A common variant in OXTR rs53576 impacts topological patterns of brain functional networks

Abstract

A common variant (rs53576, G/A) in the oxytocin receptor (OXTR) gene is associated with individual differences in social behavior and may increase the risk for neuropsychiatric disorders characterized by social impairment, especially autism. Although recent functional magnetic resonance imaging (fMRI) studies have identified functional connectivity alteration in some brain regions in risk A allele carriers, it is currently unknown whether this dysfunctional connectivity causes disruption of the topological properties of brain functional networks. We applied a graph-theoretical analysis to investigate the topological properties of brain networks derived from resting-state fMRI in relation to AA homozygotes versus G allele carriers in 290 cognitive normal young adults. We found both AA homozygotes and G allele carriers demonstrated small-world properties; however, male AA homozygotes showed lower normalized clustering coefficient, small-worldness, and local efficiency compared with male G allele carriers, no differences survived after Bonferroni correction; and the inter-group differences of all three metrics exhibited an allele-load-dependent trend (AA < AG < GG), indicating a randomization shift of their brain functional networks. No significant results were observed in any global measures in female AA homozygotes as compared to female G allele carriers. Our results suggested that the topological patterns of brain functional networks were altered in OXTR rs53576 male homozygotes for the risk A allele compared with male G allele carriers, providing evidence for the disruption of integrity in large-scale intrinsic brain networks in a sex-dimorphic manner.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2
Fig. 3

References

  1. 1.

    Feldman R, Monakhov M, Pratt M, Ebstein RP (2016) Oxytocin pathway genes: evolutionary ancient system impacting on human affiliation, sociality, and psychopathology. Biol Psychiatry 79:174–184

    CAS  PubMed  Google Scholar 

  2. 2.

    Guastella AJ, Hickie IB (2016) Oxytocin treatment, circuitry, and autism: a critical review of the literature placing oxytocin into the autism context. Biol Psychiatry 79:234–242

    CAS  PubMed  Google Scholar 

  3. 3.

    Gimpl G, Fahrenholz F (2001) The oxytocin receptor system: structure, function, and regulation. Physiol Rev 81:629–683

    CAS  PubMed  Google Scholar 

  4. 4.

    Haram M, Tesli M, Bettella F, Djurovic S, Andreassen OA et al (2015) Association between genetic variation in the oxytocin receptor gene and emotional withdrawal, but not between oxytocin pathway genes and diagnosis in psychotic disorders. Front Hum Neurosci 9:9

    PubMed  PubMed Central  Google Scholar 

  5. 5.

    Bakermans-Kranenburg MJ, van Ijzendoorn MH (2008) Oxytocin receptor (OXTR) and serotonin transporter (5-HTT) genes associated with observed parenting. Soc Cogn Affect Neurosci 3:128–134

    PubMed  PubMed Central  Google Scholar 

  6. 6.

    Rodrigues SM, Saslow LR, Garcia N, John OP, Keltner D (2009) Oxytocin receptor genetic variation relates to empathy and stress reactivity in humans. Proc Natl Acad Sci USA 106:21437–21441

    CAS  PubMed  Google Scholar 

  7. 7.

    Kim HS, Sherman DK, Sasaki JY, Xu J, Chu TQ et al (2010) Culture, distress, and oxytocin receptor polymorphism (OXTR) interact to influence emotional support seeking. Proc Natl Acad Sci USA 107:15717–15721

    CAS  PubMed  Google Scholar 

  8. 8.

    Lucht MJ, Barnow S, Sonnenfeld C, Rosenberger A, Grabe HJ et al (2009) Associations between the oxytocin receptor gene (OXTR) and affect, loneliness and intelligence in normal subjects. Prog Neuropsychopharmacol Biol Psychiatry 33:860–866

    CAS  PubMed  Google Scholar 

  9. 9.

    Chen FS, Johnson SC (2012) An oxytocin receptor gene variant predicts attachment anxiety in females and autism-spectrum traits in males. Soc Psychol Personal Sci 3:93–99

    Google Scholar 

  10. 10.

