Associations between the oxytocin receptor gene (OXTR) and affect, loneliness and intelligence in normal subjects ☆ Michael J. Lucht a, ⁎, Sven Barnow b , Christine Sonnenfeld c , Albert Rosenberger d , Hans Joergen Grabe a , Winnie Schroeder e , Henry Völzke f , Harald J. Freyberger a , Falko H. Herrmann e , Heyo Kroemer c , Dieter Rosskopf c a Department of Psychiatry and Psychotherapy, University of Greifswald, Germany b Institute for Psychology, University of Heidelberg, Germany c Institute of Pharmacology, University of Greifswald, Germany d Department of Genetic Epidemiology, University Medicine Göttingen, Germany e Institute of Human Genetics, University of Greifswald, Germany f Institute of Epidemiology and Social Medicine, University of Greifswald, Germany abstract article info Article history: Received 16 March 2008 Received in revised form 28 February 2009 Accepted 9 April 2009 Available online 17 April 2009 Keywords: Affect IQ OXTR Oxytoxin PANAS Polymorphism Associations of oxytocin receptor gene (OXTR) variants and autism spectrum disorders (ASD) have been reported in earlier studies; in one of the studies associations with IQ and daily living skills were found additionally. Variations of the oxytocin receptor gene might also regulate affect, attachment and separation beyond the diagnostic borders of autism. We tested hypotheses of associations between positive and negative affects and social and emotional loneliness (285 adults), IQ (117 adolescents) and polymorphisms of the oxytocin receptor gene (OXTR rs53576, rs2254298 and rs2228485) in normal subjects. Individuals with the oxytocin OXTR rs53576 A/A genotype showed lower positive affect scores (F = 5.532, df = 1; p =0.019). This effect was restricted to males (F = 13.098, df = 1; p = 0.00047). Haplotypes constructed with the three markers were associated with positive affect (p =0.0012), negative affect (p b 0.0001) and emotional loneliness (p b 0.0001). Non-verbal intelligence was significantly reduced in rs53576 A/A adolescents (T = 2.247, p = 0.027). Our findings support a role for the oxytocin receptor haplotypes in the generation of affectivity, emotional loneliness and IQ. © 2009 Elsevier Inc. All rights reserved. 1. Introduction Cumulative evidence suggests, that oxytocin is important for the psychophysiological calm and connection system, which is crucial for the regulation of well-being and socialization (Uvnas-Moberg et al., 2005). Disruption of social behaviour, interaction and communication is a key feature of autism. Experimental studies suggest a role for oxytocin in the pathophysiology of autism because oxytocin admin- istration in patients with autism spectrum disorders led to improve- ment of autism-specific symptoms such as repetitive behaviours and social cognition (Hollander et al., 2007, 2003). Autism is a highly heritable disorder (Pickles et al., 1995; Wu et al., 2005) and the 3p25 region, which harbours the oxytocin receptor gene, was identified as region linked to autism spectrum disorder in two genome-wide scans (Lauritsen et al., 2006; McCauley et al., 2005). Wu et al. (2005) reported associations of the OXTR rs53576 A-allele and OXTR rs2254298 A-allele with autism in a family-based association study. Haplotypes with up to four markers particularly including rs53576 were also associated with autism. Haplotypes involving OXTR rs2228485 showed an excess transmission from parents to affected offspring. In another study Jacob et al. (2007) reported an association with the OXTR rs2254298 polymorphism as well, but in contrast to Wu et al. (2005) the G-allele was overtransmitted. Yrigollen et al. (2008) found associations with both multivariate and univariate phenotypes of autism spectrum disorder (ASD) with rs2268493, a SNP located in the same linkage disequilibrium block as rs2254298. In another association study Lerer et al. (2008) observed associations between an OXTR five-locus haplotype block involving rs2254298 with autism spectrum disorder (ASD; G overtransmitted) but not with Progress in Neuro-Psychopharmacology & Biological Psychiatry 33 (2009) 860–866 Abbreviations: ASD, autism spectrum disorder; bp, base pairs; DSM-IV, Diagnostic and Statistical Manual of Mental Disorders; EDTA, ethylenediaminetetraacetic acid; HAWIE, Hamburg–Wechsler-Intelligence Test (Adults); HAWIK, Hamburg–Wechsler- Intelligence Test (Children); IQ, intelligence quotient; MANOVA, Multivariate analysis of variance; OXTR, Oxytocin receptor gene; PANAS, Positive and Negative Affect Scale; UCLA loneliness scale, University of California, Los Angeles loneliness scale. ☆ ⁎This work is part of the Community Medicine research net (CMR) of the University of Greifswald, Germany, which is funded by the Federal Ministry of Education and Research (grant ZZ9603), the Ministry of Cultural affairs and the Social Ministry of the Federal State of Mecklenburg-West Pomerania. ⁎ Corresponding author. Department of Psychiatry and Psychotherapy, University of Greifswald, Rostocker Chaussee 70,18437 Stralsund, Germany. Tel.: +49 3831 452143; fax: +49 3831 452105. E-mail address: lucht@uni-greifswald.de (M.J. Lucht). 0278-5846/$ – see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.pnpbp.2009.04.004 Contents lists available at ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp