Neuroscience Bulletin

, Volume 29, Issue 1, pp 4–15 | Cite as

The long rather than the short allele of 5-HTTLPR predisposes Han Chinese to anxiety and reduced connectivity between prefrontal cortex and amygdala

  • Haixia Long
  • Bing Liu
  • Bing Hou
  • Chao Wang
  • Jin Li
  • Wen Qin
  • Dawei Wang
  • Yuan Zhou
  • Keith M. Kendrick
  • Chunshui Yu
  • Tianzi Jiang
Original Article

Abstract

The short allele of the serotonin-transporter gene is associated with higher risk for anxiety and depression in Caucasians, but this association is still unclear in Asians. Here, we addressed this issue using behavioral and multi-modal MRI approaches in a large group of healthy Han Chinese participants (n = 233). In contrast to findings in Caucasians, we found that long-allele (L) carriers had higher anxiety scores. In another group (n = 64) experiencing significant levels of depression or anxiety, the L-allele frequency was also significantly higher. In healthy participants, L-carriers had reduced functional and anatomical connectivity between the amygdala and prefrontal cortex (PFC), which was correlated with anxiety or depression scores. Our findings demonstrated that in Chinese Han participants, in contrast to Caucasians, the L-allele confers vulnerability to anxiety or depression and weakens top-down emotional control between the PFC and amygdala. Therefore, ethnic background should be taken into account in generelated studies and their potential clinical applications.

Keywords

5-HTTLPR functional and anatomical connectivity amygdala prefrontal cortex Han Chinese 

