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Associations between serotonin transporter gene (SLC6A4) methylation and clinical characteristics and cortical thickness in children with ADHD

Published online by Cambridge University Press:  28 May 2015

S. Park ,
J.-M. Lee ,
J.-W. Kim ,
D.-Y. Cho ,
H. J. Yun ,
D. H. Han ,
J. H. Cheong  and
B.-N. Kim
S. Park
Affiliation:
Department of Psychiatry, Seoul National Hospital, Seoul, Republic of Korea
J.-M. Lee
Affiliation:
Department of Biomedical Engineering, Hanyang University, Seoul, Republic of Korea
J.-W. Kim
Affiliation:
Division of Child and Adolescent Psychiatry, Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea
D.-Y. Cho
Affiliation:
Lab Genomics Clinical Research Institute, Seoul, Republic of Korea
H. J. Yun
Affiliation:
Department of Biomedical Engineering, Hanyang University, Seoul, Republic of Korea
D. H. Han
Affiliation:
Department of Psychiatry, College of Medicine, Chung Ang University, Seoul, Republic of Korea
J. H. Cheong
Affiliation:
Uimyung Research Institute for Neuroscience, Sahmyook University, Seoul, Republic of Korea
B.-N. Kim*
Affiliation:
Division of Child and Adolescent Psychiatry, Department of Psychiatry, Seoul National University College of Medicine, Seoul, Republic of Korea
*
*Address for correspondence: Dr B.-N. Kim, Division of Child and Adolescent Psychiatry, Department of Psychiatry, Seoul National University, College of Medicine, College of Medicine, 101 Daehakro, Chongro-Gu, Seoul, South Korea. (Email: [email protected])
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Abstract

Background.

Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable psychiatric disorder. Additionally, environmental factors such as perinatal stress and early adversities contribute to the occurrence and severity of ADHD. Recently, DNA methylation has emerged as a mechanism that potentially mediates gene–environmental interaction effects in the aetiology and phenomenology of psychiatric disorders. Here, we investigated whether serotonin transporter gene (SLC6A4) methylation patterns were associated with clinical characteristics and regional cortical thickness in children with ADHD.

Method.

In 102 children with ADHD (age 6–15 years), the methylation status of the SLC6A4 promoter was measured. Brain magnetic resonance imaging was obtained and ADHD symptoms were evaluated.

Results.

A higher methylation status of the SLC6A4 promoter was significantly associated with worse clinical presentations (more hyperactive-impulsive symptoms and more commission errors). Additionally, a negative correlation was observed between SLC6A4 methylation levels and cortical thickness values in the right occipito-temproral regions.

Conclusions.

Our results suggest that the SLC6A4 methylation status may be associated with certain symptoms of ADHD, such as behavioural disinhibition, and related brain changes. Future studies that use a larger sample size and a control group are required to corroborate these results.

Keywords

Attention deficit hyperactivity disorderbrain imaginggene–environment interactionneuropsychology
Type
Original Articles
Information
Psychological Medicine , Volume 45 , Issue 14 , October 2015 , pp. 3009 - 3017
Copyright
Copyright © Cambridge University Press 2015 

