Abstract
This study was undertaken to analyze DNA methylation profiling at the monoamine oxidase A (MAOA) locus, in order to determine whether abnormal DNA methylation is involved in the development of schizophrenia. We recruited a total of 371 patients with paranoid schizophrenia (199 males and 172 females) and 288 unrelated control subjects (123 males and 165 females) for analysis of DNA methylation. Diagnosis was made based on the Structured Clinical Interview for DSM-VI. Genomic DNA extracted from peripheral blood was chemically modified using bisulfite, and DNA methylation profiles of the MAOA promoter were determined by BSP-sequencing. DNA methylation ratios of individual CpG residues and overall methylation ratios were measured on each subject. The results showed that there was no significant difference in overall DNA methylation ratios between patients and controls either in the female group (P = 0.42) or in the male group (P = 0.24). Of 15 CpG residues that showed significant differences in DNA methylation status between the patient group and the control group in females, eight of which had an increased level and seven, a decreased level, with a combined P value of 1 (df = 160). In male subjects, however, six individual CpG residues showed an increased methylation level with a combined P value of 5.80E−35 (df = 158). In conclusion, abnormalities of DNA methylation at the MAOA promoter may be associated with schizophrenia in males.
Similar content being viewed by others
Abbreviations
- MAOA:
-
Monoamine oxidase A
- MDD:
-
Major depressive disorder
- ADHD:
-
Attention deficit hyperactivity disorder
- SNP:
-
Single nucleotide polymorphism
- QUMA:
-
Quantification tool for methylation analysis
References
Abdolmaleky HM, Cheng KH, Faraone SV, Wilcox M, Glatt SJ, Gao F, Smith CL, Shafa R, Aeali B, Carnevale J et al (2006) Hypomethylation of MB-COMT promoter is a major risk factor for schizophrenia and bipolar disorder. Hum Mol Genet 15:3132–3145
Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23:185–188
APA (2000) Diagnostic and statistical manual of mental disorders, 4th edn. American Psychiatric Press, Washington DC
Bach AW, Lan NC, Johnson DL, Abell CW, Bembenek ME, Kwan SW, Seeburg PH, Shih JC (1988) cDNA cloning of human liver monoamine oxidase A and B: molecular basis of differences in enzymatic properties. Proc Natl Acad Sci USA 85:4934–4938
Brunner HG, Nelen M, Breakefield XO, Ropers HH, van Oost BA (1993a) Abnormal behavior associated with a point mutation in the structural gene for monoamine oxidase A. Science 262:578–580
Brunner HG, Nelen MR, van Zandvoort P, Abeling NG, van Gennip AH, Wolters EC, Kuiper MA, Ropers HH, van Oost BA (1993b) X-linked borderline mental retardation with prominent behavioral disturbance: phenotype, genetic localization, and evidence for disturbed monoamine metabolism. Am J Hum Genet 52:1032–1039
Carrel L, Willard HF (2005) X-inactivation profile reveals extensive variability in X-linked gene expression in females. Nature 434:400–404
Cases O, Seif I, Grimsby J, Gaspar P, Chen K, Pournin S, Muller U, Aguet M, Babinet C, Shih JC et al (1995) Aggressive behavior and altered amounts of brain serotonin and norepinephrine in mice lacking MAOA. Science 268:1763–1766
Das S, Kubota T, Song M, Daniel R, Berry-Kravis EM, Prior TW, Popovich B, Rosser L, Arinami T, Ledbetter DH (1997) Methylation analysis of the fragile X syndrome by PCR. Genet Test 1:151–155
Frommer M, McDonald LE, Millar DS, Collis CM, Watt F, Grigg GW, Molloy PL, Paul CL (1992) A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci USA 89:1827–1831
Fuke C, Shimabukuro M, Petronis A, Sugimoto J, Oda T, Miura K, Miyazaki T, Ogura C, Okazaki Y, Jinno Y (2004) Age related changes in 5-methylcytosine content in human peripheral leukocytes and placentas: an HPLC-based study. Ann Hum Genet 68:196–204
Grewal SI, Moazed D (2003) Heterochromatin and epigenetic control of gene expression. Science 301:798–802
Henikoff S, Matzke MA (1997) Exploring and explaining epigenetic effects. Trends Genet 13:293–295
Iwamoto K, Bundo M, Yamada K, Takao H, Iwayama-Shigeno Y, Yoshikawa T, Kato T (2005) DNA methylation status of SOX10 correlates with its downregulation and oligodendrocyte dysfunction in schizophrenia. J Neurosci 25:5376–5381
Jiang S, Xin R, Lin S, Qian Y, Tang G, Wang D, Wu X (2001) Linkage studies between attention-deficit hyperactivity disorder and the monoamine oxidase genes. Am J Med Genet 105:783–788
Kim JJ, Shih JC, Chen K, Chen L, Bao S, Maren S, Anagnostaras SG, Fanselow MS, De Maeyer E, Seif I et al (1997) Selective enhancement of emotional, but not motor, learning in monoamine oxidase A-deficient mice. Proc Natl Acad Sci USA 94:5929–5933
Kumaki Y, Oda M, Okano M (2008) QUMA: quantification tool for methylation analysis. Nucleic Acids Res 36:W170–W175
Kuratomi G, Iwamoto K, Bundo M, Kusumi I, Kato N, Iwata N, Ozaki N, Kato T (2008) Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins. Mol Psychiatry 13:429–441
Levenson JM, Roth TL, Lubin FD, Miller CA, Huang IC, Desai P, Malone LM, Sweatt JD (2006) Evidence that DNA (cytosine-5) methyltransferase regulates synaptic plasticity in the hippocampus. J Biol Chem 281:15763–15773
