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Studies of the 5-HTTLPR Serotonin Transporter Polymorphism (literature review)

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Neuroscience and Behavioral Physiology Aims and scope Submit manuscript

Polymorphism of the 5-HTTLPR serotonin transporter gene is one of the best studied markers of the serotoninergic system. Scientific interest in investigating 5-HTTLPR polymorphism arises because many studies have demonstrated an association between the short allele (S) and the development of a number of mental disorders. Several studies have shown that different 5-HTTLPR alleles are associated with different patterns of brain bioelectrical activity in the resting state and on performance of test tasks. However, despite a quite large number of studies of this marker, the results often contradict each other. Possible causes of disagreement between results may be that the complex structure of the SLC6A4 gene is ignored, heterogeneity in cohorts, and the use of different methods. The aim of the present work was to conduct a literature review and use this to carry out a complex analysis of psychological, behavioral, genetic, and neurophysiological data to summarize the effects associated with 5-HTTLPR polymorphism and at least partly to explain the variability in the results obtained by different authors.

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References

  • Althaus, M., Groen, Y., Wijers, A. A., et al., “Differential effects of 5-HTTLPR and DRD2/ANKK1 polymorphisms on electrocortical measures of error and feedback processing in children,” Clin. Neurophysiol., 120, 93–107 (2009).

    Article  CAS  PubMed  Google Scholar 

  • Antypa, N. and Van der Does, A. J. W., “Serotonin transporter gene, childhood emotional abuse and cognitive vulnerability to depression,” Genes Brain Behav., 9, 615–620 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  • Arango, V., Huang, Y. Y., Underwood, M. D., and Mann, J. J., “Genetics of the serotonergic system in suicidal behavior,” J. Psychiatr. Res., 37, 375–386 (2003).

    Article  PubMed  Google Scholar 

  • Ball, S. A., Tennen, H., Poling, J. C., et al., “Personality, temperament, and character dimensions and the DSM-IV personality disorders in substance abusers,” J. Abnorm. Psychol., 106, No. 4, 545 (1997).

  • Barrett, J. E. and Vanover, K. E., “5-HT receptors as targets for the development of novel anxiolytic drugs: models, mechanisms and future directions,” Psychopharmacology, 112, No. 1, 1–12 (1993).

    Article  CAS  PubMed  Google Scholar 

  • Bauer, M., Whybrow, P. C., Angst, J., et al., “World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders, part 1: acute and continuation treatment of major depressive disorder,” World J. Biol. Psychiatry, 3, No. 1, 5–43 (2002).

    Article  PubMed  Google Scholar 

  • Beevers, C. G, Gibb, B. E., McGeary, J. E., and Miller, I. W., “Serotonin transporter genetic variation and biased attention for emotional word stimuli among psychiatric inpatients,” J. Abnorm. Psychol., 116, 208–212 (2007).

    Article  PubMed  Google Scholar 

  • Beevers, C. G., Wells, T. T., Ellis, A. J., and McGeary, J. E., “Association of the serotonin transporter gene promoter region 5-HTTLPR polymorphism with biased attention for emotional stimuli,” J. Abnorm. Psychol., 118, 670–681 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  • Belousova, L. V., Volf, N. V., and Bazovkina, D. V., “Relationship between aging-related changes in baseline brain activity and polymorphism of the serotonin transporter gene 5-HTTLPR in men,” Fiziol. Cheloveka, 44, No. 4, 1–8 (2018).

    Google Scholar 

  • Belsky, J., Jonassaint, C., Pluess, M., et al., “Vulnerability genes or plasticity genes?” Mol. Psychiatry, 14, 746–754 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bismark, A. W., Moreno, F. A., Stewart, J. L., et al., “Polymorphisms of the HTR1a allele are linked to frontal brain electrical asymmetry,” Biol. Psychol., 83, 153–158 (2010).

    Article  PubMed  Google Scholar 

  • Blakely, R. D., Defelice, L. J., and Hartzell, H. C., “Molecular physiology of norepinephrine and serotonin transporters,” J. Exp. Biol., 196, 263–281 (1994).

    Article  CAS  PubMed  Google Scholar 

  • Bocharov, A. V., Savostyanov, A. N., Tamozhnikov, S. S., et al., “Impact of polymorphisms in the serotonin transporter gene on oscillatory dynamics during inhibition of planned movement in children,” Brain Sci., 9, 311 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  • Bokhan, N. A., Ivanova, S. A., and Levchuk, L. A., The Serotoninergic System in Modulation of Depressive and Addictive Behavior, Tomsk National Research State University, Tomsk (2013).

