RESEARCH ARTICLE Meta-Analysis and Association of Two Common Polymorphisms of the Human Oxytocin Receptor Gene in Autism Spectrum Disorder Thorsten M. Kranz, Marnie Kopp, Regina Waltes, Michael Sachse, Eftichia Duketis, Tomasz A. Jarczok, Franziska Degenhardt, Katharina G€ orgen, Jobst Meyer, Christine M. Freitag, and Andreas G. Chiocchetti Neuropeptides such as oxytocin (OXT) are known facilitators of social behavior across species. Variants of the OXT receptor gene (OXTR) have been tested for association with autism spectrum disorder (ASD) across manifold ethnic- ities, yielding both positive and negative findings. A recent meta-analysis, comprising 16 single nucleotide polymor- phisms (SNPs), has corroborated the implication of OXTR in the etiology of ASD. Here, we genotyped and tested two additional variants (rs237889 and rs237897) for association with ASD in two German predominantly high-functioning ASD samples. We found nominal over-transmission (OR 5 1.48, CI95 5 1.06-2.08, P 5 0.022) for the minor A allele of variant rs237889G>A in sample 1 (N 5 135 complete parent-offspring trios, 29 parent child duos), but not in sample 2 (362 trios, 69 duos). Still, in a meta-analysis comprising four different studies including the two unreported German data sets (N 5 542 families), this finding was confirmed (OR 5 1.12; CI95 5 1.01–1.24, random effects P 5 0.012). In addition, carriers of the minor risk allele rs237889-A showed significantly increased severity scores, as assessed through the autism diagnostic interview – revised (ADI-R), with highly significant increases in social interaction deficits. Our results corroborate the implication of common OXTR variants in the etiology of ASD. There is a need for functional studies to delineate the neurobiological implications of this and other association findings. (172/250). Autism Res 2016, 00: 000–000. V C 2016 International Society for Autism Research, Wiley Periodicals, Inc. Keywords: meta-analysis; autism spectrum disorder; oxytocin receptor; genotyping; social interaction; endopheno- type; genetics; oxytocin Introduction Autism Spectrum Disorder (ASD) is a neurodevelopmen- tal disorder with an estimated heritability of 80% [Ronald & Hoekstra, 2011]. ASD is marked by impair- ment of abilities in social interaction and communica- tion as well as by stereotypical behavior (DSM-5). The oxytocin receptor gene (OXTR) has been considered as risk gene for ASD due to its known function in the facilitation of social bonding and prosocial behavior [Kumsta & Heinrichs, 2013]. Modahl and colleagues [1998] first reported that ASD-affected children showed reduced oxytocin (OXT) levels in plasma in comparison to healthy controls [Modahl et al., 1998]. The rs2254298-A allele of OXTR was associated with soci- ability and increased amygdala volume [Brune, 2012]. In addition, the amygdala was observed to be enlarged in individuals with ASD [Mosconi et al., 2009]. Interest- ingly, similar volumetric aberrations were observed in anxiety disorders, a frequent comorbidity among ASD cases [Kleinhans et al., 2011]. Furthermore, rs2254298 was found to be a predictor for daughter’s depression and anxiety, when mothers had a history of recurrent major depressive disorder [Thompson et al., 2011]. At last, also animal studies on the OXT-OXTR system have corroborated its modulatory qualities on social behavior [Ferguson et al., 2000; Pobbe et al., 2012]. However, genetic association studies on OXTR and ASD in human cohorts have yielded ambiguous results: First, none of the six large genome-wide association studies identified any variants near or within OXTR as risk factor for ASD [Poelmans et al., 2013]. Second posi- tive association of or linkage with OXTR variants has been reported in candidate gene studies in Caucasian individuals [Campbell et al., 2011; Jacob et al., 2007; Lerer et al., 2008; Wermter et al., 2010; Yrigollen et al., 2008]. The largest study investigated a cohort of over 1,200 families with ASD-affected individuals and From the Department of Neurobehavioral Genetics, University of Trier, Johanniterufer 15, Trier D-54290, Germany (T.M.K., K.G., J.M.,); Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, JW Goethe University Frankfurt, Deutschordenstraße 50, Frankfurt am Main D-60528, Germany (M.K., R.W., M.S., E.D., T.A.J., C.M.F., A.G.C.,); Institute of Human Genetics, University of Bonn, Sigmund-Freud-Str. 25, Bonn D-53127, Germany (F.D.) Received July 24, 2015; accepted for publication December 03, 2015 Address for correspondence and reprints: Andreas G. Chiocchetti, PhD, Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, Johann Wolfgang Goethe University, Deutschordenstraße 50, Frankfurt am Main D-60528, Germany. E-mail: andreas.chiocchetti@ kgu.de Published online 00 Month 2016 in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/aur.1597 V C 2016 International Society for Autism Research, Wiley Periodicals, Inc. INSAR Autism Research 00: 00–00, 2016 1