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Variation in serotonin transporter linked polymorphic region (5-HTTLPR) short/long genotype modulates resting frontal electroencephalography asymmetries in children

Published online by Cambridge University Press:  20 May 2015

Antonios I. Christou ,
Satoshi Endo ,
Yvonne Wallis ,
Hayley Bair ,
Maurice P. Zeegers  and
Joseph P. McCleery
Antonios I. Christou
Affiliation:
University of Birmingham
Satoshi Endo
Affiliation:
Technische Universität München
Yvonne Wallis
Affiliation:
Birmingham Women's Hospital
Hayley Bair
Affiliation:
Birmingham Women's Hospital
Maurice P. Zeegers
Affiliation:
Maastricht University
Joseph P. McCleery*
Affiliation:
University of Birmingham Children's Hospital of Philadelphia
*
Address correspondence and reprint requests to: Joseph P. McCleery, Center for Autism Research, Children's Hospital of Philadelphia, 3535 Market Street, #860, Philadelphia, PA 19104; E-mail: MccleeryJ@email.chop.edu.
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Abstract

Previous studies have documented the serotonin transporter linked polymorphic region (5-HTTLPR) as a genetic susceptibility variant that contributes to variability in outcomes related to affective psychopathology, with the short allele associated with negative affectivity and the long allele associated with positive affectivity. In a separate but related line of research, extensive evidence suggests that frontal electroencephalography (EEG) hemispheric asymmetry in the alpha band is also associated with risk for affective psychopathologies, with leftward asymmetry associated with approach-related behavior patterns and rightward frontal EEG asymmetry associated with withdrawn behavioral tendencies. We examined frontal EEG hemispheric asymmetries in relation to 5-HTTLPR genotyping in 70 children between 4 and 6 years of age. Analyses revealed that frontal EEG lateralization interacted with genotype such that children homozygous for the short allele exhibited rightward frontal EEG asymmetries, children who were homozygous for the long allele consistently exhibited a positive pattern of leftward asymmetry, and heterozygotes exhibited equivalent left and right frontal activity. These findings suggest that the 5-HTTLPR short allele may provide a degree of susceptibility for later affective psychopathology in adolescence and adulthood, through mediation of frontal brain activity that is associated with cognitive–behavioral withdrawal tendencies and negative affectivity.

Type
Regular Articles
Information
Development and Psychopathology , Volume 28 , Issue 1 , February 2016 , pp. 239 - 250
Copyright
Copyright © Cambridge University Press 2015 

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References

Achenbach, T., & Rescorla, L. (2001). The manual for the ASEBA School-Age Forms & Profiles. Burlington, VT: University of Vermont, Research Center for Children, Youth, and Families.Google Scholar
Allen, J. J. B., & Kline, J. P. (2004). Frontal EEG asymmetry, emotion and psychopathology: The first, and the next, twenty-five years. Biological Psychology, 67, 1–5.Google Scholar
Althaus, M., Groen, Y., Wijers, A. A., Mulder, L. J., Minderaa, R. B., Kema, I. P., et al. (2009). Differential effects of 5-HTTLPR and DRD2/ANKK1 polymorphisms on electrocortical measures of error and feedback processing in children. Clinical Neurophysiology, 120, 93–107.CrossRefGoogle ScholarPubMed
Beck, A. T. (2008). The evolution of the cognitive model of depression and its neurobiological correlates. American Journal of Psychiatry, 165, 969–977.Google Scholar