    Google Scholar 

  • Borg, J., Henningsson, S., Saijo, T., et al., “Serotonin transporter genotype is associated with cognitive performance but not regional 5-HT1A receptor binding in humans,” Int. J. Neuropsychopharmacol., 12, 783–792 (2009).

    Article  CAS  PubMed  Google Scholar 

  • Brocke, B., Armbruster, D., Muller, J., et al., “Serotonin transporter gene variation impacts innate fear processing: Acoustic startle response and emotional startle,” Mol. Psychiatry, 11, 1106–1112 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Brummett, B. H., Boyle, S. H., Siegler, I. C., et al., “Effects of environmental stress and gender on associations among symptoms of depression and the serotonin transporter gene linked polymorphic region (5-HTTLPR),” Behav. Genet., 38, 34–43 (2008).

    Article  PubMed  Google Scholar 

  • Canli, T., Qiu, M., Omura, K., et al., “Neural correlates of epigenesist,” Proc. Natl. Acad. Sci. USA, 103, 16,033–16,038 (2006).

  • Caspi, A., Sugden, K., Moffitt, T. E., et al., “Influence of life stress on depression: Moderation by a polymorphism in the 5-HTT gene,” Science, 301, 386–389 (2003).

  • Cassel, J. C. and Jeltsch, H., “Serotonergic modulation of cholinergic function in the central nervous system: cognitive implications,” Neuroscience, 69, No. 1, 1–41 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Cerasa, A., Quattrone, A., Piras, F., et al., “5-HTTLPR, anxiety and gender interaction moderates right amygdala volume in healthy subjects,” Soc Cogn. Affect. Neurosci., 9, No. 10, 1537–1545 (2014).

    Article  PubMed  Google Scholar 

  • Chiao, J. Y. and Blizinsky, K. D., “Culture-gene coevolution of individualism-collectivism and the serotonin transporter gene,” Proc. R. Soc. B. Biol. Sci., 277, No. 1681, 529–537 (2009).

    Article  Google Scholar 

  • Chipman, P., Jorm, A. F., Prior, M., et al., “No interaction between the serotonin transporter polymorphism (5-HTTLPR) and childhood adversity or recent stressful life events on symptoms of depression: Results from two community surveys,” Am. J. Med. Genet. B. Neuropsychiatr. Genet., 144, No. 4, 561–565 (2007).

    Article  Google Scholar 

  • Christian, J. C., Morzorati, S., Norton, J. A., et al., “Genetic analysis of the resting electroencephalographic power spectrum in human twins,” Psychophysiology, 33, 584–591 (1996).

    Article  CAS  PubMed  Google Scholar 

  • Clarke, H., Flint, J., Attwood, A. S., and Munafo, M. R., “Association of the 5-HTTLPR genotype and unipolar depression: a meta-analysis,” Psychol. Med., 40, 1767–1778 (2010).

    Article  CAS  PubMed  Google Scholar 

  • Clasen, P. C., Wells, T. T., Knopik, V. S., et al., “5-HTTLPR and BDNF Val66Met polymorphisms moderate effects of stress on rumination,” Genes Brain Behav., 10, No. 7, 740–746 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cloninger, C. R., “A systematic method for clinical description and classification of personality variants,” Arch. Gen. Psychiatry, 44, 573–588 (1987).

    Article  CAS  PubMed  Google Scholar 

  • Collier, D. A., Stöber, G., Li, T., Heils, A., et al., “A novel functional polymorphism within the promoter of the serotonin transporter gene: possible role in susceptibility to affective disorders,” Mol. Psychiatry, 1, No. 6, 453–460 (1996).

    CAS  PubMed  Google Scholar 

  • Costa, P. T. and McCrae, R. R., Revised NEO Personality Factor Inventory (NEO PI-R) and NEO Five Factor Inventory. Professional Manual, Psychological Assessment Resources, Odessa (1992).

  • Crisan, L. G., Pana, S., Vulturar, R., et al., “Genetic contributions of the serotonin transporter to social learning of fear and economic decision making,” Soc. Cogn. Affect. Neurosci., 4, 399–408 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  • Dannlowski, U., Konrad, C., Kugel, H., et al., “Emotion specifi c modulation of automatic amygdala responses by 5-HTTLPR genotype,” NeuroImage, 53, 893–898 (2010).

    Article  CAS  PubMed  Google Scholar 

  • De Vry, J., Glaser, T., Schuurman, T., et al., “5-HT 1A receptors in anxiety,” in: New Concepts in Anxiety, (1991), pp. 94–129.