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References

  1. [1]
    Wong ML, Licinio J. Research and treatment approaches to depression. Nat Rev Neurosci 2001, 2: 343–351.PubMedCrossRefGoogle Scholar
  2. [2]
    Lesch KP, Mossner R. Genetically driven variation in serotonin uptake: is there a link to affective spectrum, neurodevelopmental, and neurodegenerative disorders? Biol Psychiatry 1998, 44: 179–192.PubMedCrossRefGoogle Scholar
  3. [3]
    Schloss P, Williams DC. The serotonin transporter: a primary target for antidepressant drugs. J Psychopharmacol 1998, 12: 115–121.PubMedCrossRefGoogle Scholar
  4. [4]
    Lesch KP, Bengel D, Heils A, Sabol SZ, Greenberg BD, Petri S, et al. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science 1996, 274: 1527–1531.PubMedCrossRefGoogle Scholar
  5. [5]
    Heils A, Teufel A, Petri S, Stober G, Riederer P, Bengel D, et al. Allelic variation of human serotonin transporter gene expression. J Neurochem 1996, 66: 2621–2624.PubMedCrossRefGoogle Scholar
  6. [6]
    Osher Y, Hamer D, Benjamin J. Association and linkage of anxiety-related traits with a functional polymorphism of the serotonin transporter gene regulatory region in Israeli sibling pairs. Mol Psychiatry 2000, 5: 216–219.PubMedCrossRefGoogle Scholar
  7. [7]
    Caspi A, Sugden K, Moffitt TE, Taylor A, Craig IW, Harrington H, et al. Influence of life stress on depression: moderation by a polymorphism in the 5-HTT gene. Science 2003, 301: 386–389.PubMedCrossRefGoogle Scholar
  8. [8]
    Kim DK, Lim SW, Lee S, Sohn SE, Kim S, Hahn CG, et al. Serotonin transporter gene polymorphism and antidepressant response. Neuroreport 2000, 11: 215–219.PubMedCrossRefGoogle Scholar
  9. [9]
    Kim H, Lim SW, Kim S, Kim JW, Chang YH, Carroll BJ, et al. Monoamine transporter gene polymorphisms and antidepressant response in koreans with late-life depression. JAMA 2006, 296: 1609–1618.PubMedCrossRefGoogle Scholar
  10. [10]
    Yoshida K, Ito K, Sato K, Takahashi H, Kamata M, Higuchi H, et al. Influence of the serotonin transporter gene-linked polymorphic region on the antidepressant response to fluvoxamine in Japanese depressed patients. Prog Neuropsychopharmacol Biol Psychiatry 2002, 26: 383–386.PubMedCrossRefGoogle Scholar
  11. [11]
    Zhang K, Xu Q, Xu Y, Yang H, Luo J, Sun Y, et al. The combined effects of the 5-HTTLPR and 5-HTR1A genes modulates the relationship between negative life events and major depressive disorder in a Chinese population. J Affect Disord 2009, 114: 224–231.PubMedCrossRefGoogle Scholar
  12. [12]
    Lee BT, Ham BJ. Serotonergic genes and amygdala activity in response to negative affective facial stimuli in Korean women. Genes Brain Behav 2008, 7: 899–905.PubMedCrossRefGoogle Scholar
  13. [13]
    LeDoux J. The amygdala. Curr Biol 2007, 17: R868–874.PubMedCrossRefGoogle Scholar
  14. [14]
    Siegle GJ, Thompson W, Carter CS, Steinhauer SR, Thase ME. Increased amygdala and decreased dorsolateral prefrontal BOLD responses in unipolar depression: related and independent features. Biol Psychiatry 2007, 61: 198–209.PubMedCrossRefGoogle Scholar
  15. [15]
    Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion perception I: The neural basis of normal emotion perception. Biol Psychiatry 2003, 54: 504–514.PubMedCrossRefGoogle Scholar
  16. [16]
    Phillips ML, Drevets WC, Rauch SL, Lane R. Neurobiology of emotion perception II: Implications for major psychiatric disorders. Biol Psychiatry 2003, 54: 515–528.PubMedCrossRefGoogle Scholar
  17. [17]
    Heinz A, Braus DF, Smolka MN, Wrase J, Puls I, Hermann D, et al. Amygdala-prefrontal coupling depends on a genetic variation of the serotonin transporter. Nat Neurosci 2005, 8: 20–21.PubMedCrossRefGoogle Scholar
  18. [18]
    Friedel E, Schlagenhauf F, Sterzer P, Park SQ, Bermpohl F, Strohle A, et al. 5-HTT genotype effect on prefrontal-amygdala coupling differs between major depression and controls. Psychopharmacology (Berl) 2009, 205: 261–271.CrossRefGoogle Scholar
  19. [19]
    Pezawas L, Meyer-Lindenberg A, Drabant EM, Verchinski BA, Munoz KE, Kolachana BS, et al. 5-HTTLPR polymorphism impacts human cingulate-amygdala interactions: a genetic susceptibility mechanism for depression. Nat Neurosci 2005, 8: 828–834.PubMedCrossRefGoogle Scholar
  20. [20]