Belsky, J. (1997). Theory testing, effect-size evaluation, and differential susceptibility to rearing influence: The case of mothering and attachment. Child Development, 68, 598–600.Google Scholar
Belsky, J., Bakermans-Kranenbur, M. J., & van IJzendoorn, M. H. (2007). For better and for worse: Differential susceptibility to environmental influences. Current Direction in Psychological Science, 16, 300–304.Google Scholar
Belsky, J., Jonassaint, C., Pluess, M., Stanton, M., Brummett, B., & Williams, R. (2009). Vulnerability genes or plasticity genes? Molecular Psychiatry, 14, 746–754.Google Scholar
Bertoletti, E., Zanoni, A., Giorda, R., & Battaglia, M. (2012). Influence of the OPRM1 gene polymorphism upon children's degree of withdrawal and brain activation in response to facial expressions. Developmental Cognitive Neuroscience, 2, 103–109.Google Scholar
Berument, S. K., Rutter, M., Lord, C., Pickles, A., & Bailey, A. (1999). Autism screening questionnaire: Diagnostic validity. British Journal of Psychiatry, 175, 444–451.Google Scholar
Bismark, A. W., Moreno, F. A., Stewart, J. L., Towers, D. N., Coan, J. A., Oas, J., et al. (2010). Polymorphisms of the HTR1a allele are linked to frontal brain electrical asymmetry. Biological Psychology, 83, 153–158.Google Scholar
Bogdan, R., Agrawal, A., Gaffrey, M. S., Tillman, R., & Luby, J. L. (2014). Serotonin transporter linked polymorphic region (5-HTTLPR) genotype and stressful life events interact to predict preschool-onset depression: A replication and developmental extension. Journal of Child Psychology and Psychiatry, 55, 448–457.Google Scholar
Boyce, W. T., & Ellis, B. J. (2005). Biological sensitivity to context: I. An evolutionary–developmental theory of the origins and functions of stress reactivity. Developmental Psychopathology, 17, 271–301.Google Scholar
Bruder, G. E., Keilp, J. G., Xu, H., Shikhman, M., Schori, E., Gorman, J. M., et al. (2005). Catechol-O-methyltransferase (COMT) genotypes and working memory: Associations with differing cognitive operations. Biological Psychiatry, 58, 901–907.Google Scholar
Calkins, S. D., & Dedmon, S. A. (2000). Physiological and behavioral regulation in two-year-old children with aggressive/destructive behavior problems. Journal of Abnormal Child Psychology, 28, 103–118.Google Scholar
Card, N. A., & Little, T. D. (2006). Proactive and reactive aggression in childhood and adolescence: A meta-analysis of differential relations with psychosocial adjustment. International Journal of Behavioral Development, 30, 466–480.Google Scholar
Caspi, A., McClay, J., Moffitt, T. E., Mil, J., Martin, J., Craig, I. W., et al. (2002). Role of genotype in the cycle of violence in maltreated children. Science, 297, 851–854.Google Scholar
Caspi, A., Sugden K., Moffitt, T. E., Taylor, A., Craig, I. W., Harrington, H. L., et al. (2003). Influence of life stress on depression: Moderation by a polymorphism in the 5-HHT gene. Science, 301, 291–293.Google Scholar
Coan, J. A., & Allen, J. J. B. (2003). Frontal EEG asymmetry and the behavioural activation and inhibition systems. Psychophysiology, 40, 106–114.Google Scholar
Davidson, R. J. (1993). Cerebral asymmetry and emotion: Methodological conundrums. Cognition and Emotion, 7, 115–138.Google Scholar
Davidson, R. J. (2004). What does the prefrontal cortex “do” in affect: Perspectives in frontal EEG asymmetry research. Biological Psychology, 67, 219–234.Google Scholar
Davidson, R. J., Ekman, P., Saron, C. D., Senulis, J. A., & Friesen, W. V. (1990). Approach–withdrawal and cerebral asymmetry: Emotional expression and brain physiology. Journal of Personality and Social Psychology, 58, 330–341.Google Scholar