  • Deary, I. J., Battersby, S., Whiteman, M. C., et al., “Neuroticism and polymorphisms in the serotonin transporter gene,” Psychol. Med., 29, No. 3, 735–739 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Delorme, R., Betancur, C., Wagner, M., et al., “Support for the association between the rare functional variant I425V of the serotonin transporter gene and susceptibility to obsessive-compulsive disorder,” Mol. Psychiatry, 10, 1059–1061 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dolan, M., Anderson, I. M., and Deakin, J. F. W., “Relationship between 5-HT function and impulsivity and aggression in male offenders with personality disorders,” Brit. J. Psychiatry, 178, No. 4, 352–359 (2001).

    Article  CAS  Google Scholar 

  • Du, L., Bakish, D. and Hrdina, P. D., “Gender differences in association between serotonin transporter gene polymorphism and personality traits,” Psychiatr. Genet., 10, No. 4, 159–164 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Eley, T. C., Sugden, K., Corsico, A., et al., “Gene–environment interaction analysis of serotonin system markers with adolescent depression,” Mol. Psychiatry, 9, No. 10, 908–915 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Fallgatter, A. J., Jatzke, S., Bartsch, A. J., et al., “Serotonin transporter promoter polymorphism infl uences topography of inhibitory motor control,” Int. J. Neuropsychopharmacol., 2, 115–120 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Feinn, R., Nellissery, M., and Kranzler, H. R., “Meta-analysis of the association of a functional serotonin transporter promoter polymorphism with alcohol dependence,” Am J. Med. Genet. B Neuropsychiatr. Genet., 133B, 79–84 (2005).

  • Finger, E. C., Marsh, A. A., Buzas, B., et al., “The impact of tryptophan depletion and 5-HTTLPR genotype on passive avoidance and response reversal instrumental learning tasks,” Neuropsychopharmacology, 32, No. 1, 206–215 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Fiskerstrand, C. E., Lovejoy, E. A., and Quinn, J. P., “An intronic polymorphic domain often associated with susceptibility to affective disorders has allele dependent differential enhancer activity in embryonic stem cells,” FEBS Lett., 458, No. 2, 171–174 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Flory, J. D., Manuck, S. B., Matthews, K. A., and Muldoon, M. F., “Serotonergic function in the central nervous system is associated with daily ratings of positive mood,” Psychiatry Res., 129, No. 1, 11–19 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Fox, E., Ridgewell, A., and Ashwin, C., “Looking on the bright side: biased attention and the human serotonin transporter gene,” Proc. R. Soc. B. Biol. Sci., 276, No. 1663, 1747–1751 (2009).

    Article  Google Scholar 

  • Gelernter, J., Pakstis, A. J., and Kidd, K. K., “Linkage mapping of serotonin transporter protein gene slc6a4 on chromosome-17,” Hum. Genet., 95, 677–680 (1995).

    Article  CAS  PubMed  Google Scholar 

  • Gillihan, S. J., Rao, H. Y., Brennan, L., et al., “Serotonin transporter genotype modulates the association between depressive symptoms and amygdala activity among psychiatrically healthy adults,” Psychiatry Res., 193, 161–167 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gilman, T. L., Latsko, M., Matt, L., et al., “Variation of 5-HTTLPR and deficits in emotion regulation: A pathway to risk?” Psychol. Neurosci., 8, 397–413 (2015).

    Article  Google Scholar 

  • Giuliani, N. and Gross, J. J., “Reappraisal,” in: Sander, D. and Scherer, K. (eds.), Oxford Companion to the Affective Sciences, Oxford University Press, New York, New York (2009), pp. 329–330.

    Google Scholar 

  • Glahn, D. C., Curran, J. E., Winkler, A. M., et al., “High dimensional endophenotype ranking in the search for major depression risk genes,” Biol. Psychiatry, 71, No. 1, 6–14 (2012).

    Article  PubMed  Google Scholar 

  • Gottesman, I. I. and Gould, T. D., “The endophenotype concept in psychiatry: etymology and strategic intentions,” Am. J. Psychiatry, 160, No. 4, 636–645 (2003).

    Article  PubMed  Google Scholar 

  • Gottesman, I. I. and Shields, J., “A polygenic theory of schizophrenia,” Int. J. Mental Health, 1, No. 1–2, 107–115 (1972).