    Pacheco J, Beevers CG, Benavides C, McGeary J, Stice E, Schnyer DM. Frontal-limbic white matter pathway associations with the serotonin transporter gene promoter region (5-HTTLPR) polymorphism. J Neurosci 2009, 29: 6229–6233.PubMedCrossRefGoogle Scholar
  21. [21]
    Spielberger CD, Gorsuch RL, Lushene R, Vagg PR, Jacob GA. Manual for the State-Trait Anxiety Inventory. Palo Alto, CA: Consulting Psychologists Press, 1983.Google Scholar
  22. [22]
    Lasa L, Ayuso-Mateos JL, Vazquez-Barquero JL, Diez-Manrique FJ, Dowrick CF. The use of the Beck Depression Inventory to screen for depression in the general population: a preliminary analysis. J Affect Disord 2000, 57: 261–265.PubMedCrossRefGoogle Scholar
  23. [23]
    Beck AT, Steer RA, Brown GK. Manual for the Beck Depression Inventory-II. San Antonio, TX: Psychological Corporation, 1996.Google Scholar
  24. [24]
    Thomas G, Sinville R, Sutton S, Farquar H, Hammer RP, Soper SA, et al. Capillary and microelectrophoretic separations of ligase detection reaction products produced from low-abundant point mutations in genomic DNA. Electrophoresis 2004, 25: 1668–1677.PubMedCrossRefGoogle Scholar
  25. [25]
    Yi P, Chen Z, Zhao Y, Guo J, Fu H, Zhou Y, et al. PCR/LDR/capillary electrophoresis for detection of single-nucleotide differences between fetal and maternal DNA in maternal plasma. Prenat Diagn 2009, 29: 217–222.PubMedCrossRefGoogle Scholar
  26. [26]
    Burghy CA, Stodola DE, Ruttle PL, Molloy EK, Armstrong JM, Oler JA, et al. Developmental pathways to amygdala-prefrontal function and internalizing symptoms in adolescence. Nat Neurosci 2012, 15: 1736–1741.PubMedCrossRefGoogle Scholar
  27. [27]
    Roy AK, Shehzad Z, Margulies DS, Kelly AM, Uddin LQ, Gotimer K, et al. Functional connectivity of the human amygdala using resting state fMRI. Neuroimage 2009, 45: 614–626.PubMedCrossRefGoogle Scholar
  28. [28]
    Chai XJ, Castanon AN, Ongur D, Whitfield-Gabrieli S. Anticorrelations in resting state networks without global signal regression. Neuroimage 2012, 59: 1420–1428.PubMedCrossRefGoogle Scholar
  29. [29]
    Amunts K, Kedo O, Kindler M, Pieperhoff P, Mohlberg H, Shah NJ, et al. Cytoarchitectonic mapping of the human amygdala, hippocampal region and entorhinal cortex: intersubject variability and probability maps. Anat Embryol (Berl) 2005, 210: 343–352.CrossRefGoogle Scholar
  30. [30]
    Wei SM, Eisenberg DP, Kohn PD, Kippenhan JS, Kolachana BS, Weinberger DR, et al. Brain-derived neurotrophic factor Val66Met polymorphism affects resting regional cerebral blood flow and functional connectivity differentially in women versus men. J Neurosci 2012, 32: 7074–7081.PubMedCrossRefGoogle Scholar
  31. [31]
    Petrides M, Pandya DN. Efferent association pathways from the rostral prefrontal cortex in the macaque monkey. J Neurosci 2007, 27: 11573–11586.PubMedCrossRefGoogle Scholar
  32. [32]
    Kier EL, Staib LH, Davis LM, Bronen RA. MR imaging of the temporal stem: anatomic dissection tractography of the uncinate fasciculus, inferior occipitofrontal fasciculus, and Meyer’s loop of the optic radiation. AJNR Am J Neuroradiol 2004, 25: 677–691.PubMedGoogle Scholar
  33. [33]
    Hoefgen B, Schulze TG, Ohlraun S, von Widdern O, Hofels S, Gross M, et al. The power of sample size and homogenous sampling: association between the 5-HTTLPR serotonin transporter polymorphism and major depressive disorder. Biol Psychiatry 2005, 57: 247–251.PubMedCrossRefGoogle Scholar
  34. [34]
    Kiyohara C, Yoshimasu K. Association between major depressive disorder and a functional polymorphism of the 5-hydroxytryptamine (serotonin) transporter gene: a metaanalysis. Psychiatr Genet 2010, 20: 49–58.PubMedCrossRefGoogle Scholar
  35. [35]
    Smeraldi E, Zanardi R, Benedetti F, Di Bella D, Perez J, Catalano M. Polymorphism within the promoter of the serotonin transporter gene and antidepressant efficacy of fluvoxamine. Mol Psychiatry 1998, 3: 508–511.PubMedCrossRefGoogle Scholar
  36. [36]
    Goldman N, Glei DA, Lin YH, Weinstein M. The serotonin transporter polymorphism (5-HTTLPR): allelic variation and links with depressive symptoms. Depress Anxiety 2010, 27: 260–269.PubMedCrossRefGoogle Scholar
  37. [37]
    Ochsner KN, Bunge SA, Gross JJ, Gabrieli JD. Rethinking feelings: an FMRI study of the cognitive regulation of emotion. J Cogn Neurosci 2002, 14: 1215–1229.PubMedCrossRefGoogle Scholar
  38. [38]