Davidson, R. J., Jackson, D. C., & Kalin, N. H. (2000). Emotion, plasticity, context, and regulation: Perspectives from affective neuroscience. Psychological Bulletin, 126, 890–909.Google Scholar
Dawson, G., Klinger, L. G., Panagiotides, H., Lewy, A., & Castello, P. (1995). Subgroups of autistic children based on social behavior display distinct patterns of brain activity. Journal of Abnormal Child Psychology, 23, 569–583.Google Scholar
Dietz, L. J., Jennings, K. D., Kelley, S. A., & Marshal, M. (2009). Maternal depression, paternal psychopathology, and toddlers' behavior problems. Journal of Clinical Child and Adolescent Psychology, 38, 48–61.Google Scholar
Dimidjian, S., Barrera, M., Martell, C., Munoz, R. F., & Lewinsohn, P. M. (2011). The origins and current status of behavioral activation treatments for depression. Annual Review of Clinical Psychology, 7, 1–38.Google Scholar
Dobson, K. S., Hollon, S. D., Dimidjian, S., Schmaling, K. B., Kohlenberg, R. J., & Gallop, R. J. (2008). Randomized trial of behavioral activation, cognitive therapy, and antidepressant medication in the prevention of relapse and recurrence in major depression. Journal of Consulting and Clinical Psychology, 76, 468–477.Google Scholar
Ducharme, S., Albaugh, M. D., Hudziak, J. J., Botteron, K. N., Nguyen, T. V., Truong, C., et al. (2013). Anxious/depressed symptoms are linked to right ventromedial prefrontal cortical thickness maturation in healthy children and young adults. Cerebral Cortex. Advance online publication.Google Scholar
Duman, R. S., Heninger, G. R., & Nestler, E. J. (1997). A molecular and cellular theory of depression. Archives of General Psychiatry, 54, 597–606.Google Scholar
Eley, T. C., Sugden, K., Corsico, A., Gregory, A. M., Sham, P., & Craig, I. W. (2004). Gene–environment interaction analysis of serotonin system markers with adolescent depression. Molecular Psychiatry, 9, 908–915.Google Scholar
Elliot, C. D., Smith, P., & McCulloch, K. (1996). British Ability Scales. Windsor: NFER-Nelson.Google Scholar
Feng, X., Shaw, D. S., & Silk, J. S. (2008). Developmental trajectories of anxiety symptoms among boys across early and middle childhood. Journal of Abnormal Psychology, 117, 32–47.Google Scholar
Forbes, E. E., Shaw, D. S., Silk, J. S., Feng, X., & Kovacs, M. (2008) Children's affect expression and frontal EEG asymmetry: Transactional associations with mothers' depressive symptoms. Journal of Abnormal Child Psychology, 36, 207–221.Google Scholar
Fortier, P., Van Lieshout, R. J., Waxman, J. A., Boyle, M. H., Saigal, S., & Schmidt, L. A. (2014). Are orchids left and dandelions right? Frontal brain activation asymmetry and its sensitivity to developmental context. Psychological Science, 25, 1526–1533.Google Scholar
Fox, N. A. (1991). If it's not left, it's right. Electroencephalograph asymmetry and the development of emotion. American Psychologist, 46, 863–872.Google Scholar
Fox, N. A. (1994). Dynamic cerebral processes underlying emotion regulation. Monographs of the Society for Research in Child Development, 56, 52–166.Google Scholar
Fox, N. A., Nichols, K. E., Henderson, H. A., Rubin, K., Schmidt, L., Hamer, D., et al. (2005). Evidence for a gene–environment interaction in predicting behavioural inhibition in middle childhood. Psychological Science, 16, 921–926.Google Scholar
Graham, K. A. (2014). Social processing, frontal asymmetries and the effect of emotion based disorders upon brain functioning and behaviour in infancy. PhD thesis, University of Birmingham.Google Scholar