    Article  Google Scholar 

  • Graff-Guerrero, A., De la Fuente-Sandoval, C., Camarena, B., et al., “Frontal and limbic metabolic differences in subjects selected according to genetic variation of the SLC6A4 gene polymorphism,” NeuroImage, 25, 1197–1204 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Greenberg, B. D., Li, Q., Lucas, F. R., et al., “Association between the serotonin transporter promoter polymorphism and personality traits in a primarily female population sample,” Am. J. Med. Genet., 96, No. 2, 202–216 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Gressier, F., Calati, and R., Serretti, A., “5-HTTLPR and gender differences in affective disorders: a systematic review,” J. Affect. Disord., 190, 193–207 (2016).

  • Haberstick, B. C., Smolen, A., Williams, R. B., et al., “Population frequencies of the triallelic 5HTTLPR in six ethnically diverse samples from North America, Southeast Asia, and Africa,” Behav. Genet., 45, No. 2, 255–261 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  • Handley, S. L., “5-Hydroxytryptamine pathways in anxiety and its treatment,” Oharmacol. Ther., 66, No. 1, 103–148 (1995).

    Article  CAS  Google Scholar 

  • Hardy, G. H., “Mendelian proportions in a mixed population,” in: Classic Papers in Genetics, Prentice-Hall, Inc., Englewood Cliffs, NJ (1908), pp. 60–62.

  • Hariri, A. and Holmes, A., “Genetics of emotional regulation: the role of the serotonin transporter in neural function,” Trends Cogn. Sci., 10, No. 4b, 182–191 (2006).

    Article  PubMed  Google Scholar 

  • Hariri, A. R., Mattay, V. S., Tessitore, A., et al., “Serotonin transporter genetic variation and the response of the human amygdala,” Science, 297, 400–403 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Harro, J., Merenäkk, L., Nordquist, N., et al., “Personality and the serotonin transporter gene: Associations in a longitudinal population-based study,” Biol. Psychol., 81, No. 1, 9–13 (2009).

    Article  PubMed  Google Scholar 

  • Heils, A., Teufel, A., Petri, S., et al., “Allelic variation of human serotonin transporter gene expression,” J. Neurochem., 66, No. 6, 2621–2624 (1996).

    Article  CAS  PubMed  Google Scholar 

  • Heinz, A., Braus, D. F., Smolka, M. N., et al., “Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter,” Nat. Neurosci., 8, 20–21 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Homberg, J. R. and Lesch, K. P., “Looking on the bright side of serotonin transporter gene variation,” Biol. Psychiatry, 69, 513–519 (2011).

    Article  CAS  PubMed  Google Scholar 

  • Hornung, J. P., “The human raphe nuclei and the serotonergic system,” J. Chem. Neuroanat., 26, No. 4, 331–343 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Hornung, J. P., Fritschey, J. M., and Tork, I., “Distribution of two morphologically distinct subsets of serotonergic axons in the cerebral cortex of the marmoset,” J. Comp. Neurol., 279, 165–181 (1990).

    Article  Google Scholar 

  • Horschitz, S., Hummerich, R., and Schloss, P., “Structure, function and regulation of the 5-hydroxytryptamine (serotonin) transporter,” Biochem. Soc. Trans., 29, No. 6, 728–732 (2001).

    Article  CAS  PubMed  Google Scholar 

  • Hu, X. Z., Oroszi, G., Chun, J., et al., “An expanded evaluation of the relationship of four alleles to the level of response to alcohol and the alcoholism risk,” Alcohol Clin. Exp. Res., 29, 8–16 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Jeronimus, B. F., Kotov, R., Riese, H., and Ormel, J., “Neuroticism’s prospective association with mental disorders halves after adjustment for baseline symptoms and psychiatric history, but the adjusted association hardly decays with time: a meta-analysis on 59 longitudinal/prospective studies with 443,313 participants,” Psychol. Med., 46, No. 14, 2883–2906 (2016).

    Article  CAS  PubMed  Google Scholar 

  • Karg, K., Burmeister, M., Shedden, K., and Sen, S., “The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: evidence of genetic moderation,” Arch. Gen. Psychiatry, 68, No. 5, 444–454 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  • Kaufman, J., Yang, B. Z., Douglas-Palumberi, H., et al., “Social supports and serotonin transporter gene moderate depression in maltreated children,” Proc. Natl. Acad. Sci. USA, 101, No. 49, 17316–17321 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kim, H. S. and Sasaki, J. Y., “Emotion regulation: The interplay of culture and genes,” Social and Personality Psychology Compass, 6, 865–877 (2012).

    Article  Google Scholar 

  • Knyazev, G. G., Bazovkina, D. V., Savostyanov, A. N., et al., “Suppression mediates the effect of 5-HTTLPR by stress interaction on depression,” Scand. J. Psychol., 58, No. 5, 373–378 (2017).

