Eva Loth1, Jean-Baptiste Poline2, Benjamin Thyreau2, Tianye Jia3, Chenyang Tao4, Anbarasu Lourdusamy3, David Stacey3, Anna Cattrell3, Sylvane Desrivières3, Barbara Ruggeri3, Virgile Fritsch2, Tobias Banaschewski5, Gareth J Barker6, Arun L W Bokde7, Christian Büchel8, Fabiana M Carvalho3, Patricia J Conrod9, Mira Fauth-Buehler5, Herta Flor5, Jürgen Gallinat10, Hugh Garavan11, Andreas Heinz10, Ruediger Bruehl12, Claire Lawrence13, Karl Mann14, Jean-Luc Martinot15, Frauke Nees5, Tomáš Paus16, Zdenka Pausova17, Luise Poustka5, Marcella Rietschel5, Michael Smolka5, Maren Struve18, Jianfeng Feng19, Gunter Schumann6. 1. Institute of Psychiatry, King's College London; MRC Social, Genetic and Developmental Psychiatry Centre, London. Electronic address: eva.loth@kcl.ac.uk. 2. Neurospin, Commissariat à l'Energie Atomique, CEA-Saclay Center. 3. Institute of Psychiatry, King's College London; MRC Social, Genetic and Developmental Psychiatry Centre, London. 4. Center for Computational Systems Biology, School of Mathematical Science, Fudan University, Shanghai, China. 5. Central Institute of Mental Health, University of Mannheim. 6. Institute of Psychiatry, King's College London. 7. Institute of Neuroscience , Trinity College, Dublin, Ireland. 8. University Medical Centre Hamburg-Eppendorf, Hamburg. 9. Institute of Psychiatry, King's College London; Department of Psychiatry , Université de Montreal, CHU St Justine Hosptial. 10. Department of Psychiatry and Psychotherapy, Charité-Universitätsmedizin Berlin. 11. Institute of Neuroscience , Trinity College, Dublin, Ireland; Departments of Psychiatry and Psychology, University of Vermont, Burlington, Vermont. 12. Physikalisch-Technische Bundesanstalt, Braunschweig und Berlin. 13. School of Psychology, University of Nottingham, Nottingham, United Kingdom. 14. Central Institute of Mental Health, Medical Faculty Mannheim/Heidelberg University, Department of Addictive Behaviour and Addiction Medicine, Mannheim. 15. Institut National de la Santé et de la Recherche Médicale, INSERM CEA Unit 1000 "Imaging and Psychiatry," University Paris Sud, Orsay, and AP-HP Department of Adolescent Psychopathology and Medicine, Maison de Solenn, University Paris Descartes, Paris, France. 16. School of Psychology, University of Nottingham, Nottingham, United Kingdom; The Rotman Research Institute, Baycrest; Montreal Neurological Institute, McGill University, Montreal. 17. The Hospital for Sick Children, University of Toronto, Toronto, Canada. 18. Department of Psychiatry and Psychotherapy; Neuroimaging Center, Department of Psychology, Technische Universität Dresden, Dresden, Germany. 19. Department of Computer Science, University of Warwick, Coventry, United Kingdom.
Abstract
BACKGROUND: Common variants in the oxytocin receptor gene (OXTR) have been shown to influence social and affective behavior and to moderate the effect of adverse experiences on risk for social-affective problems. However, the intermediate neurobiological mechanisms are not fully understood. Although human functional neuroimaging studies have reported that oxytocin effects on social behavior and emotional states are mediated by amygdala function, animal models indicate that oxytocin receptors in the ventral striatum (VS) modulate sensitivity to social reinforcers. This study aimed to comprehensively investigate OXTR-dependent brain mechanisms associated with social-affective problems. METHODS: In a sample of 1445 adolescents we tested the effect of 23-tagging single nucleotide polymorphisms across the OXTR region and stressful life events (SLEs) on functional magnetic resonance imaging blood oxygen level-dependent activity in the VS and amygdala to animated angry faces. Single nucleotide polymorphisms for which gene-wide significant effects on brain function were found were then carried forward to examine associations with social-affective problems. RESULTS: A gene-wide significant effect of rs237915 showed that adolescents with minor CC-genotype had significantly lower VS activity than CT/TT-carriers. Significant or nominally significant gene × environment effects on emotional problems (in girls) and peer problems (in boys) revealed a strong increase in clinical symptoms as a function of SLEs in CT/TT-carriers but not CC-homozygotes. However, in low-SLE environments, CC-homozygotes had more emotional problems (girls) and peer problems (boys). Moreover, among CC-homozygotes, reduced VS activity was related to more peer problems. CONCLUSIONS: These findings suggest that a common OXTR-variant affects brain responsiveness to negative social cues and that in "risk-carriers" reduced sensitivity is simultaneously associated with more social-affective problems in "favorable environments" and greater resilience against stressful experiences.
BACKGROUND: Common variants in the oxytocin receptor gene (OXTR) have been shown to influence social and affective behavior and to moderate the effect of adverse experiences on risk for social-affective problems. However, the intermediate neurobiological mechanisms are not fully understood. Although human functional neuroimaging studies have reported that oxytocin effects on social behavior and emotional states are mediated by amygdala function, animal models indicate that oxytocin receptors in the ventral striatum (VS) modulate sensitivity to social reinforcers. This study aimed to comprehensively investigate OXTR-dependent brain mechanisms associated with social-affective problems. METHODS: In a sample of 1445 adolescents we tested the effect of 23-tagging single nucleotide polymorphisms across the OXTR region and stressful life events (SLEs) on functional magnetic resonance imaging blood oxygen level-dependent activity in the VS and amygdala to animated angry faces. Single nucleotide polymorphisms for which gene-wide significant effects on brain function were found were then carried forward to examine associations with social-affective problems. RESULTS: A gene-wide significant effect of rs237915 showed that adolescents with minor CC-genotype had significantly lower VS activity than CT/TT-carriers. Significant or nominally significant gene × environment effects on emotional problems (in girls) and peer problems (in boys) revealed a strong increase in clinical symptoms as a function of SLEs in CT/TT-carriers but not CC-homozygotes. However, in low-SLE environments, CC-homozygotes had more emotional problems (girls) and peer problems (boys). Moreover, among CC-homozygotes, reduced VS activity was related to more peer problems. CONCLUSIONS: These findings suggest that a common OXTR-variant affects brain responsiveness to negative social cues and that in "risk-carriers" reduced sensitivity is simultaneously associated with more social-affective problems in "favorable environments" and greater resilience against stressful experiences.
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