Grossmann, T., & Johnson, M. H. (2007). The development of the social brain in human infancy. European Journal of Neuroscience, 25, 909–919.Google Scholar
Hankin, B., Nederhof, E., Oppenheimer, C. W., Jenness, J., Young, J. F., Abela, J. R. Z., et al. (2011). Differential susceptibility in youth: Evidence that 5HTTLPR x positive parenting is associated with positive affect “for better and worse.” Translational Psychiatry, 44, 1–7.Google Scholar
Hariri, A. R., Mattay, V. S., Tessitore, A., Kolachana, B., Fera, F., Goldman, D., et al. (2002). Serotonin transporter genetic variation and the response of the human amygdala. Science, 297, 400–403.Google Scholar
Hu, X., Lipsky, R. H, Zhu, G., Akhtar, L. A., Taubman, J., & Greenberg, B. D. (2006). Serotonin transporter promoter gain-of-function genotypes are linked to obsessive–compulsive disorder. American Journal of Human Genetics, 78, 815–826.Google Scholar
Jackson, D. C., Mueller, C. J., Dolski, I., Dalton, K. M., Nitschke, J. B., Urry, H. L., et al. (2003). Now you feel it, now you don't: Frontal brain electrical asymmetry and individual differences in emotion regulation. Psychological Science, 14, 612–617.CrossRefGoogle ScholarPubMed
Karg, K., Burmeister, M., Shedden, K., & Sen, S. (2011). The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: Evidence of genetic moderation. Archives of General Psychiatry, 68, 444–454.Google Scholar
Kato, M., Ikenaga, Y., Wakeno, M., Okugawa, G., Nobuhara, K., Fukuda, T., et al. (2005). Controlled clinical comparison of paroxetine and fluvoxamine considering the serotonin transporter promoter polymorphism. International Clinical Psychopharmacology, 20, 151–156.Google Scholar
Kaufman, J., Yang, B. Z., Douglas-Palumberi, H., Houshyar, S., Lipschitz, D., Krystal, J. H., et al. (2004). Social supports and serotonin transporter gene moderate depression in maltreated children. Proceedings of the National Academy of Sciences, 101, 17316–17321.Google Scholar
Lachman, H. M., Papolos, D. F., Saito, T., Yu, Y. M., Szumlanski, C. L., & Weinshilboum, R. M. (1996). Human catechol-O-methyl transferase pharmacogenetics: Description of a functional polymorphism and its potential application to neuropsychiatric disorders. Pharmacogenetics, 6, 243–250.Google Scholar
Lee, B. T., & Ham, B. J. (2008). Serotonergic genes and amygdala activity in response to negative affective facial stimuli in Korean women. Genes, Brain and Behaviour, 7, 899–890.Google Scholar
Lesch, K.-P., Bengel, D., Heils, A., Sabol, S. Z., Greenberg, B. D., Petri, S., et al. (1996). Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science, 274, 1527–1531.Google Scholar
Luu, P., & Ferree, T. (2000). Determination of the Geodesic Sensor Nets' average electrode positions and their 10-10 international equivalents (Tech. note). Eugene, OR: Electrical Geodesics.Google Scholar
Manji, H. K., Drevets, W. C., & Charney, D. S. (2001). The cellular neurobiology of depression. Nature Medicine, 7, 541–547.Google Scholar
Marsee, M. A., & Frick, P. J. (2007). Exploring the cognitive and emotional correlates to proactive and reactive aggression in a sample of detained girls. Journal of Abnormal Child Psychology, 35, 969–981.Google Scholar
Marshall, P. J., Bar-Haim, Y., & Fox, N. A. (2002). Development of the EEG from 5 months to 4 years of age. Clinical Neurophysiology, 113, 1199–1208.Google Scholar
McDonald, A. J. (1998). Cortical pathways to the mammalian amygdala. Progress in Neurobiology, 55, 257–332.Google Scholar