    Article  PubMed  Google Scholar 

  • Köhler, C. and Steinbusch, H., “Identifi cation of serotonin and non-serotonin-containing neurons of the mid-brain raphe projecting to the entorhinal area and the hippocampal formation. A combined immunohistochemical and fluorescent retrograde tracing study in the rat brain,” Neuroscience, 7, No. 4, 951–975 (1982).

    Article  PubMed  Google Scholar 

  • Kranz, G. S., Kasper, S., and Lanzenberger, R., “Reward and the serotonergic system,” Neuroscience, 166, No. 4, 1023–1035 (2010).

    Article  CAS  PubMed  Google Scholar 

  • Kuhnen, C. M. and Chiao, J. Y., “Genetic determinants of fi nancial risk taking,” PLoS One, 4, e4362 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  • Kulikov, A. V. and Popova, N. K., “Forms of aggressive behavior and their genetic determination,” Usp. Sovrem. Genet., 17, 131–152 (1991).

    Google Scholar 

  • Kumakiri, C., Kodama, K., Shimizu, E., et al., “Study of the association between the serotonin transporter gene regulatory region polymorphism and personality traits in a Japanese population,” Neurosci. Lett., 263, No. 2–3, 205–207 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Lan, M. Y., Chang, Y. Y., Chen, W. H., et al., “Serotonin transporter gene promoter polymorphism is associated with body mass index and obesity in non-elderly stroke patients,” J. Endocrinol. Invest., 32, 119–122 (2009).

    Article  CAS  PubMed  Google Scholar 

  • Lebedeva, N. B., Ardashova, N. Yu., and Barbarash, O. L., “Association of polymorphic variants of serotoninergic system genes with depression and ischemic heart disease (literature review),” Sib. Zh. Klin. Eksperim. Med., 31, No. 3, 16–22 (2016).

    Google Scholar 

  • Lee, T. W., Yu, Y. W. Y., Hong, C. J., et al., “The influence of serotonin transporter polymorphisms on cortical activity: A resting EEG study,” BMC Neurosci., 12, No. 1, 33 (2011).

  • Lee, Y. S., Han, D. H., Yang, K. C., et al., “Depression like characteristics of 5-HTTLPR polymorphism and temperament in excessive internet users,” J. Affect. Disord., 109, 165–169 (2008).

    Article  CAS  PubMed  Google Scholar 

  • Lerman, C., Caporaso, N. E., Audrain, J., et al., “Interacting effects of the serotonin transporter gene and neuroticism in smoking practices and nicotine dependence,” Mol. Psychiatry, 5, 189–192 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Lesch, K. P. and Mössner, R., “Genetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders?” Biol. Psychiatry, 44, No. 3, 179–192 (1998).

    Article  CAS  PubMed  Google Scholar 

  • Lesch, K. P., Bengel, D., Heils, A., et al., “Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region,” Science, 274, 1527–1531 (1996).

    Article  CAS  PubMed  Google Scholar 

  • Lesch, K. P., Greenberg, B. D., Higley, J. D., et al., “Serotonin transporter, personality, and behavior: toward dissection of gene–gene and gene–environment interaction,” Mol. Genet. Hum. Personal., 109–135 (2002).

  • Lesch, K. P., Meyer, J., Glatz, K., et al., “The 5-HT transporter gene-linked polymorphic region (5-HTTLPR) in evolutionary perspective: alternative biallelic variation in rhesus monkeys,” J. Neural. Transm., 104, No. 11–12, 1259–1266 (1997).

    Article  CAS  PubMed  Google Scholar 

  • Li, D. and He, L., “Meta-analysis supports association between serotonin transporter (5-HTT) and suicidal behavior,” Mol. Psychiatry, 12, No. 1, 47 (2007).

  • Li, S., Zou, Q., Li, J., et al., “5-HTTLPR polymorphism impacts taskevoked and resting-state activities of the amygdala in Han Chinese,” PLoS One, 7, No. 5, e36513 (2012).

  • Ma, Y. N., Li, B. F., Wang, C. B., et al., “5-HTTLPR polymorphism modulates neural mechanisms of negative self-refl ection,” Cereb. Cortex, 24, 2421–2429 (2014).

    Article  PubMed  Google Scholar 

  • Mandelli, L., Nivoli, A., and Serretti, A., “Genetics of mood disorders,” in: The Handbook of Neuropsychiatric Biomarkers, endophenotypes and Genes, Ritsner, M. S. (ed.), (2009), Vol. 4, pp. 125–133.

