev Neurosci, 2014, 15(6): 410-424.
3	Gelernter J. Genetics of complex traits in psychiatry[J]. Biol Psychiatry, 2015, 77(1): 36-42.
4	Ludwig B, Dwivedi Y. Dissecting bipolar disorder complexity through epigenomic approach[J]. Mol Psychiatry, 2016, 21(11): 1490-1498.
5	Nestler EJ, Peña CJ, Kundakovic M, et al. Epigenetic basis of mental illness[J]. Neurosci, 2016, 22(5): 447-463.
6	International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and OCD Collaborative Genetics Association Studies (OCGAS). Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis[J]. Mol Psychiatry, 2018, 23(5): 1181-1188.
7	den Braber A, Zilhão NR, Fedko IO, et al. Obsessive-compulsive symptoms in a large population-based twin-family sample are predicted by clinically based polygenic scores and by genome-wide SNPs[J]. Transl Psychiatry, 2016, 6(2): e731.
8	Stewart SE, Yu D, Scharf JM, et al. Genome-wide association study of obsessive-compulsive disorder[J]. Mol Psychiatry, 2013, 18(7): 788-798.
9	Mattheisen M, Samuels JF, Wang Y, et al. Genome-wide association study in obsessive-compulsive disorder: results from the OCGAS[J]. Mol Psychiatry, 2015, 20(3): 337-344.
10	Gazzellone MJ, Zarrei M, Burton CL, et al. Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation[J]. J Neurodev Disord, 2016, 8: 36.
11	Cappi C, Oliphant ME, Péter Z, et al. De novo damaging DNA coding mutations are associated with obsessive-compulsive disorder and overlap with Tourette's disorder and autism[J]. Biol Psychiatry, 2020, 87(12): 1035-1044.
12	Hanna GL, Veenstra-VanderWeele J, Cox NJ, et al. Genome-wide linkage analysis of families with obsessive-compulsive disorder ascertained through pediatric probands[J]. Am J Med Genet, 2002, 114(5): 541-552.
13	Willour VL, Yao Shugart Y, Samuels J, et al. Replication study supports evidence for linkage to 9p24 in obsessive-compulsive disorder[J]. Am J Hum Genet, 2004, 75(3): 508-513.
14	Carpenter L, Chung MC. Childhood trauma in obsessive compulsive disorder: the roles of alexithymia and attachment[J]. Psychol Psychother, 2011, 84(4): 367-388.
15	Brander G, Pérez-Vigil A, Larsson H, et al. Systematic review of environmental risk factors for obsessive-compulsive disorder: a proposed roadmap from association to causation[J]. Neurosci Biobehav Rev, 2016, 65: 36-62.
16	McGregor NW, Hemmings SMJ, Erdman L, et al. Modification of the association between early adversity and obsessive-compulsive disorder by polymorphisms in the MAOA, MAOB and COMT genes[J]. Psychiatry Res, 2016, 246: 527-532.
17	Cavalli G, Heard E. Advances in epigenetics link genetics to the environment and disease[J]. Nature, 2019, 571(7766): 489-499.
18	Greenberg MVC, Bourc' his D. The diverse roles of DNA methylation in mammalian development and disease[J]. Nat Rev Mol Cell Biol, 2019, 20(10): 590-607.
19	Lawrence M, Daujat S, Schneider R. Lateral thinking: how histone modifications regulate gene expression[J]. Trends Genet, 2016, 32(1): 42-56.
20	Alural B, Genc S, Haggarty SJ. Diagnostic and therapeutic potential of microRNAs in neuropsychiatric disorders: past, present, and future[J]. Prog Neuropsychopharmacol Biol Psychiatry, 2017, 73: 87-103.
21	Catalanotto C, Cogoni C, Zardo G. MicroRNA in control of gene expression: an overview of nuclear functions[J]. Int J Mol Sci, 2016, 17(10): 1712.
22	D'Addario C, Bellia F, Benatti B, et al. Exploring the role of BDNF DNA methylation and hydroxymethylation in patients with obsessive compulsive disorder[J]. J Psychiatr Res, 2019, 114: 17-23.