    Wu N, Li Z, Su Y (2012) The association between oxytocin receptor gene polymorphism (OXTR) and trait empathy. J Affect Disord 138:468–472

    CAS  PubMed  Google Scholar 

  11. 11.

    Tost H, Kolachana B, Hakimi S, Lemaitre H, Verchinski BA et al (2010) A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function. Proc Natl Acad Sci USA 107:13936–13941

    CAS  PubMed  Google Scholar 

  12. 12.

    Saphire-Bernstein S, Way BM, Kim HS, Sherman DK, Taylor SE (2011) Oxytocin receptor gene (OXTR) is related to psychological resources. Proc Natl Acad Sci USA 108:15118–15122

    CAS  PubMed  Google Scholar 

  13. 13.

    Wu S, Jia M, Ruan Y, Liu J, Guo Y et al (2005) Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population. Biol Psychiatry 58:74–77

    CAS  PubMed  Google Scholar 

  14. 14.

    Wang J, Qin W, Liu B, Wang D, Zhang Y et al (2013) Variant in OXTR gene and functional connectivity of the hypothalamus in normal subjects. Neuroimage 81:199–204

    CAS  PubMed  Google Scholar 

  15. 15.

    Wang J, Qin W, Liu B, Zhou Y, Wang D et al (2014) Neural mechanisms of oxytocin receptor gene mediating anxiety-related temperament. Brain Struct Funct 219:1543–1554

    CAS  PubMed  Google Scholar 

  16. 16.

    Drakesmith M, Caeyenberghs K, Dutt A, Lewis G, David AS et al (2015) Overcoming the effects of false positives and threshold bias in graph theoretical analyses of neuroimaging data. Neuroimage 118:313–333

    CAS  PubMed  PubMed Central  Google Scholar 

  17. 17.

    Colon-Perez LM, Couret M, Triplett W, Price CC, Mareci TH (2016) Small worldness in dense and weighted connectomes. Front Phys. https://doi.org/10.3389/fphy.2016.00014

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Huang H, Shu N, Mishra V, Jeon T, Chalak L et al (2015) Development of human brain structural networks through infancy and childhood. Cereb Cortex 25:1389–1404

    Google Scholar 

  19. 19.

    Baron-Cohen S, Knickmeyer RC, Belmonte MK (2005) Sex differences in the brain: implications for explaining autism. Science 310:819–823

    CAS  Google Scholar 

  20. 20.

    Achard S, Bullmore E (2007) Efficiency and cost of economical brain functional networks. PLoS Comput Biol 3:e17

    PubMed  PubMed Central  Google Scholar 

  21. 21.

    Fox MD, Zhang D, Snyder AZ, Raichle ME (2009) The global signal and observed anticorrelated resting state brain networks. J Neurophysiol 101:3270–3283

    PubMed  PubMed Central  Google Scholar 

  22. 22.

    Liu F, Guo W, Fouche JP, Wang Y, Wang W et al (2015) Multivariate classification of social anxiety disorder using whole brain functional connectivity. Brain Struct Funct 220:101–115

    CAS  PubMed  Google Scholar 

  23. 23.

    Lei D, Li K, Li L, Chen F, Huang X et al (2015) Disrupted functional brain connectome in patients with posttraumatic stress disorder. Radiology 276:818–827

    PubMed  Google Scholar 

  24. 24.

    Suo X, Lei D, Li K, Chen F, Li F et al (2015) Disrupted brain network topology in pediatric posttraumatic stress disorder: a resting-state fMRI study. Hum Brain Mapp 36:3677–3686

    PubMed  PubMed Central  Google Scholar 

  25. 25.

    van den Heuvel MP, de Lange SC, Zalesky A, Seguin C, Yeo BTT et al (2017) Proportional thresholding in resting-state fMRI functional connectivity networks and consequences for patient-control connectome studies: issues and recommendations. Neuroimage 152:437–449

    PubMed  Google Scholar 

  26. 26.

    Grabow C, Grosskinsky S, Kurths J, Timme M (2015) Collective relaxation dynamics of small-world networks. Phys Rev E Stat Nonlin Soft Matter Phys 91:052815

    PubMed  Google Scholar 

  27. 27.

    Rubinov M, Sporns O (2010) Complex network measures of brain connectivity: uses and interpretations. Neuroimage 52:1059–1069

    Google Scholar 

  28. 28.

    Zhang J, Wang J, Wu Q, Kuang W, Huang X et al (2011) Disrupted brain connectivity networks in drug-naive, first-episode major depressive disorder. Biol Psychiatry 70:334–342

    PubMed  Google Scholar 

  29. 29.

    Murphy K, Birn RM, Handwerker DA, Jones TB, Bandettini PA (2009) The impact of global signal regression on resting state correlations: are anti-correlated networks introduced? Neuroimage 44:893–905

    PubMed  Google Scholar 

  30. 30.

    Fornito A, Zalesky A, Bullmore ET (2010) Network scaling effects in graph analytic studies of human resting-state FMRI data. Front Syst Neurosci 4:22

    PubMed  PubMed Central  Google Scholar 

  31. 31.

    Zalesky A, Fornito A, Harding IH, Cocchi L, Yucel M et al (2010) Whole-brain anatomical networks: does the choice of nodes matter? Neuroimage 50:970–983

    PubMed  Google Scholar 

  32. 32.

    Yao Z, Hu B, Xie Y, Moore P, Zheng J (2015) A review of structural and functional brain networks: small world and atlas. Brain Inform 2:45–52

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Achard S, Salvador R, Whitcher B, Suckling J, Bullmore E (2006) A resilient, low-frequency, small-world human brain functional network with highly connected association cortical hubs. J Neurosci 26:63–72

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Bassett DS, Meyer-Lindenberg A, Achard S, Duke T, Bullmore E (2006) Adaptive reconfiguration of fractal small-world human brain functional networks. Proc Natl Acad Sci USA 103:19518–19523

    CAS  PubMed  Google Scholar 

  35. 35.

    Sporns O (2013) Network attributes for segregation and integration in the human brain. Curr Opin Neurobiol 23:162–171

    CAS  Google Scholar 

  36. 36.

    Alexander-Bloch AF, Gogtay N, Meunier D, Birn R, Clasen L et al (2010) Disrupted modularity and local connectivity of brain functional networks in childhood-onset schizophrenia. Front Syst Neurosci 4:147

    PubMed  PubMed Central  Google Scholar 

  37. 37.

    Caeyenberghs K, Taymans T, Wilson PH, Vanderstraeten G, Hosseini H et al (2016) Neural signature of developmental coordination disorder in the structural connectome independent of comorbid autism. Dev Sci 19:599–612

    PubMed  Google Scholar 

  38. 38.

    Liu F, Zhuo C, Yu C (2016) Altered cerebral blood flow covariance network in schizophrenia. Front Neurosci 10:308

    PubMed  PubMed Central  Google Scholar 

  39. 39.

    Lo CY, Wang PN, Chou KH, Wang J, He Y et al (2010) Diffusion tensor tractography reveals abnormal topological organization in structural cortical networks in Alzheimer's disease. J Neurosci 30:16876–16885

    CAS  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Wang Z, Yuan Y, Bai F, You J, Zhang Z (2016) Altered topological patterns of brain networks in remitted late-onset depression: a resting-state fMRI study. J Clin Psychiatry 77:123–130

    PubMed  Google Scholar 

  41. 41.

    Barttfeld P, Wicker B, Cukier S, Navarta S, Lew S et al (2011) A big-world network in ASD: dynamical connectivity analysis reflects a deficit in long-range connections and an excess of short-range connections. Neuropsychologia 49:254–263

    PubMed  Google Scholar 

  42. 42.

    Peters JM, Taquet M, Vega C, Jeste SS, Fernandez IS et al (2013) Brain functional networks in syndromic and non-syndromic autism: a graph theoretical study of EEG connectivity. BMC Med 11:54

    PubMed  PubMed Central  Google Scholar 

  43. 43.

    Rudie JD, Brown JA, Beck-Pancer D, Hernandez LM, Dennis EL et al (2012) Altered functional and structural brain network organization in autism. Neuroimage Clin 2:79–94

    CAS  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Zeng K, Kang J, Ouyang G, Li J, Han J et al (2017) Disrupted brain network in children with autism spectrum disorder. Sci Rep 7:16253

    PubMed  PubMed Central  Google Scholar 

  45. 45.

    Carter CS (2007) Sex differences in oxytocin and vasopressin: implications for autism spectrum disorders? Behav Brain Res 176:170–186

    CAS  Google Scholar 

  46. 46.

    de Vries GJ (2008) Sex differences in vasopressin and oxytocin innervation of the brain. Prog Brain Res 170:17–27

    PubMed  Google Scholar 

  47. 47.

    Rilling JK, Demarco AC, Hackett PD, Chen X, Gautam P et al (2014) Sex differences in the neural and behavioral response to intranasal oxytocin and vasopressin during human social interaction. Psychoneuroendocrinology 39:237–248

    CAS  PubMed  Google Scholar 

  48. 48.

    Wang J, Braskie MN, Hafzalla GW, Faskowitz J, McMahon KL et al (2017) Relationship of a common OXTR gene variant to brain structure and default mode network function in healthy humans. Neuroimage 147:500–506

    CAS  PubMed  Google Scholar 

  49. 49.

    Domes G, Lischke A, Berger C, Grossmann A, Hauenstein K et al (2010) Effects of intranasal oxytocin on emotional face processing in women. Psychoneuroendocrinology 35:83–93

    CAS  Google Scholar 

  50. 50.

    Murata T, Murata E, Liu CX, Narita K, Honda K et al (2000) Oxytocin receptor gene expression in rat uterus: regulation by ovarian steroids. J Endocrinol 166:45–52

    CAS  PubMed  Google Scholar 

  51. 51.

    Bakermans-Kranenburg MJ, van Ijzendoorn MH (2014) A sociability gene? Meta-analysis of oxytocin receptor genotype effects in humans. Psychiatr Genet 24:45–51

    CAS  PubMed  Google Scholar 

Download references

Funding

This work was supported by the Natural Science Foundation of China (Grant nos. 81871431, 81301201 and 81271551), the Natural Science Foundation of Tianjin Municipal Science and Technology Commission (Grant Nos. 18JCYBJC26300 and 18JCQNJC10900) and 2017 "New Century" Talent Training Project of Tianjin Medical University General Hospital.

Author information

Affiliations

Authors

Contributions

Guarantors of integrity of the entire study: JW and FL; study concepts/study design or data acquisition or data analysis/ interpretation: all authors; manuscript drafting for important intellectual content: all authors; approval of final version of submitted manuscript: all authors; literature research, JW, YZ, ZY, DZ, FL, and WQ; clinical studies, JZ and BL; experimental studies, WQ, JZ, and BL; statistical analysis, JW, YZ, ZY, DZ, FL, and WQ.

Corresponding authors

Correspondence to Junping Wang or Feng Liu.

Ethics declarations

Conflict of interest

All the authors declare that they have no competing interests.

Ethical approval

All procedures performed in our studies involving 324 healthy young adults were in accordance with the ethical standards of Tianjin Medical University General Hospital and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. After a complete description of our study, written informed consent was obtained from all participants.

Availability of data and material

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 2163 kb)

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wang, J., Zhang, Y., Zhu, D. et al. A common variant in OXTR rs53576 impacts topological patterns of brain functional networks. Eur Child Adolesc Psychiatry 29, 993–1002 (2020). https://doi.org/10.1007/s00787-019-01414-5

Download citation

Keywords

  • Oxytocin receptor gene
  • Resting-state functional magnetic resonance imaging
  • Small-world network
  • Graph-theoretical analysis