  • McGuire, M. T. and Troisi, A., “Prevalence differences in depression among males and females: Are there evolutionary explanations?” Br. J. Med. Psychol., 71, 479–491 (1998).

    Article  PubMed  Google Scholar 

  • Mellings, M. B. and Alden, L. E., “Cognitive processes in social anxiety: the effects of self-focus, rumination, and anticipatory processing,” Behav. Res. Ther., 38, 243–257 (2000).

    Article  CAS  PubMed  Google Scholar 

  • Meyer-Lindenberg, A., “The future of fMRI and genetics research,” NeuroImage, 62, 1286–1292 (2012).

    Article  CAS  PubMed  Google Scholar 

  • Miu, A. C., Vulturar, R., Chiş, A., et al., “Reappraisal as a mediator in the link between 5-HTTLPR and social anxiety symptoms,” Emotion, 13, No. 6, 1012 (2013).

  • Munafo, M. R., Durrant, C., Lewis, G., and Flint, J., “Gene–environment interactions at the serotonin transporter locus,” Biol. Psychiatry, 65, 211–219 (2009).

    Article  CAS  PubMed  Google Scholar 

  • Murphy, D. L., Lerner, A., Rudnick, G., and Lesch, K. P., “Serotonin transporter: gene, genetic disorders, and pharmacogenetics,” Mol. Interv., 4, No. 2, 109 (2004).

  • Murphy, F. C., Sahakian, B. J., and Rubinsztein, J. S., “Emotional bias and inhibitory control processes in mania and depression,” Psychol. Med., 29, No. 6, 1307–1321 (1999).

    Article  CAS  PubMed  Google Scholar 

  • Nakamura, T., Muramatsu, T., Ono, Y., et al., “Serotonin transporter gene regulatory region polymorphism and anxiety-related traits in the Japanese,” Am. J. Med. Genet., 74, No. 5, 544–545 (1997).

    Article  CAS  PubMed  Google Scholar 

  • Osinsky, R., Reuter, M., Kupper, Y., et al., “Variation in the serotonin transporter gene modulates selective attention to threat,” Emotion, 8, 584–588 (2008).

    Article  PubMed  Google Scholar 

  • Ozaki, N., Goldman, D., Kaye, W. H., et al., “Serotonin transporter missense mutation associated with a complex neuropsychiatric phenotype,” Mol. Psychiatry, 8, 933–936 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Papousek, I., Reiser, E. M., Schulter, G., et al., “Serotonin transporter genotype 5-HTTLPR and electrocortical responses indicating the sensitivity to negative Emotional cues,” Emotion, 13, 1173–1181 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  • Perez de Castro, I., Ibanez, A., Saiz-Ruiz, J., and Fernandez-Piqueras, J., “Concurrent positive association between pathological gambling and functional DNA polymorphisms at the MAO-A and the 5-HT transporter genes,” Mol. Psychiatry, 7, 927–928 (2002).

    Article  CAS  PubMed  Google Scholar 

  • Peyron, C., Tighe, D. K., Van Den Pol, A. N., et al., “Neurons containing hypocretin (orexin) project to multiple neuronal systems,” J. Neurosci., 18, No. 23, 9996–10,015 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pezawas, L., Meyer-Lindenberg, A., Drabant, E. M., et al., “5-HTTLPR polymorphism impacts human cingulate–amygdala interactions: a genetic susceptibility mechanism for depression,” Nat. Neurosci., 8, 828–834 (2005).

    Article  CAS  PubMed  Google Scholar 

  • Proshina, E. A., Savostyanov, A. N., Bocharov, A. V., and Knyazev, G. G., “Effect of 5-HTTLPR on current source density, connectivity, and topological properties of resting state EEG networks,” Brain Res., 1697, 67–75 (2018).

    Article  CAS  PubMed  Google Scholar 

  • Rachmann, S., Gruter-Andrew, J., and Shafran, R., “Post-event processing in social anxiety,” Behav. Res. Ther., 38, 611–617 (2000).

    Article  Google Scholar 

  • Raleigh, M. J., McGuire, M. T., Brammer, G. L., et al., “Serotonergic mechanisms promote dominance acquisition in adult male vervet monkeys,” Brain Res., 559, No. 2, 181–190 (1991).