Munafò, M. R., Freimer, N. B., Ng, W., Ophoff, R., Veijola, J., Miettunen, J., et al. (2008). 5-HTTLPR genotype and anxiety-related personality traits: A meta-analysis and new data. American Journal of Medical Genetics, 150, 271–281.Google Scholar
Murphy, S. E., Norbury, R., Godlewska, B. R., Cowen, P. J., Mannie, Z. M., Harmer, C. J., et al. (2013). The effect of the serotonin transporter polymorphism (5-HTTLPR) on amygdala function: A meta-analysis. Molecular Psychiatry, 18, 512–520.Google Scholar
Nestler, E. J., Barrot, M., DiLeone, R. J., Eisch, A. J., Gold, S. J., & Monteggia, L. M. (2002). Neurobiology of depression. Neuron, 34, 13–25.Google Scholar
Nusslock, R., Shackman, A. J., Harmon-Jones, E., Alloy, L. B., Coan, J. A., & Abramson, L. Y. (2011). Cognitive vulnerability and frontal brain asymmetry: Common predictors of first prospective depressive episode. Journal of Abnormal Psychology, 120, 497–503.Google Scholar
Ochsner, K. N., & Gross, J. J. (2008). Cognitive emotion regulation: Insights from social cognitive and affective neuroscience. Currents Directions in Psychological Science, 17, 153–158.Google Scholar
Papousek, I., Reiser, E. M., Schulter, G., Fink, A., Holmes, E. A., Niederstätter, H., et al. (2013). Serotonin transporter genotype (5-HTTLPR) and electrocortical responses indicating the sensitivity to negative emotional cues. Emotion, 13, 1173–1181.Google Scholar
Peltola, M. J., Bakermans-Kranenburg, M. J., Alink, L. R., Huffmeijer, R., Biro, S., & van IJzendoorn, M. H. (2014). Resting frontal EEG asymmetry in children: Meta-analyses of the effects of psychosocial risk factors and associations with internalizing and externalizing behaviour. Developmental Psychobiology, 56, 1377–1389.Google Scholar
Pezawas, L., Meyer-Lindenberg, A., Drabant, E. M., Verchinski, B. A., Munoz, K. E., Kolachana, B. S., et al. (2005). 5-HTTLPR polymorphism impacts human cingulate–amygdala interactions: A genetic susceptibility mechanism for depression. Nature Neuroscience, 8, 828–834.Google Scholar
Pluess, M., & Belsky, J. (2009). Differential susceptibility to rearing experience: The case of childcare. Journal of Child Psychology and Psychiatry and Allied Disciplines, 50, 396–404.Google Scholar
Pluess, M., Belsky, J., Way, B. M., & Taylor, S. E. (2010). 5-HTTLPR moderates effects of current life events on neuroticism: Differential susceptibility to environmental influences. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 34, 1070–1074.Google Scholar
Risch, N., Herrell, R., Lehner, T., Liang, K. Y., Eaves, L., Hoh, J., et al. (2009). Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: A meta-analysis. Journal of the American Medical Association, 301, 2462–2471.Google Scholar
Ronald, A., Happe, F., & Plomin, R. (2005) The genetic relationship between individual differences in social and non-social behaviours characteristic of autism. Developmental Science, 8, 444–458.Google Scholar
Rutter, M., Bailey, A., & Lord, C. (2003). Social Communication Questionnaire—WPS (SCQ-WPS). Los Angeles: Western Psychological Services.Google Scholar
Rutter, M., Moffitt, T. E., & Caspi, A. (2006). Gene–environment interplay and psychopathology: Multiple varieties but real effects. Journal of Child Psychology and Psychiatry, 47, 226–261.Google Scholar
Santesso, D. L., Becker, D. L., Schmidt, L. A., & Segalowitz, S. J. (2006). Frontal electroencephalogram activation asymmetry, emotional intelligence, and externalizing behaviours in 10-year-old children. Child Psychiatry and Human Development, 36, 311–328.Google Scholar
Schaul, N. (1998). The fundamental neural mechanisms of electroencephalography. Electroencephalography and Clinical Neurophysiology, 106, 101–107.Google Scholar