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References

Aron, AR, Poldrack, RA (2005). The cognitive neuroscience of response inhibition: relevance for genetic research in attention-deficit/hyperactivity disorder. Biological Psychiatry 57, 1285–1292.Google Scholar
Barkley, RA (1997). Behavioral inhibition, sustained attention, and executive functions: constructing a unifying theory of ADHD. Psychological Bulletin 121, 65–94.Google Scholar
Ben Amor, L, Grizenko, N, Schwartz, G, Lageix, P, Baron, C, Ter-Stepanian, M, Zappitelli, M, Mbekou, V, Joober, R (2005). Perinatal complications in children with attention-deficit hyperactivity disorder and their unaffected siblings. Journal of Psychiatry and Neuroscience 30, 120–126.Google ScholarPubMed
Biederman, J, Faraone, SV (2005). Attention-deficit hyperactivity disorder. Lancet 366, 237–248.CrossRefGoogle ScholarPubMed
Bird, AP (1986). CpG-rich islands and the function of DNA methylation. Nature 321, 209–213.Google Scholar
Bollati, V, Baccarelli, A, Hou, L, Bonzini, M, Fustinoni, S, Cavallo, D, Byun, HM, Jiang, J, Marinelli, B, Pesatori, AC, Bertazzi, PA, Yang, AS (2007). Changes in DNA methylation patterns in subjects exposed to low-dose benzene. Cancer Research 67, 876–880.Google Scholar
Carli, M, Baviera, M, Invernizzi, RW, Balducci, C (2006). Dissociable contribution of 5-HT1A and 5-HT2A receptors in the medial prefrontal cortex to different aspects of executive control such as impulsivity and compulsive perseveration in rats. Neuropsychopharmacology 31, 757–767.CrossRefGoogle ScholarPubMed
Cheng, MC, Liao, DL, Hsiung, CA, Chen, CY, Liao, YC, Chen, CH (2008). Chronic treatment with aripiprazole induces differential gene expression in the rat frontal cortex. International Journal of Neuropsychopharmacology 11, 207–216.Google Scholar
Devlin, AM, Brain, U, Austin, J, Oberlander, TF (2010). Prenatal exposure to maternal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation in infants at birth. PLoS ONE 5, e12201.Google Scholar
Dougherty, DM, Marsh, DM, Mathias, CW, Dawes, MA, Bradley, DM, Morgan, CJ, Badawy, AA (2007). The effects of alcohol on laboratory-measured impulsivity after L-tryptophan depletion or loading. Psychopharmacology (Berlin) 193, 137–150.Google Scholar
Elia, J, Laracy, S, Allen, J, Nissley-Tsiopinis, J, Borgmann-Winter, K (2012). Epigenetics: genetics versus life experiences. Current Topics in Behavioral Neurosciences 9, 317–340.Google Scholar
Evenden, JL (1999). Varieties of impulsivity. Psychopharmacology (Berlin) 146, 348–361.CrossRefGoogle ScholarPubMed
Fahim, C, He, Y, Yoon, U, Chen, J, Evans, A, Perusse, D (2011). Neuroanatomy of childhood disruptive behavior disorders. Aggressive Behavior 37, 326–337.Google Scholar
Faraone, SV, Perlis, RH, Doyle, AE, Smoller, JW, Goralnick, JJ, Holmgren, MA, Sklar, P (2005). Molecular genetics of attention-deficit/hyperactivity disorder. Biological Psychiatry 57, 1313–1323.Google Scholar
Goll, MG, Bestor, TH (2005). Eukaryotic cytosine methyltransferases. Annual Review of Biochemistry 74, 481–514.CrossRefGoogle ScholarPubMed
Greenberg, LM, Waldman, ID (1993). Developmental normative data on the test of variables of attention (T.O.V.A.). Journal of Child Psychology and Psychiatry 34, 1019–1030.CrossRefGoogle ScholarPubMed
Grizenko, N, Shayan, YR, Polotskaia, A, Ter-Stepanian, M, Joober, R (2008). Relation of maternal stress during pregnancy to symptom severity and response to treatment in children with ADHD. Journal of Psychiatry and Neuroscience 33, 10–16.Google ScholarPubMed