    Article  CAS  PubMed  Google Scholar 

  • Ramamoorthy, S., Bauman, A. L., Moore, K. R., et al., “Antidepressantand cocaine-sensitive human serotonin transporter: molecular cloning, expression, and chromosomal localization,” Proc. Natl. Acad. Sci. USA, 90, No. 6, 2542–2546 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ramautar, J. R., Slagter, H. A., Kok, A., and Ridderinkhof, K. R., “Probability effects in the stop-signal paradigm: the insula and the signifi cance of failed inhibition,” Brain Res., 1105, No. 1, 143–154 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Rao, H. Y., Gillihan, S. J., Wang, J. J., et al., “Genetic variation in serotonin transporter alters resting brain function in healthy individuals,” Biol. Psychiatry, 62, 600–606 (2007).

    Article  CAS  PubMed  Google Scholar 

  • Ridderinkhof, K. R., Ullsperger, M., Crone, E. A., and Nieuwenhuis, S., “The role of the medial frontal cortex in cognitive control,” Science, 306, No. 5695, 443–447 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Risch, N., Herrell, R., Lehner, T., et al., “Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression. A meta-analysis,” JAMA, 301, 2462–2471 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Roiser, J. P., Rogers, R. D., Cook, L. J., and Sahakian, B. J., “The effect of polymorphism at the serotonin transporter gene on decision-making, memory and executive function in ecstasy users and controls,” Psychopharmacology, 188, 213–227 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Savostyanov, A. N., Sinyakova, N. A., L’vova, M. N., et al., “Interaction of levels of anxiety with polymorphic variants of the serotonin transporter gene in Russians and Tuvans,” Vavilov. Zh. Genet. Selekts., 18, No. 4/3, 1268–1280 (2014).

  • Schinka, J. A., Busch, R. M., and Robichaux-Keene, N., “A meta-analysis of the association between the serotonin transporter gene polymorphism 5-HTTLPR and trait anxiety,” Mol. Psychiatry, 9, 197–202 (2004).

    Article  CAS  PubMed  Google Scholar 

  • Selvaraj, S., Godlewska, B. R., Norbury, R., et al., “Decreased regional gray matter volume in S’ allele carriers of the 5-HTTLPR triallelic polymorphism,” Mol. Psychiatry, 16, 472–473 (2011).

    Article  CAS  Google Scholar 

  • Sen, S., Burmeister, M., and Ghosh, D., “Meta-analysis of the association between a serotonin transporter promoter polymorphism 5-HTTLPR and anxiety-related personality traits,” Am. J. Med. Genet. B. Neuropsychiatr. Genet., 127B, 85–89 (2004).

    Article  PubMed  Google Scholar 

  • Sharpley, C. F., Palanisamy, S. K. A., Glyde, N. S., et al., “An update on the interaction between the serotonin transporter promoter variant 5-HTTLPR stress and depression plus an exploration of non-confirming findings,” Behav. Brain Res., 273, 89–105 (2014).

    Article  CAS  PubMed  Google Scholar 

  • Sheppes, G. and Gross, J. J., “Is timing everything? Temporal considerations in emotion regulation,” Pers. Soc. Psychol. Rev., 15, 319–331 (2011).

    Article  PubMed  Google Scholar 

  • Sjöberg, R. L., Nilsson, K. W., Nordquist, N., et al., “Development of depression: sex and the interaction between environment and a promoter polymorphism of the serotonin transporter gene,” Int. J. Neuropsychopharmacol., 9, No. 4, 443–449 (2006).

    Article  PubMed  Google Scholar 

  • Steiner, M., Dunn, E., and Born, L., “Hormones and mood: from menarche to menopause and beyond,” J. Affect. Disord., 74, 67–83 (2003).

    Article  CAS  PubMed  Google Scholar 

  • Stoltenberg, S. F., Twitchell, G. R., Hanna, G. L., et al., “Serotonin transporter promoter polymorphism, peripheral indexes of serotonin function, and personality measures in families with alcoholism,” Am. J. Med. Genet., 114, No. 2, 230–234 (2002).

    Article  PubMed  Google Scholar 

  • Sutcliffe, J. S., Delahanty, R. J., Prasad, H. C., et al., “Allelic heterogeneity at the serotonin transporter locus (SLC6A4) confers susceptibility to autism and rigid-compulsive behaviors,” Am. J. Hum. Genet., 77, 265–279 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szasz, P. L., Szentagotai, A., and Hofmann, S. G., “The effect of emotion-regulation strategies on anger,” Behav. Res. Ther., 49, 114–119 (2011).

    Article  PubMed  Google Scholar 

  • Taylor, S. E., Way, B. M., Welch, W. T., et al., “Early family environment, current adversity, the serotonin transporter promoter polymorphism, and depressive symptomatology,” Biol. Psychiatry, 60, 671–676 (2006).