23	Ferrer Albertí A, Barrachina M, Labad J, et al. The role of DNA methylation of BDNF gene on clinical severity and cognitive performance in obsessive-compulsive disorder[J]. Eur Neuropsychopharmacol, 2019, 29: S508-S509.
24	Nissen JB, Hansen CS, Starnawska A, et al. DNA methylation at the neonatal state and at the time of diagnosis: preliminary support for an association with the estrogen receptor 1, γ-aminobutyric acid B receptor 1, and myelin oligodendrocyte glycoprotein in female adolescent patients with OCD[J]. Front Psychiatry, 2016, 7: 35.
25	Grünblatt E, Marinova Z, Roth A, et al. Combining genetic and epigenetic parameters of the serotonin transporter gene in obsessive-compulsive disorder[J]. J Psychiatr Res, 2018, 96: 209-217.
26	Schiele MA, Thiel C, Weidner M, et al. Serotonin transporter gene promoter hypomethylation in obsessive-compulsive disorder: predictor of impaired response to exposure treatment?[J]. J Psychiatr Res, 2020, 132: 18-22.
27	Cappi C, Diniz JB, Requena GL, et al. Epigenetic evidence for involvement of the oxytocin receptor gene in obsessive-compulsive disorder[J]. BMC Neurosci, 2016, 17(1): 79.
28	Schiele MA, Thiel C, Kollert L, et al. Oxytocin receptor gene DNA methylation: a biomarker of treatment response in obsessive-compulsive disorder?[J]. Psychother Psychosom, 2021, 90(1): 57-63.
29	Bellia F, Benatti B, Grancini B, et al. Transcriptional regulation of BDNF and oxytocin receptor genes in obsessive compulsive disorder[J]. Eur Neuropsychopharmacol, 2019, 29: S511-S512.
30	Park CI, Kim HW, Jeon S, et al. Reduced DNA methylation of the oxytocin receptor gene is associated with obsessive-compulsive disorder[J]. Clin Epigenetics, 2020, 12(1): 101.
31	Schiele MA, Thiel C, Deckert J, et al. Monoamine oxidase A hypomethylation in obsessive-compulsive disorder: reversibility by successful psychotherapy?[J]. Int J Neuropsychopharmacol, 2020, 23(5): 319-323.
32	Yue WH, Cheng WQ, Liu ZR, et al. Genome-wide DNA methylation analysis in obsessive-compulsive disorder patients[J]. Sci Rep, 2016, 6: 31333.
33	Muiños-Gimeno M, Guidi M, Kagerbauer B, et al. Allele variants in functional microRNA target sites of the neurotrophin-3 receptor gene (NTRK3) as susceptibility factors for anxiety disorders[J]. Hum Mutat, 2009, 30(7): 1062-1071.
34	Kandemir H, Erdal ME, Selek S, et al. Microribonucleic acid dysregulations in children and adolescents with obsessive-compulsive disorder[J]. Neuropsychiatr Dis Treat, 2015, 11: 1695-1701.
35	Yue JH, Zhang BL, Wang H, et al. Dysregulated plasma levels of miRNA-132 and miRNA-134 in patients with obsessive-compulsive disorder[J]. Ann Transl Med, 2020, 8(16): 996.
36	Rodrigues-Amorim D, Rivera-Baltanás T, Bessa J, et al. The neurobiological hypothesis of neurotrophins in the pathophysiology of schizophrenia: a meta-analysis[J]. J Psychiatr Res, 2018, 106: 43-53.
37	Fernandes BS, Molendijk ML, Köhler CA, et al. Peripheral brain-derived neurotrophic factor (BDNF) as a biomarker in bipolar disorder: a meta-analysis of 52 studies[J]. BMC Med, 2015, 13: 289.
38	Koo JW, Chaudhury D, Han MH, et al. Role of mesolimbic brain-derived neurotrophic factor in depression[J]. Biol Psychiatry, 2019, 86(10): 738-748.
