Progress in Neuro-Psychopharmacology and Biological Psychiatry
Associations between the oxytocin receptor gene (OXTR) and affect, loneliness and intelligence in normal subjects☆
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 administration in patients with autism spectrum disorders led to improvement of autism-specific symptoms such as repetitive behaviours and social cognition (Hollander et al., 2007, Hollander et al., 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 rs2254298 alone. rs2254298 alone was however associated with Vineland Adaptive Behavior Scale (VABS) daily living skills and communication subdomain scores with G being the risk allele. With the VABS a caregiver assesses a child's daily living skills. OXTR rs4686301 and rs1042778, but not rs2254298 was also associated with intelligence (IQ) as measured with standard intelligence tests.
Based on their findings Lerer et al. (2008) suggested that OXTR shapes ASD-related phenotypes such as social activities and intelligence beyond diagnostic boundaries.
Other possible phenotypes might include affect regulation, social interactions and loneliness, which have frequently been found in individuals with autism (Bieberich and Morgan, 2004, Whalen et al., 2006). Oxytocin administration and social support increase calmness and reduce anxiety and stress-response (Heinrichs et al., 2003) and oxytocin administration in humans increased trust (Kosfeld et al., 2005). Function of the human amygdala, a key structure for emotion regulation, is strongly modulated by intranasal application of oxytocin (Domes et al., 2007a, Kirsch et al., 2005). Oxytocin is also involved in the modulation of learning, memory and intelligence in animal as well as human studies (de Wied et al., 1993, Lerer et al., 2008).
Furthermore oxytocin is involved in the regulation of social bonding and separation not only in subjects with autism (Panksepp, 2003b). Mind reading (making sense of or predict another person's behaviour), a key ability required for social interaction, is increased after intranasal administration of oxytocin in normal subjects (Domes et al., 2007b). Separation, the disruption of social bonds, is a painful experience which might be buffered by oxytocin (Panksepp, 2003b). Accordingly Meinlschmidt and Heim (2007) found stress system reactivity to be attenuated after application of oxytocin in subjects with early parental separation. There is good evidence that loneliness is the human equivalent of separation distress in animals (Panksepp, 2003a) and so Panksepp et al. (1997) hypothesized that an orally effective ligand for oxytocin receptors should prove to be a powerful alleviator of loneliness in humans.
Based on those results we attempted to explore possible associations between OXTR rs53576, rs2254298, rs2228485 and positive/negative affect, different degrees of loneliness and intelligence in normal subjects.
Section snippets
Population
Participants derive from the population-based representative Study of Health in Pomerania (SHIP-I; n = 4310; age between 20 and 79; final response of 68.8%), Germany (Grabe et al., 2005, John et al., 2001). A smaller family sample (adult probands living in families and children aged between 11 and 18) was recruited from SHIP for subsamples to investigate pathways to addiction (Greifswald family study). The Greifswald family study was initially designed to investigate pathways to addiction (Barnow
Results
Genotype frequencies for rs53576, rs2254298 and rs2228485 in the adult and adolescent sample were in accordance with the Hardy–Weinberg-equilibrium (p > 0.05). No sex differences could be detected for rs53576 (χ2 = 1.120; df = 2, p = 0.571), rs2254298 (χ2 = 3.405; df = 2, p = 0.182) and rs2228485 (χ2 = 1.497; df = 2, p = 0.473) in the adult sample, due to low sample size no gender-specific calculations were performed for the adolescent sample. We counted allele frequencies of A = 0.33 and G = 0.67 for rs53576 in our
Discussion
Our data indicate that different haplotypes of three OXTR receptor gene polymorphisms are associated with positive affect, negative affect and emotional loneliness scores in normal human subjects. Analyses of each polymorphisms separately showed, that particularly one genotype, the OXTR rs53576 A/A was associated with (1) positive affect in the adult sample and (2) intelligence deficits in a smaller sample of adolescents. These results are consistent with earlier evidence for a role of the
Conclusions
Our findings corroborate the assumption that OXTR polymorphisms might not only influence symptomatology in patients with ASD but also psychological dimensions in normals. The associations between oxytocin receptor polymorphisms or haplotypes and affect, loneliness and intelligence are in accordance with the results of the experimental and imaging studies suggesting an influence of the oxytonergic system on affect regulation, social interaction and cognition. Conclusions of our results should be
Acknowledgements
We thank Ines Ulrich, Ulrike Höpfner and Andreas Schattenberg for their contributions in laboratory work, DNA sampling and data processing.
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⁎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.