Harrison, AA, Everitt, BJ, Robbins, TW (1997). Central 5-HT depletion enhances impulsive responding without affecting the accuracy of attentional performance: interactions with dopaminergic mechanisms. Psychopharmacology (Berlin) 133, 329–342.CrossRefGoogle ScholarPubMed
Heils, A, Teufel, A, Petri, S, Stober, G, Riederer, P, Bengel, D, Lesch, KP (1996). Allelic variation of human serotonin transporter gene expression. Journal of Neurochemistry 66, 2621–2624.Google Scholar
Hochberg, Z, Feil, R, Constancia, M, Fraga, M, Junien, C, Carel, JC, Boileau, P, Le Bouc, Y, Deal, CL, Lillycrop, K, Scharfmann, R, Sheppard, A, Skinner, M, Szyf, M, Waterland, RA, Waxman, DJ, Whitelaw, E, Ong, K, Albertsson-Wikland, K (2011). Child health, developmental plasticity, and epigenetic programming. Endocrine Review 32, 159–224.Google Scholar
Ikegame, T, Bundo, M, Sunaga, F, Asai, T, Nishimura, F, Yoshikawa, A, Kawamura, Y, Hibino, H, Tochigi, M, Kakiuchi, C, Sasaki, T, Kato, T, Kasai, K, Iwamoto, K (2013). DNA methylation analysis of BDNF gene promoters in peripheral blood cells of schizophrenia patients. Neuroscience Research 77, 208–214.Google Scholar
Jans, LA, Riedel, WJ, Markus, CR, Blokland, A (2007). Serotonergic vulnerability and depression: assumptions, experimental evidence and implications. Molecular Psychiatry 12, 522–543.Google Scholar
Kang, HJ, Kim, JM, Stewart, R, Kim, SY, Bae, KY, Kim, SW, Shin, IS, Shin, MG, Yoon, JS (2013). Association of SLC6A4 methylation with early adversity, characteristics and outcomes in depression. Progress in Neuro-Psychopharmacology and Biological Psychiatry 44, 23–28.Google Scholar
Kaufman, J, Birmaher, B, Brent, D, Rao, U, Flynn, C, Moreci, P, Williamson, D, Ryan, N (1997). Schedule for affective disorders and schizophrenia for school-age children-present and lifetime version (K-SADS-PL): initial reliability and validity data. Journal of the American Academy of Child and Adolescent Psychiatry 36, 980–988.Google Scholar
Kim, JS, Singh, V, Lee, JK, Lerch, J, Ad-Dab'bagh, Y, MacDonald, D, Lee, JM, Kim, SI, Evans, AC (2005). Automated 3-D extraction and evaluation of the inner and outer cortical surfaces using a Laplacian map and partial volume effect classification. Neuroimage 27, 210–221.CrossRefGoogle ScholarPubMed
Kim, YS, Cheon, KA, Kim, BN, Chang, SA, Yoo, HJ, Kim, JW, Cho, SC, Seo, DH, Bae, MO, So, YK, Noh, JS, Koh, YJ, McBurnett, K, Leventhal, B (2004). The reliability and validity of kiddie-schedule for affective disorders and schizophrenia-present and lifetime version- Korean version (K-SADS-PL-K). Yonsei Medical Journal 45, 81–89.Google Scholar
Langley, K, Rice, F, van den Bree, MB, Thapar, A (2005). Maternal smoking during pregnancy as an environmental risk factor for attention deficit hyperactivity disorder behaviour. A review. Minerva Pediatrica 57, 359–371.Google ScholarPubMed
Laucht, M, Treutlein, J, Schmid, B, Blomeyer, D, Becker, K, Buchmann, AF, Schmidt, MH, Esser, G, Jennen-Steinmetz, C, Rietschel, M, Zimmermann, US, Banaschewski, T (2009). Impact of psychosocial adversity on alcohol intake in young adults: moderation by the LL genotype of the serotonin transporter polymorphism. Biological Psychiatry 66, 102–109.Google Scholar
Lerch, JP, Pruessner, JC, Zijdenbos, A, Hampel, H, Teipel, SJ, Evans, AC (2005). Focal decline of cortical thickness in Alzheimer's disease identified by computational neuroanatomy. Cerebral Cortex 15, 995–1001.Google Scholar
MacDonald, D, Kabani, N, Avis, D, Evans, AC (2000). Automated 3-D extraction of inner and outer surfaces of cerebral cortex from MRI. Neuroimage 12, 340–356.Google Scholar