Lubin FD, Roth TL, Sweatt JD (2008) Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. J Neurosci 28:10576–10586
Marsden CA (2006) Dopamine: the rewarding years. Br J Pharmacol 147(Suppl 1):S136–S144
Meltzer HY (1989) Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia. Psychopharmacology (Berl) 99 Suppl S18–27
Meltzer HY, Roth B (2000) Psychopharmacology - 4th generation of progress. American College of Neuropsychopharmacology, Brentwood
Mill J, Tang T, Kaminsky Z, Khare T, Yazdanpanah S, Bouchard L, Jia P, Assadzadeh A, Flanagan J, Schumacher A et al (2008) Epigenomic profiling reveals DNA-methylation changes associated with major psychosis. Am J Hum Genet 82:696–711
Nestler EJ (2009) Epigenetic mechanisms in psychiatry. Biol Psychiatry 65:189–190
Ou XM, Chen K, Shih JC (2006) Monoamine oxidase A and repressor R1 are involved in apoptotic signaling pathway. Proc Natl Acad Sci USA 103:10923–10928
Philibert RA, Gunter TD, Beach SR, Brody GH, Madan A (2008) MAOA methylation is associated with nicotine and alcohol dependence in women. Am J Med Genet B Neuropsychiatr Genet 147B:565–570
Philibert RA, Beach SR, Gunter TD, Brody GH, Madan A, Gerrard M (2010) The effect of smoking on MAOA promoter methylation in DNA prepared from lymphoblasts and whole blood. Am J Med Genet B Neuropsychiatr Genet 153B:619–628
Qiu HT, Meng HQ, Song C, Xiu MH, Chen da C, Zhu FY, Wu GY, Kosten TA, Kosten TR, Zhang XY (2009) Association between monoamine oxidase (MAO)-A gene variants and schizophrenia in a Chinese population. Brain Res 1287:67-73
Rivera M, Gutierrez B, Molina E, Torres-Gonzalez F, Bellon JA, Moreno-Kustner B, King M, Nazareth I, Martinez-Gonzalez LJ, Martinez-Espin E et al (2009) High-activity variants of the uMAOA polymorphism increase the risk for depression in a large primary care sample. Am J Med Genet B Neuropsychiatr Genet 150B:395–402
Rosa A, Picchioni MM, Kalidindi S, Loat CS, Knight J, Toulopoulou T, Vonk R, van der Schot AC, Nolen W, Kahn RS et al (2008) Differential methylation of the X-chromosome is a possible source of discordance for bipolar disorder female monozygotic twins. Am J Med Genet B Neuropsychiatr Genet 147B:459–462
Schulze TG, Muller DJ, Krauss H, Scherk H, Ohlraun S, Syagailo YV, Windemuth C, Neidt H, Grassle M, Papassotiropoulos A et al (2000) Association between a functional polymorphism in the monoamine oxidase A gene promoter and major depressive disorder. Am J Med Genet 96:801–803
Shifman S, Johannesson M, Bronstein M, Chen SX, Collier DA, Craddock NJ, Kendler KS, Li T, O’Donovan M, O’Neill FA et al (2008) Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet 4:e28
Shih JC, Chen K, Ridd MJ (1999) Monoamine oxidase: from genes to behavior. Annu Rev Neurosci 22:197–217
Shimabukuro M, Sasaki T, Imamura A, Tsujita T, Fuke C, Umekage T, Tochigi M, Hiramatsu K, Miyazaki T, Oda T et al (2007) Global hypomethylation of peripheral leukocyte DNA in male patients with schizophrenia: a potential link between epigenetics and schizophrenia. J Psychiatr Res 41:1042–1046
Whitlock MC (2005) Combining probability from independent tests: the weighted Z-method is superior to Fisher’s approach. J Evol Biol 18:1368–1373
Williams HJ, Owen MJ, O’Donovan MC (2009) New findings from genetic association studies of schizophrenia. J Hum Genet 54:9–14
Xu Q, Jia YB, Zhang BY, Zou K, Tao YB, Wang YP, Qiang BQ, Wu GY, Shen Y, Ji HK et al (2004) Association study of an SNP combination pattern in the dopaminergic pathway in paranoid schizophrenia: a novel strategy for complex disorders. Mol Psychiatry 9:510–521
Zhu QS, Grimsby J, Chen K, Shih JC (1992) Promoter organization and activity of human monoamine oxidase (MAO) A and B genes. J Neurosci 12:4437–4446
Zhu QS, Chen K, Shih JC (1994) Bidirectional promoter of human monoamine oxidase A (MAO A) controlled by transcription factor Sp1. J Neurosci 14:7393–7403
Acknowledgments
This work was supported by the research grants from the National Basic Research Program of China (2010CB529603, 2012CB517902), the National Natural Science Foundation of China (30971001, 31021091), the Beijing Natural Science Foundation (7102109) and the Fok Ying Tong Education Foundation (121024).
Conflict of interest
None declared.
Author information
Authors and Affiliations
Corresponding author
Additional information
The authors Y. Chen and J. Zhang contributed equally to this work.
Electronic supplementary material
Below is the link to the electronic supplementary material.
439_2011_1131_MOESM2_ESM.bmp
Supplementary Figure 1. Detailed positions of two CpG islands and BS-PCR primers in the MAOA genepromoter and exon 1.The primer-annealing sites are depicted by red squares and solid green lines indicate the amplified regions.The exon 1 region is indicated in purple. The VNTR region is represented by light orange (BMP 913 kb)
Rights and permissions
About this article
Cite this article
Chen, Y., Zhang, J., Zhang, L. et al. Effects of MAOA promoter methylation on susceptibility to paranoid schizophrenia. Hum Genet 131, 1081–1087 (2012). https://doi.org/10.1007/s00439-011-1131-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-011-1131-5