39	Şimşek Ş, Gençoğlan S, Yüksel T, et al. Cortisol and brain-derived neurotrophic factor levels prior to treatment in children with obsessive-compulsive disorder[J]. J Clin Psychiatry, 2016, 77(7): e855-e859.
40	Wang Y, Zhang H, Li Y, et al. BDNF Val66Met polymorphism and plasma levels in Chinese Han population with obsessive-compulsive disorder and generalized anxiety disorder[J]. J Affect Disord, 2015, 186: 7-12.
41	Shimizu E, Hashimoto K, Okamura N, et al. Alterations of serum levels of brain-derived neurotrophic factor (BDNF) in depressed patients with or without antidepressants[J]. Biol Psychiatry, 2003, 54(1): 70-75.
42	Robbins TW, Vaghi MM, Banca P. Obsessive-compulsive disorder: puzzles and prospects[J]. Neuron, 2019, 102(1): 27-47.
43	Sinopoli VM, Erdman L, Burton CL, et al. Serotonin system genes and obsessive-compulsive trait dimensions in a population-based, pediatric sample: a genetic association study[J]. J Child Psychol Psychiatry, 2019, 60(12): 1289-1299.
44	Sinopoli VM, Burton CL, Kronenberg S, et al. A review of the role of serotonin system genes in obsessive-compulsive disorder[J]. Neurosci Biobehav Rev, 2017, 80: 372-381.
45	Taylor S. Disorder-specific genetic factors in obsessive-compulsive disorder: a comprehensive meta-analysis[J]. Am J Med Genet B, 2016, 171B(3): 325-332.
46	Richter MA, de Jesus DR, Hoppenbrouwers S, et al. Evidence for cortical inhibitory and excitatory dysfunction in obsessive compulsive disorder[J]. Neuropsychopharmacology, 2012, 37(5): 1144-1151.
47	Zai G, Arnold P, Burroughs E, et al. Evidence for the γ-amino-butyric acid type B receptor 1 (GABBR1) gene as a susceptibility factor in obsessive-compulsive disorder[J]. Am J Med Genet B, 2005, 134B(1): 25-29.
48	Zai G, Bezchlibnyk YB, Richter MA, et al. Myelin oligodendrocyte glycoprotein (MOG) gene is associated with obsessive-compulsive disorder[J]. Am J Med Genet B, 2004, 129B(1): 64-68.
49	Karpinski M, Mattina GF, Steiner M. Effect of gonadal hormones on neurotransmitters implicated in the pathophysiology of obsessive-compulsive disorder: a critical review[J]. Neuroendocrinology, 2017, 105(1): 1-16.
50	Alonso P, Gratacòs M, Segalàs C, et al. Variants in estrogen receptor α gene are associated with phenotypical expression of obsessive-compulsive disorder[J]. Psychoneuroendocrinology, 2011, 36(4): 473-483.
51	Jurek B, Neumann ID. The oxytocin receptor: from intracellular signaling to behavior[J]. Physiol Rev, 2018, 98(3): 1805-1908.
52	Kang JI, Kim HW, Kim CH, et al. Oxytocin receptor gene polymorphisms exert a modulating effect on the onset age in patients with obsessive-compulsive disorder[J]. Psychoneuroendocrinology, 2017, 86: 45-52.
53	Kulikov AV, Gainetdinov RR, Ponimaskin E, et al. Interplay between the key proteins of serotonin system in SSRI antidepressants efficacy[J]. Expert Opin Ther Targets, 2018, 22(4): 319-330.
54	Taylor S. Molecular genetics of obsessive-compulsive disorder: a comprehensive meta-analysis of genetic association studies[J]. Mol Psychiatry, 2013, 18(7): 799-805.
55	段昕妤, 肖蘅, 陈善元. DNA甲基化测序技术及其在哺乳动物中的应用研究进展[J]. 生物学杂志, 2018, 35(5): 79-82, 86.