    McRae K, Hughes B, Chopra S, Gabrieli JD, Gross JJ, Ochsner KN. The neural bases of distraction and reappraisal. J Cogn Neurosci 2010, 22: 248–262.PubMedCrossRefGoogle Scholar
  39. [39]
    Ohira H, Nomura M, Ichikawa N, Isowa T, Iidaka T, Sato A, et al. Association of neural and physiological responses during voluntary emotion suppression. Neuroimage 2006, 29: 721–733.PubMedCrossRefGoogle Scholar
  40. [40]
    Blair KS, Smith BW, Mitchell DG, Morton J, Vythilingam M, Pessoa L, et al. Modulation of emotion by cognition and cognition by emotion. Neuroimage 2007, 35: 430–440.PubMedCrossRefGoogle Scholar
  41. [41]
    Ramnani N, Owen AM. Anterior prefrontal cortex: insights into function from anatomy and neuroimaging. Nat Rev Neurosci 2004, 5: 184–194.PubMedCrossRefGoogle Scholar
  42. [42]
    Christoff K, Gabrieli JDE. The frontopolar cortex and human cognition: Evidence for a rostrocaudal hierarchical organization within the human prefrontal cortex. Psychobiology 2000, 28: 168–186.Google Scholar
  43. [43]
    Sakaki M, Niki K, Mather M. Updating existing emotional memories involves the frontopolar/orbito-frontal cortex in ways that acquiring new emotional memories does not. J Cogn Neurosci 2011, 23: 3498–3514.PubMedCrossRefGoogle Scholar
  44. [44]
    Banks SJ, Eddy KT, Angstadt M, Nathan PJ, Phan KL. Amygdala-frontal connectivity during emotion regulation. Soc Cogn Affect Neurosci 2007, 2: 303–312.PubMedCrossRefGoogle Scholar
  45. [45]
    Hariri AR, Mattay VS, Tessitore A, Kolachana B, Fera F, Goldman D, et al. Serotonin transporter genetic variation and the response of the human amygdala. Science 2002, 297: 400–403.PubMedCrossRefGoogle Scholar
  46. [46]
    Hariri AR, Drabant EM, Munoz KE, Kolachana BS, Mattay VS, Egan MF, et al. A susceptibility gene for affective disorders and the response of the human amygdala. Arch Gen Psychiatry 2005, 62: 146–152.PubMedCrossRefGoogle Scholar
  47. [47]
    Murphy SE, Norbury R, Godlewska BR, Cowen PJ, Mannie ZM, Harmer CJ, et al. The effect of the serotonin transporter polymorphism (5-HTTLPR) on amygdala function: a metaanalysis. Mol Psychiatry 2012. doi: 10.1038/mp.2012.19.Google Scholar
  48. [48]
    von dem Hagen EA, Passamonti L, Nutland S, Sambrook J, Calder AJ. The serotonin transporter gene polymorphism and the effect of baseline on amygdala response to emotional faces. Neuropsychologia 2011, 49: 674–680.CrossRefGoogle Scholar
  49. [49]
    Li S, Zou Q, Li J, Li J, Wang D, Yan C, et al. 5-HTTLPR polymorphism impacts task-evoked and resting-state activities of the amygdala in Han Chinese. PLoS One 2012, 7: e36513.PubMedCrossRefGoogle Scholar
  50. [50]
    Phan KL, Orlichenko A, Boyd E, Angstadt M, Coccaro EF, Liberzon I, et al. Preliminary evidence of white matter abnormality in the uncinate fasciculus in generalized social anxiety disorder. Biol Psychiatry 2009, 66: 691–694.PubMedCrossRefGoogle Scholar
  51. [51]
    Taylor WD, MacFall JR, Gerig G, Krishnan RR. Structural integrity of the uncinate fasciculus in geriatric depression: Relationship with age of onset. Neuropsychiatr Dis Treat 2007, 3: 669–674.PubMedGoogle Scholar
  52. [52]
    Glenn AL. The other allele: exploring the long allele of the serotonin transporter gene as a potential risk factor for psychopathy: a review of the parallels in findings. Neurosci Biobehav Rev 2011, 35: 612–620.PubMedCrossRefGoogle Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS and Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Haixia Long
    • 1
  • Bing Liu
    • 1
  • Bing Hou
    • 1
  • Chao Wang
    • 2
  • Jin Li
    • 1
  • Wen Qin
    • 3
  • Dawei Wang
    • 3
  • Yuan Zhou
    • 4
  • Keith M. Kendrick
    • 2
  • Chunshui Yu
    • 3
  • Tianzi Jiang
    • 1
    • 2
    • 5
  1. 1.LIAMA Center for Computational Medicine, National Laboratory of Pattern Recognition, Institute of AutomationChinese Academy of SciencesBeijingChina
  2. 2.Key Laboratory for NeuroInformation of the Ministry of Education, School of Life Science and TechnologyUniversity of Electronic Science and Technology of ChinaChengduChina
  3. 3.Department of RadiologyTianjin Medical University General HospitalTianjinChina
  4. 4.Key Laboratory of Behavioral Science, Institute of PsychologyChinese Academy of SciencesBeijingChina
  5. 5.Queensland Brain InstituteUniversity of QueenslandBrisbaneAustralia

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