Association of Genetic Variation in the Promoter Region of OXTR with Differences in Social Affective Neural Processing

Garret O’Connell, Heather C. Whalley, Prerona Mukherjee, Andrew C. Stanfield, Christian Montag, Jeremy Hall, Martin Reuter

Center for Economics and Neuroscience, University of Bonn, Bonn, Germany.
Department of Psychology, University of Bonn, Bonn, Germany.
Division of Psychiatry, University of Edinburgh, Scotland, UK.

DOI: 10.4236/jbbs.2012.21007                

Abstract

Evidence supports the involvement of oxytocin in social behavior. The oxytocin receptor gene (OXTR) has been associated with differences in social brain function and risk for autism. Motivated by recent work, we investigated the effect of variation in the common functional rs2268498 T/C polymorphism in the promoter region of OXTR on neural responses to fear expressions. 46 healthy subjects were divided into genotype groups of C carriers (n = 32) and TT ho-mozygous (n = 14) and neural activity was measured during the recognition of fear and neutral expressions. Results showed that during the recognition of fear expressions, the TT genotype group exhibited increased responding in the inferior occipital gyrus, considered important for face processing, compared to carriers of the C allele (P < 0.005; cluster corrected for whole brain), an effect not found for neutral faces. These results indicate the impact of this OXTR genetic variant on individual differences in social affective neural processing.

Keywords

OXTR; Promoter Region; Inferior Occipital Gyrus; fMRI; Emotional Facial Processing

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	T. Insel and L. Shapiro, “Oxytocin Receptor Distribution Reflects Social Organization in Monogamous and Polygamous Voles,” Proceedings of the National Academy of Sciences USA, Vol. 89, No. 13, 1992, pp. 5981-5985. doi:10.1073/pnas.89.13.5981
[2]	L. J. Young and Z. Wang, “The Neurobiology of Pair Bonding,” Nature Neuroscience, Vol. 7, No. 10, 2004, pp. 1048-1054. doi:10.1038/nn1327
[3]	R. Landgraf and I. D. Neumann, “Vasopressin and Oxytocin Release within the Brain: A Dynamic Concept of Multiple and Variable Modes of Neuropeptide Communication,” Frontiers in Neuroendocrinology, Vol. 25, No. 3-4, 2004, pp. 150-176. doi:10.1016/j.yfrne.2004.05.001
[4]	M. Kosfeld, M. Heinrichs, P. J. Zak, U. Fischbacher and E. Fehr, “Oxytocin Increases Trust in Humans,” Nature, Vol. 435, No. 7042, 2005, pp. 673-676. doi:10.1038/nature03701
[5]	P. Zak, A. A. Stanton and S. Ahmadi, “Oxytocin Increases Generosity in Humans,” PLoS ONE, Vol. 2, No. 11, 2007, pp. e1128. doi:10.1371/journal.pone.0001128
[6]	T. Baumgartner, M. Heinrichs, A. Vonlanthen, U. Fischbacher and E. Fehr, “Oxytocin Shapes the Neural Circuitry of Trust and Trust Adaptation in Humans,” Neuron, Vol. 58, No. 4, 2008, pp. 639-650. doi:10.1016/j.neuron.2008.04.009
[7]	S. G. Shamay-Tsoory, et al., “Intranasal Administration of Oxytocin Increases Envy and Schadenfreude (Gloating),” Biological Psychiatry, Vol. 66, No. 9, 2009, pp. 864-870. doi:10.1016/j.biopsych.2009.06.009
[8]	A. H. Kemp and A. J. Guastella, “Oxytocin: Prosocial Behavior, Social Salience, or Approach-Related Behavior?” Biological Psychiatry, Vol. 67, No. 6, 2010, pp. e33-34. doi:10.1016/j.biopsych.2009.11.019
[9]	J. A. Bartz, et al., “Oxytocin Selectively Improves Empathic Accuracy,” Psychological Science, Vol. 21, No. 10, 2010, pp. 1426-1428. doi:10.1177/0956797610383439
[10]	G. Domes, M. Heinrichs, A. Michel, C. Berger and S. Herpertz, “Oxytocin Improves “Mind-Reading” in Humans,” Biological Psychiatry, Vol. 61 No. 6, 2007b, pp. 731-733. doi:10.1016/j.biopsych.2006.07.015
[11]	A. Guastella, P. Mitchell and M. Dadds, “Oxytocin Increases Gaze to the Eye Region of Human Faces,” Biological Psychiatry, Vol. 63, No. 1, 2008, pp. 3-5. doi:10.1016/j.biopsych.2007.06.026
[12]	A. J. Guastella, et al., “Intranasal Oxytocin Improves Emotion Recognition for Youth with Autism Spectrum Disorders,” Biological Psychiatry, Vol. 67, No. 7, 2010, pp. 692-694. doi:10.1016/j.biopsych.2009.09.020
[13]	E. Hollander, et al., “Oxytocin Increases Retention of Social Cognition in Autism,” Biological Psychiatry, Vol. 61, No. 4, 2007, pp. 498-503. doi:10.1016/j.biopsych.2006.05.030
[14]	J. Green and E. Hollander, “Autism and Oxytocin: New Developments in Translational Approaches to Therapeutics,” Neurotherapeutics, Vol. 7, No. 3, 2010, pp. 250-257. doi:10.1016/j.nurt.2010.05.006
[15]	Y. Chen, A. Ehlers, D. Clark and W. Mansell, “Patients with Generalized Social Phobia Direct Their Attention Away from Faces,” Behaviour Research Therapy, Vol. 40, No. 6, 2002, pp. 677-687. doi:10.1016/S0005-7967(01)00086-9
[16]	J. C. Rohner, “The Time-Course of Visual Threat Processing: High Trait Anxious Individuals Eventually Avert Their Gaze from Angry Faces,” Cognition & Emotion, Vol. 16, No. 6, 2002, pp. 837-844. doi:10.1080/02699930143000572
[17]	S. Evans, S. S. Shergill and B. B. Averbeck, “Oxytocin Decreases Aversion to Angry Faces in an Associative Learning Task,” Neuropsychopharmacology, Vol. 35, No. 13, 2010, pp. 2502-2509. doi:10.1038/npp.2010.123
[18]	I. Labuschagne, et al., “Oxytocin Attenuates Amygdala Reactivity to Fear in Generalized Social Anxiety Disorder,” Neuropsychopharmacology, Vol. 35, No. 12, 2010, pp. 2403-2413. doi:10.1016/j.biopsych.2007.06.026
[19]	A. Guastella, P. Mitchell and M. Dadds, “Oxytocin Increases Gaze to the Eye Region of Human Faces,” Biological Psychiatry, Vol. 63, No. 1, 2008, pp. 3-5. doi:10.1016/j.biopsych.2007.06.026
[20]	K. M. Dalton, et al., “Gaze Fixation and the Neural Circuitry of Face Processing in Autism,” Nature Neuroscience, Vol. 8, No.4, 2005, pp. 519-526. doi:10.1038/nn1421
[21]	E. Andari, et al., “Promoting Social Behavior with Oxytocin in High-Functioning Autism Spectrum Disorders,” Proceedings of the National Academy of Sciences USA, Vol. 107, No. 9, 2010, pp. 4389-4394. doi.org/10.1073/pnas.0910249107