56	Muiños-Gimeno M, Espinosa-Parrilla Y, Guidi M, et al. Human microRNAs miR-22, miR-138-2, miR-148a, and miR-488 are associated with panic disorder and regulate several anxiety candidate genes and related pathways[J]. Biol Psychiatry, 2011, 69(6): 526-533.
57	Rodriguez A, Vigorito E, Clare S, et al. Requirement of bic/microRNA-155 for normal immune function[J]. Science, 2007, 316(5824): 608-611.
58	Gerentes M, Pelissolo A, Rajagopal K, et al. Obsessive-compulsive disorder: autoimmunity and neuroinflammation[J]. Curr Psychiatry Rep, 2019, 21(8): 78.
59	Klein ME, Lioy DT, Ma L, et al. Homeostatic regulation of MeCP2 expression by a CREB-induced microRNA[J]. Nat Neurosci, 2007, 10(12): 1513-1514.
60	Gao J, Wang WY, Mao YW, et al. A novel pathway regulates memory and plasticity via SIRT1 and miR-134[J]. Nature, 2010, 466(7310): 1105-1109.

Finding	Sample type	Gene	Reference
DNA methylation
Promoter hypomethylation and hyperhydroxymethylation in exonⅠ	Blood	BDNF	[22]
Promoter Ⅳ hypermethylation	Blood	BDNF	[23]
Promoter hypomethylation	Blood	BDNF	[24]
Promoter hypermethylation in children and adolescents, promoter hypomethylation in adults	Saliva	SLC6A4	[25]
Prediction of impaired treatment response of CBT by lower baseline promoter methylation	Blood	SLC6A4	[26]
Promoter hypermethylation	Blood	GABBR1/MOG	[24]
Promoter hypomethylation	Blood	MOG	[24]
Promoter hypomethylation	Blood	ESR1	[24]
Promoter hypermethylation in exon Ⅲ	Blood	OXTR	[27]
Promoter hypermethylation in exon Ⅲ, prediction of impaired treatment response of CBT by higher baseline promoter methylation	Blood	OXTR	[28]
Promoter hypermethylation	Blood	OXTR	[29]
Promoter hypomethylation	Blood	OXTR	[30]
Promoter hypomethylation, higher promoter methylation level after CBT	Blood	MAOA	[31]
Alteration of DNA methylation	Blood	BCYRN1, BCOR, FGF13, etc.	[32]
microRNA
Target gene of miR-485-3p associated with obsessive-compulsive disorder	Blood	NTRK3	[33]
Increased level of miR-22-3p	Blood	BDNF, MAOA, etc.	[34]
Increased level of miR-24-3p	Blood	－	[34]
Increased level of miR-106b-5p	Blood	－	[34]
Increased level of miR-125b-5p	Blood	－	[34]
Increased level of miR-155a-5p	Blood	－	[34]
Increased level of miR-132	Blood	BDNF	[35]
Increased level of miR-134	Blood	BDNF	[35]

Finding	Sample type	Gene	Reference
DNA methylation
Promoter hypomethylation and hyperhydroxymethylation in exonⅠ	Blood	BDNF	[22]
Promoter Ⅳ hypermethylation	Blood	BDNF	[23]
Promoter hypomethylation	Blood	BDNF	[24]
Promoter hypermethylation in children and adolescents, promoter hypomethylation in adults	Saliva	SLC6A4	[25]
Prediction of impaired treatment response of CBT by lower baseline promoter methylation	Blood	SLC6A4	[26]
Promoter hypermethylation	Blood	GABBR1/MOG	[24]
Promoter hypomethylation	Blood	MOG	[24]
Promoter hypomethylation	Blood	ESR1	[24]
Promoter hypermethylation in exon Ⅲ	Blood	OXTR	[27]
Promoter hypermethylation in exon Ⅲ, prediction of impaired treatment response of CBT by higher baseline promoter methylation	Blood	OXTR	[28]
Promoter hypermethylation	Blood	OXTR	[29]
Promoter hypomethylation	Blood	OXTR	[30]
Promoter hypomethylation, higher promoter methylation level after CBT	Blood	MAOA	[31]
Alteration of DNA methylation	Blood	BCYRN1, BCOR, FGF13, etc.	[32]
microRNA
Target gene of miR-485-3p associated with obsessive-compulsive disorder	Blood	NTRK3	[33]
Increased level of miR-22-3p	Blood	BDNF, MAOA, etc.	[34]
Increased level of miR-24-3p	Blood	－	[34]
Increased level of miR-106b-5p	Blood	－	[34]
Increased level of miR-125b-5p	Blood	－	[34]
Increased level of miR-155a-5p	Blood	－	[34]
Increased level of miR-132	Blood	BDNF	[35]
Increased level of miR-134	Blood	BDNF	[35]

[1]	李璞玉, 程佳月, 顾秋梦, 阮瀚阳, 王勇, 刘强, 吴艳茹, 王振. 强迫症患者的强迫信念和冲动特质对症状维度的影响[J]. 上海交通大学学报(医学版), 2021, 41(6): 756-760.