    Article  CAS  PubMed  Google Scholar 

  • Tsai, A. C., Jung, T. P., Chien, V. S., et al., “Cortical surface alignment in multi-subject spatiotemporal independent EEG source imaging,” NeuroImage, 87, 297–310 (2014).

    Article  PubMed  Google Scholar 

  • Uher, R. and McGuffin, P., “The moderation by the serotonin transporter gene of environmental adversity in the etiology of depression: 2009 update,” Mol. Psychiatry, 15, No. 1, 18 (2010).

  • Umekage, T., Tochigi, M., Marui, T., et al., “Serotonin transporter-linked promoter region polymorphism and personality traits in a Japanese population,” Neurosci. Lett., 337, No. 1, 13–16 (2003).

    Article  CAS  PubMed  Google Scholar 

  • van Beijsterveldt, C. E. M. and van Baal, G. C. M., “Twin and family studies of the human electroencephalogram: a review and a meta-analysis,” Biol. Psychol., 61, 111–138 (2002).

    Article  PubMed  Google Scholar 

  • van Beijsterveldt, C. E. M., Molenaar, P. C. M., de Geus, E. J. C., and Boomsma, D. I., “Genetic and environmental infl uences on EEG coherence,” Behav. Genet., 28, 443–453 (1998).

    Article  PubMed  Google Scholar 

  • Van Praag, H. M., “Depressive and anxiety disorders and aggression: attempts to unravel the Gordian knot,” Medikografiya 20, No. 2, 27–34 (1998).

    Google Scholar 

  • Volf, N. V., Belousova, L. V., and Kulikov, A. V., “Association between the 5-HTTLPR polymorphism of serotonin transporter gene and EEG in young and postmenopausal women,” Zh. Vyssh. Nerv. Deyat., 65, 324–332 (2015a).

    CAS  Google Scholar 

  • Volf, N. V., Belousova, L. V., Knyazev, G. G., and Kulikov, A. V., “Gender differences in association between serotonin transporter gene polymorphism and resting-state EEG activity,” Neurosci., 284, 513–521 (2015b).

    Article  CAS  Google Scholar 

  • Volf, N. V., Belousova, L. V., Knyazev, G. G., and Kulikov, A. V., “Interactive effect of 5-HTTLPR genotype and age on sources of cortical rhythms in healthy women,” Internat. J. Psychophysiol., 109, 107–115 (2016).

    Article  Google Scholar 

  • Volf, N. V., Kulikov, A. V., Bortsov, C. U., and Popova, N. K., “Association of verbal and fi gural creative achievement with polymorphism in the human serotonin transporter gene,” Neurosci. Lett., 463, 154–157 (2009).

    Article  CAS  PubMed  Google Scholar 

  • Volf, N. V., Sinyakova, N. A., Osipova, L. P., et al., “Association between intelligence quotient and the 5-HTTLPR polymorphism of human serotonin transporter coding gene,” Ann. Neurosci. Psychol., 2, 6 (2015c).

    Google Scholar 

  • Watkins, P. C., Vache, K., and Verney, S. P., “Unconscious mood-congruent memory bias in depression,” J. Abnorm. Psychol., 105, No. 1, 34–41 (1996).

    Article  CAS  PubMed  Google Scholar 

  • Weinberg, W., “On the demonstration of heredity in man (1908),” in: Papers on Genetics (1963).

  • Wells, A., Clark, D. M., Salkovskis, P., et al., “Social phobia: the role of in situation safety behaviors in maintaining anxiety and negative beliefs,” Behav. Ther., 26, 153–161 (1995).

    Article  Google Scholar 

  • Wiggins, J. L., Bedoyan, J. K., Peltier, S. J., et al., “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 (2012).

    Article  CAS  PubMed  Google Scholar 

  • Williams, R., Marchuk, D., Gadde, K., et al., “Serotonin-related gene polymorphisms and central nervous system serotonin function,” Neuropsychopharmacology, 28, 533–541 (2003).

    Article  CAS  PubMed  Google Scholar 

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Correspondence to E. A. Proshina.

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Translated from Zhurnal Vysshei Nervnoi Deyatel’nosti imeni I. P. Pavlova, Vol. 71, No. 6, pp. 803–819, November–December, 2021.

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Proshina, E.A., Bocharov, A.V., Savostyanov, A.N. et al. Studies of the 5-HTTLPR Serotonin Transporter Polymorphism (literature review). Neurosci Behav Physi 52, 899–909 (2022). https://doi.org/10.1007/s11055-022-01314-3

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