[22]	M. Fischer-Shofty, S. G. Shamay-Tsoory, H. Harari and Y. Levkovitz, “The Effect of Intranasal Administration of Oxytocin on Fear Recognition,” Neuropsychologia, Vol. 48, No. 1, 2010, pp. 179-184. doi:10.1016/j.neuropsychologia.2009.09.003
[23]	E. Savaskan, R. Ehrhardt, A. Schulz, M. Walter and H. Schachinger, “Post-Learning Intranasal Oxytocin Modulates Human Memory for Facial Identity,” Psychoneuroendocrinology, Vol. 33, No. 3, 2008, pp. 368-374. doi:10.1016/j.psyneuen.2007.12.004
[24]	P. Kirsch, et al., “Oxytocin Modulates Neural Circuitry for Social Cognition and Fear in Humans,” Journal of Neuroscience, Vol. 25, No.49, 2005, pp. 11489-11493. doi:10.1523/JNEUROSCI.3984-05.2005
[25]	D. Huber, P. Veinante and R. Stoop, “Vasopressin and Oxytocin Excite Distinct Neuronal Populations in the Central Amygdala,” Science, Vol. 308, No. 5719, 2005, pp. 245–248. doi:10.1126/science.1105636
[26]	R. Adolphs and M. Spezio, “Role of the Amygdala in Processing Visual Social Stimuli,” Progress in Brain Research, Vol. 156, 2006, pp. 363-378. doi:10.1016/S0079-6123(06)56020-0
[27]	J. Haxby, E. Hoffman and M. Gobbini, “Human Neural Systems for Face Recognition and Social Communication,” Biological Psychiatry, Vol. 51, No. 1, 2002, pp. 59-67. doi:10.1016/S0006-3223(01)01330-0
[28]	P. Vuilleumier and G. Pourtois, “Distributed and Interactive Brain Mechanisms during Emotion Face Perception: Evidence from Functional Neuroimaging,” Neuropsychologia, No. 45 No. 1, 2007, pp. 174-194. doi:10.1016/j.neuropsychologia.2006.06.003
[29]	J. S. Morris, et al., “A Neuromodulatory Role for the Human Amygdala in Processing Emotional Facial Expressions,” Brain Cognition, Vol. 121 No. Pt 1, 1998, pp. 47-57. doi: 10.1093/brain/121.1.47
[30]	G. Domes, M. Heinrichs, J. Gl?scher, C. Büchel, D. Braus and S. Herpertz, “Oxytocin Attenuates Amygdala Responses to Emotional Faces Regardless of Valence,” Biological Psychiatry, Vol. 62, No.10, 2007a, pp. 1187-1190. doi:10.1016/j.biopsych.2007.03.025
[31]	P. Petrovic, R. Kalisch, T. Singer and R. J. Dolan, “Oxytocin Attenuates Affective Evaluations of Conditioned Faces and Amygdala Activity,” Journal of Neuroscience, Vol. 28, No. 26, 2008, pp. 6607-6615. doi:10.1523/JNEUROSCI.4572-07.2008
[32]	G. Domes, et al., “Effects of Intranasal Oxytocin on Emotional Face Processing in Women,” Psychoneuroendocrinology, Vol. 35, No. 1, 2010, pp. 83-93. doi:10.1016/j.psyneuen.2009.06.016
[33]	J. A. Bartz, J. Zaki, N. Bolger and K. Ochsner, “Social Effects of Oxytocin in Humans: Context and Person Matter,” Trends in Cognitive Sciences, Vol. 15, No. 7, pp. 301-309. doi: 10.1016/j.tics.2011.05.002
[34]	M. Gamer, B. Zurowski and C. Büchel, “Different Amygdala Subregions Mediate Valence-Related and Attentional Effects of Oxytocin in Humans,” Proceedings of the National Academy of Sciences USA, Vol. 107, No. 2, 2010, pp. 9400-9405. doi:10.1073/pnas.1000985107
[35]	T. Kimura, O. Tanizawa, K. Mori, M. J. Brownstein and H. Okayama, “Structure and Expression of a Human Oxytocin Receptor,” Nature, Vol. 356, No. 6369, 1992, pp. 526–529. doi:10.1038/356526a0
[36]	S. Jacob, C. W. Brune, C. S. Carter, B. L. Leventhal, C. Lord and E. H. Cook Jr., “Association of the Oxytocin Receptor Gene (OXTR) in Caucasian Children and Adolescents with Autism,” Neuroscience Letters, Vol. 417, No. 1, 2007, pp. 6-9. doi:10.1016/j.neulet.2007.02.001
[37]	E. Lerer, S. Levi, S. Salomon, A. Darvasi, N. Yirmiya and R. P. Ebstein, “Association between the Oxytocin Receptor (OXTR) Gene and Autism: Relationship to Vineland Adaptive Behavior Scales and Cognition,” Molecular Psychiatry, Vol. 13, No. 10, 2007, pp. 980-988. doi:10.1038/sj.mp.4002087
[38]	S. Wu, et al., “Positive Association of the Oxytocin Receptor Gene (OXTR) with Autism in the Chinese Han Population,” Biological Psychiatry, Vol. 58, No. 1, 2005, pp. 74-77. doi:10.1016/j.biopsych.2005.03.013
[39]	A. K. Wermter, I. Kamp-Becker, P. Hesse, G. Schulte-K?rne, K. Strauch and H. Remschmidt, “Evidence for the Involvement of Genetic Variation in the Oxytocin Receptor Gene (OXTR) in the Etiology of Autistic Disorders on High-Functioning Level,” American Journal of Medical Genetics Part B: Neuropsychiatric Genetics, Vol. 153B, No. 2, 2009, pp. 629-639. doi:10.1002/ajmg.b.31032