[2]	万淑君, 孔祥, 吕坤. 非编码RNA与糖尿病血管病变的关系[J]. 上海交通大学学报(医学版), 2021, 41(5): 665-670.
[3]	姜梦迪, 张文. 糖尿病肾病中的组蛋白修饰与靶向干预的研究进展[J]. 上海交通大学学报(医学版), 2021, 41(1): 103-107.
[4]	邬静莹1，刘晓黎2，曹立1. 原发性肌张力障碍的遗传学进展和诊断策略[J]. 上海交通大学学报（医学版）, 2020, 40(3): 373-.
[5]	项思莹，李宁宁，徐一峰#，陈剑华#. 抗精神病药物诱发代谢综合征的DNA甲基化研究进展[J]. 上海交通大学学报(医学版), 2020, 40(12): 1656-1659.
[6]	戴芹1，王伟铭2. 组蛋白乙酰化在IgA肾病发病中的作用[J]. 上海交通大学学报(医学版), 2020, 40(08): 1063-1068.
[7]	程佳月，李璞玉，顾秋梦，王佩，陈珏，刘强#，王振#. 强迫症患者的强迫症状在归因方式与抑郁症状间的中介作用[J]. 上海交通大学学报(医学版), 2020, 40(06): 785-790.
[8]	吕娜，叶惠玲，范青#，肖泽萍#. 伴囤积症状强迫症患者的临床特征研究[J]. 上海交通大学学报(医学版), 2020, 40(06): 791-797.
[9]	陆海洋，赵维莅. 胃肠道微生物在肿瘤发生中的作用[J]. 上海交通大学学报（医学版）, 2019, 39(9): 1083-.
[10]	程佳月，王振. 经颅直流电刺激治疗强迫症的研究进展[J]. 上海交通大学学报（医学版）, 2019, 39(9): 1089-.
[11]	余玲芳，张晨. 抑郁症的遗传学研究进展[J]. 上海交通大学学报（医学版）, 2019, 39(8): 914-.
[12]	任延燕，王振. 强迫症增效治疗机制的研究进展[J]. 上海交通大学学报（医学版）, 2019, 39(8): 919-.
[13]	施炜慧 1, 2，刘雪丽 1, 2，叶木槿 1, 2，陈松长 1, 2，黄荷凤 2, 3，徐晨明 1, 2. 常染色体显性多囊肾病致男性生殖障碍的机制及辅助生殖治疗结局分析[J]. 上海交通大学学报（医学版）, 2019, 39(7): 744-.
[14]	周雨鑫 1，高睿 1，王振 2，王纯 3，范青 4. 网络认知行为疗法治疗强迫症的效果与卫生经济学分析[J]. 上海交通大学学报（医学版）, 2019, 39(6): 622-.
[15]	欧阳也 1，秦玉婷 1，姚超 2，沈南 1, 2. 利用 ATAC -seq技术研究Ⅰ型干扰素通路活化后人单核细胞的染色质开放性改变[J]. 上海交通大学学报（医学版）, 2019, 39(5): 451-.