Schmidt, L. A., Fox, N. A., Perez-Edgar, K., & Hamer, D. H. (2009). Linking gene, brain, and behavior: DRD4, frontal asymmetry, and temperament. Psychological Science, 20, 831–837.Google Scholar
Schmidt, L. A., & Miskovic, V. (2013). A new perspective on temperamental shyness: Differential susceptibility to endogenous environmental influences. Social and Personality Psychology Compass, 7, 141–157.Google Scholar
Shehzad, Z., DeYoung, C. G., Kang, Y., Grigorenko, E. L., & Gray, J. R. (2012). Interaction of COMT val158met and externalizing behavior: Relation to prefrontal brain activity and behavioral performance. NeuroImage, 60, 2158–2168.Google Scholar
Smit, D. J., Posthuma, D., Boomsma, D. I., & de Geus, E. J. (2007). The relation between frontal EEG asymmetry and the risk for anxiety and depression. Biological Psychology, 74, 26–33.Google Scholar
Smith, C. L., & Bell, M. A. (2010). Stability in infant frontal asymmetry as a predictor of toddlerhood internalizing and externalizing behaviors. Developmental Psychobiology, 52, 158–167.Google Scholar
Srinivasan, R., Nunez, P. L., Tucker, D. M., Silberstein, R. B., & Cadusch, P. J. (1996). Spatial sampling and filtering of EEG with spline Laplacians to estimate cortical potentials. Brain Topography, 8, 355–366.Google Scholar
Stollstorff, M., Foss-Feig, J., Cook, E. H., Stein, M., Gaillard, W. D., & Vaidya, C. J. (2010). Neural response to working memory load varies by dopamine transporter genotype in children. NeuroImage, 53, 970–977.Google Scholar
Tomarken, A. J., Dichter, G. S., Garber, J., & Simien, C. (2004). Resting frontal brain activity: Linkages to maternal depression and socioeconomic status among adolescents. Biological Psychology, 67, 77–102.Google Scholar
Tunbridge, E. M., Harrison, P. J., & Weinberger, D. R. (2006). Catechol-O-methyltransferase, cognition, and psychosis: Val 158 Met and beyond. Biological Psychiatry, 60, 141–151.Google Scholar
van Ijzendoorn, M. H., Belsky, J., & Bakermans-Kranenburg, M. J. (2012). Serotonin transporter genotype 5HTTLPR as a marker of differential susceptibility? A meta-analysis of child and adolescent gene-by-environment studies. Translational Psychiatry, 2, 147.Google Scholar
Vuga, M., Fox, N. A., Cohn, J. F., Kovacs, M., & George, C. J. (2008). Long-term stability of electroencephalographic asymmetry and power in 3- to 9-year-old children. International Journal of Psychophysiology, 67, 70–77.Google Scholar
Walsh, N. D., Dalgleish, T., Dunn, V. J., Abbott, R., St Clair, M. C., Owens, M., et al. (2012) 5-HTTLPR-environment interplay and its effects on neural reactivity in adolescents. NeuroImage, 63, 1670–1680.Google Scholar
Wendland, J. R., Martin, B. J., Kruse, M. R., Lesch, K. P., & Murphy, D. L. (2006). Simultaneous genotyping of four functional loci of human SLC6A4, with a reappraisal of 5-HTTLPR and rs25531. Molecular Psychiatry, 11, 224–226.Google Scholar
Wiggins, J. L., Bedoyan, J. K., Peltier, S. J., Ashinoff, S., Carrasco, M., Weng, S. J., et al. (2012). The impact of serotonin transporter (5-HTTLPR) genotype on the development of resting-state functional connectivity in children and adolescents: A preliminary report. NeuroImage, 59, 2760–2770.Google Scholar
Zalsman, G., Huang, Y. Y., Oquendo, M. A., Burke, A. K., Hu, X.-Z., Brent, D. A., et al. (2006). Association of a triallelic serotonin transporter gene promoter region (5-HTTLPR) polymorphism with stressful life events and severity of depression. American Journal of Psychiatry, 163, 1588–1593.Google Scholar
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