[40]	X. Liu, et al., “Association of the Oxytocin Receptor (OXTR) Gene Polymorphisms with Autism Spectrum Disorder (ASD) in the Japanese Population,” Journal of Human Genetics, Vol. 55, No. 3, 2010, pp. 137-141. doi:10.1038/jhg.2009.140
[41]	C. Yrigollen, et al., “Genes Controlling Affiliative Behavior as Candidate Genes for Autism,” Biological Psychiatry, Vol. 63, No. 10, 2008, pp. 911-916. doi:10.1016/j.biopsych.2007.11.015
[42]	K. E. Tansey, et al., “Oxytocin Receptor (OXTR) Does Not Play a Major Role in the Aetiology of Autism: Genetic and Molecular Studies,” Neuroscience Letters, Vol. 474, No. 3, 2010, pp. 163-167. doi:10.1016/j.neulet.2010.03.035
[43]	S. Israel, et al., “The Oxytocin Receptor (OXTR) Contributes to Prosocial Fund Allocations in the Dictator Game and the Social Value Orientations Task,” PLoS ONE, Vol. 4, No. 5, 2009, p. e5535. doi:10.1371/journal.pone.0005535
[44]	M. J. Bakermans-Kranenburg and M. H. van Ijzendoorn, “Oxytocin Receptor (OXTR) and Serotonin Transporter (5-HTT) Genes Associated with Observed Parenting,” Social Cognitive and Affective Neuroscience, Vol. 3, No. 2, 2008, pp. 128-134. doi:10.1093/scan/nsn004
[45]	S. M. Rodrigues, L. R. Saslow, N. Garcia, O. P. John and D. Keltner, “Oxytocin Receptor Genetic Variation Relates to Empathy and Stress Reactivity in Humans,” Proceedings of the National Academy of Sciences USA, Vol. 106, No. 50, 2009, pp. 21437-21441. doi:10.1073/pnas.0909579106
[46]	H. Tost, et al., “A common Allele in the Oxytocin Receptor Gene (OXTR) Impacts Prosocial Temperament and Human Hypothalamic-Limbic Structure and Function,” Proceedings of the National Academy of Sciences USA, Vol. 107, No. 31, 2010, 13936-13941. doi:10.1073/pnas.1003296107
[47]	H. Inoue, H. Yamasue, M. Tochigi, O. Abe, X. Liu, Y. Kawamura, et al., “Association between the Oxytocin Receptor Gene and Amygdalar Volume in Healthy Adults,” Biological Psychiatry, Vol. 68, No. 11, 2010, pp. 1066-1072. doi:10.1016/j.biopsych.2010.07.019
[48]	D. J. Furman, M. C. Chen and I. H. Gotlib, “Variant in Oxytocin Receptor Gene is Associated with Amygdala Volume,” Psychoneuroendocrinology, Vol. 36, No. 6, 2011, pp. 891-897. doi:10.1016/j.psyneuen.2010.12.004
[49]	C. Montag, C. J. Fiebach, P. Kirsch and M. Reuter, “Interaction of 5-HTTLPR and a Variation on the Oxytocin Receptor Gene Influences Negative Emotionality,” Biological Psychiatry, Vol. 69, No. 6, 2011, pp. 601-603. doi:10.1016/j.biopsych.2010.10.026
[50]	H. E. Nelson, “National Adult Reading Test,” 2nd Edition, NFER-Nelson, Windsor, 1991.
[51]	J. C. Barrett, B. Fry, J. Maller and M. J. Daly, “Haploview: Analysis and Visualization of LD and Haplotype Maps,” Bioinfomatics, Vol. 21, No. 2, 2005, pp. 263-265. doi:10.1093/bioinformatics/bth457
[52]	H. C. Breiter, et al., “Response and Habituation of Human Amygdala during Visual Processing of Facial Expression,” Neuron, Vol. 17, No. 5, 1996, pp. 875-887. doi:10.1016/S0896-6273(00)80219-6
[53]	J. E. LeDoux, “The Emotional Brain,” Simon and Shuster, New York, 1996.
[54]	L. Pessoa, M. McKenna, E. Gutierrez and L. G. Ungerleider, “Neural Processing of Emotional Faces Requires Attention,” Proceedings of the National Academy of Sciences USA, Vol. 99, No. 17, 2002, pp. 11458-11463. doi:10.1073/pnas.172403899
[55]	R. T. Schultz, “Developmental Deficits in Social Perception in Autism: The Role of the Amygdala and Fusiform Face Area,” International Journal of Developmental Neuroscience, Vol. 23, No. 2-3, 2005, pp. 125-141. doi:10.1016/j.ijdevneu.2004.12.012
[56]	K. Pierce, R. A. Müller, A. G. Allen and E. Courchesne, “Face Processing Occurs outside the Fusiform ‘Face Area’ in Autism: Evidence from fMRI,” Brain, Vol. 124, No. 10, 2001, pp. 2059-2037. doi:10.1093/brain/124.10.2059
[57]	F. Champagne, D. Francis, A. Mar and M. Meaney, “Variations in Maternal Care in the Rat as a Mediating Influence for the Effects of Environment on Development,” Physiology & Behavior, Vol. 79, No. 3, 2003, pp. 359-371. doi:10.1016/S0031-9384(03)00149-5
[58]	H. S. Kim, et al., “Culture, Distress, and Oxytocin Receptor Polymorphism (OXTR) Interact to Influence Emotional Support Seeking,” Proceedings of the National Academy of Sciences USA, Vol. 107, No. 36, 2010, pp. 15717-15721. doi:10.1073/pnas.1010830107