Merry, SN, Andrews, LK (1994). Psychiatric status of sexually abused children 12 months after disclosure of abuse. Journal of the American Academy of Child and Adolescent Psychiatry 33, 939–944.CrossRefGoogle ScholarPubMed
Ouyang, LJ, Fang, XM, Mercy, J, Perou, R, Grosse, SD (2008). Attention-deficit/hyperactivity disorder symptoms and child maltreatment: a population-based study. Journal of Pediatrics 153, 851–856.Google Scholar
Park, S, Cho, SC, Kim, JW, Shin, MS, Yoo, HJ, Min Oh, S, Hyun Han, D, Hoon Cheong, J, Kim, BN (2014). Differential perinatal risk factors in children with attention-deficit/hyperactivity disorder by subtype. Psychiatry Research 11, 6743–6756.Google Scholar
Philibert, R, Madan, A, Andersen, A, Cadoret, R, Packer, H, Sandhu, H (2007). Serotonin transporter mRNA levels are associated with the methylation of an upstream CpG island. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics 144B, 101–105.CrossRefGoogle ScholarPubMed
Rampon, C, Jiang, CH, Dong, H, Tang, YP, Lockhart, DJ, Schultz, PG, Tsien, JZ, Hu, Y (2000). Effects of environmental enrichment on gene expression in the brain. Proceedings of the National Academy of Sciences USA 97, 12880–12884.Google Scholar
Roth, TL, Lubin, FD, Funk, AJ, Sweatt, JD (2009). Lasting epigenetic influence of early-life adversity on the BDNF gene. Biological Psychiatry 65, 760–769.Google Scholar
Shin, MS, Cho, S, Chun, SY, Hong, KE (2000). A study of the development and standardization of ADHD Diagnostic System. Korean Journal of Child and Adolescent Psychiatry 11, 91–99.Google Scholar
So, YK, Noh, JS, Kim, YS, Ko, SG, Koh, YJ (2002). The reliability and validity of Korean parent and teacher ADHD rating scale. Journal of Korean Neuropsychiatric Association 41, 283–289.Google Scholar
Szyf, M (2013). The genome- and system-wide response of DNA methylation to early life adversity and its implication on mental health. Canadian Journal of Psychiatry 58, 697–704.Google Scholar
van Mil, NH, Steegers-Theunissen, RP, Bouwland-Both, MI, Verbiest, MM, Rijlaarsdam, J, Hofman, A, Steegers, EA, Heijmans, BT, Jaddoe, VW, Verhulst, FC, Stolk, L, Eilers, PH, Uitterlinden, AG, Tiemeier, H (2014). DNA methylation profiles at birth and child ADHD symptoms. Journal of Psychiatric Research 49, 51–59.Google Scholar
Wahlund, K, Kristiansson, M (2009). Aggression, psychopathy and brain imaging – Review and future recommendations. International Journal of Law and Psychiatry 32, 266–271.Google Scholar
Walderhaug, E, Landro, NI, Magnusson, A (2008). A synergic effect between lowered serotonin and novel situations on impulsivity measured by CPT. Journal of Clinical and Experimental Neuropsychology 30, 204–211.Google Scholar
Wang, D, Szyf, M, Benkelfat, C, Provencal, N, Turecki, G, Caramaschi, D, Cote, SM, Vitaro, F, Tremblay, RE, Booij, L (2012). Peripheral SLC6A4 DNA methylation is associated with in vivo measures of human brain serotonin synthesis and childhood physical aggression. PLoS ONE 7, e39501.Google Scholar
Winstanley, CA, Eagle, DM, Robbins, TW (2006). Behavioral models of impulsivity in relation to ADHD: translation between clinical and preclinical studies. Clinical Psychology Review 26, 379–395.Google Scholar
Zepf, FD, Holtmann, M, Stadler, C, Demisch, L, Schmitt, M, Wockel, L, Poustka, F (2008). Diminished serotonergic functioning in hostile children with ADHD: tryptophan depletion increases behavioural inhibition. Pharmacopsychiatry 41, 60–65.Google Scholar
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