The oxytocin receptor gene (OXTR) has been studied as a risk factor for autism spectrum disorder (ASD) owing to converging evidence from multiple levels of analysis that oxytocin (OXT) has an important role in the regulation of affiliative behavior and social bonding in both nonhuman mammals and humans. Inconsistency in the effect sizes of the OXTR variants included in association studies render it unclear whether OXTR is truly associated with ASD, and, if so, which OXTR single-nucleotide polymorphisms (SNPs) are associated. Thus, a meta-analytic review of extant studies is needed to determine whether OXTR shows association with ASD, and to elucidate which specific SNPs have a significant effect on ASD. The current meta-analysis of 16 OXTR SNPs included 3941 individuals with ASD from 11 independent samples, although analyses of each individual SNP included a subset of this total. We found significant associations between ASD and the SNPs rs7632287, rs237887, rs2268491 and rs2254298. OXTR was also significantly associated with ASD in a gene-based test. The current meta-analysis is the largest and most comprehensive investigation of the association of OXTR with ASD and the findings suggest directions for future studies of the etiology of ASD.
Your institute does not have access to this article
Open Access articles citing this article.
Signal Transduction and Targeted Therapy Open Access 11 July 2022
Journal of Autism and Developmental Disorders Open Access 23 June 2022
Translational Psychiatry Open Access 15 June 2022
Subscribe to Journal
Get full journal access for 1 year
only $9.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Volkmar FR, Lord C, Bailey A, Schultz RT, Klin A . Autism and pervasive developmental disorders. J Child Psychol Psychiatry 2004; 45: 135–170.
Freitag CM, Staal W, Klauck SM, Duketis E, Waltes R . Genetics of autistic disorders: review and clinical implications. Eur Child Adolesc Psychiatry 2010; 19: 169–178.
Lichtenstein P, Carlström E, Råstam M, Gillberg C, Anckarsäter H . The genetics of autism spectrum disorders and related neuropsychiatric disorders in childhood. Am J Psychiatry 2010; 167: 1357–1363.
Lim MM, Young LJ . Neuropeptidergic regulation of affiliative behavior and social bonding in animals. Horm Behav 2006; 50: 506–517.
Heinrichs M, Domes G . Neuropeptides and social behaviour: effects of oxytocin and vasopressin in humans. Prog Brain Res 2008; 170: 337–350.
Modahl C, Green L, Fein D, Morris M, Waterhouse L, Feinstein C et al. Plasma oxytocin levels in autistic children. Bio Psychiatry 1998; 43: 270–277.
Boso M, Emanuele E, Politi P, Pace A, Arra M, Ucelli di Nemi S et al. Reduced plasma apelin levels in patients with autistic spectrum disorder. Arch Med Res 2007; 38: 70–74.
Yates D . Neurogenetics: unravelling the genetics of autism. Nat Rev Neurosci 2012; 13: 359.
Yang M, Gill M . A review of gene linkage, association and expression studies in autism and an assessment of convergent evidence. Int J Dev Neurosci 2007; 25: 69–85.
Lauritsen MB, Als TD, Dahl HA, Flint TJ, Wang AG, Vang M et al. A genome-wide search for alleles and haplotypes associated with autism and related pervasive developmental disorders on the Faroe Islands. Mol Psychiatry 2006; 11: 37–46.
Ma D, Salyakina D, Jaworski JM, Konidari I, Whitehead PL, Andersen AN et al. A genome-wide association study of autism reveals a common novel risk locus at 5p14.1. Ann Hum Genet 2009; 73: 263–273.
Hussman JP, Chung RH, Griswold AJ, Jaworski JM, Salyakina D, Ma D et al. A noise-reduction GWAS analysis implicates altered regulation of neurite outgrowth and guidance in autism. Mol Autism 2011; 2: 1.
Schaaf CP, Zoghbi HY . Solving the autism puzzle a few pieces at a time. Neuron 2011; 70: 806–808.
Sebat J, Lakshmi B, Malhotra D, Troge J . Strong association of de novo copy number mutations with autism. Science 2007; 316: 445–449.
Levy D, Ronemus M, Yamrom B, Lee YH, Leotta A, Kendall J et al. Rare de novo and transmitted copy-number variation in autistic spectrum disorders. Neuron 2011; 70: 886–897.
O’Roak BJ, Vives L, Girirajan S, Karakoc E, Krumm N, Coe BP et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature 2012; 485: 246–250.
Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature 2012; 485: 237–241.
Neale BM, Kou Y, Liu L, Ma'ayan A, Samocha KE, Sabo A et al. Patterns and rates of exonic de novo mutations in autism spectrum disorders. Nature 2012; 485: 242–245.
Campbell DB, D'Oronzio R, Garbett K, Ebert PJ, Mirnics K, Levitt P et al. Disruption of cerebral cortex MET signaling in autism spectrum disorder. Ann Neurol 2007; 62: 243–250.
Skaar DA, Shao Y, Haines JL, Stenger JE, Jaworski J, Martin ER et al. Analysis of the RELN gene as a genetic risk factor for autism. Mol Psychiatry 2005; 10: 563–571.
Zimmerman AW, Connors SL, Pardo-Villamizar CA . Neuroimmunology and neurotransmitters in autism. In: Tuchman R, Rabin I (eds), Autism: A Neurological Disorder of Early Brain Development. Mac Keith Press: London, UK, 2006, pp 141–159.
The International HapMap Consortium. A second generation human haplotype map of over 3.1 million SNPs. Nature 2007; 449: 851–861.
Tansey KE, Brookes KJ, Hill MJ, Cochrane LE, Gill M, Skuse D et al. Oxytocin receptor (OXTR) does not play a major role in the aetiology of autism: genetic and molecular studies. Neurosci Lett 2010; 474: 163–167.
Landgraf R, Neumann I . Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Front Neuroendocrinol 2004; 25: 150–176.
Ross H, Young L . Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior. Front Neuroendocrinol 2009; 30: 534–547.
McGraw L, Young L . The prairie vole: an emerging model organism for understanding the social brain. Trends Neurosci 2010; 33: 1–14.
Lee HJ, Caldwell HK, Macbeth AH, Tolu SG, Young WSY . A conditional knockout mouse line of the oxytocin receptor. Endocrinol 2008; 149: 3256–3263.
Nishimori K, Takayanagi Y, Yoshida M, Kasahara Y, Young LJ, Kawamata M . New aspects of oxytocin receptor function revealed by knockout mice: sociosexual behavior and control of energy balance. Prog Brain Res 2008; 180: 79–90.
Heinrichs M, Baumgartner T, Kirschbaum C, Ehlert U . Social support and oxytocin interact to suppress cortisol and subjective responses to psychosocial stress. Biol Psychiatry 2003; 54: 1389–1398.
Domes G, Heinrichs M, Michel A, Berger C, Herpertz SC . Oxytocin improves ‘mind-reading’ in humans. Biol Psychiatry 2007; 61: 731–733.
Guastella AJ, Mitchell PB, Dadds MR . Oxytocin increases gaze to the eye region of human faces. Biol Psychiatry 2008; 63: 3–5.
Kosfeld M, Heinrichs M, Zak PJ, Fischbacher U, Fehr E . Oxytocin increases trust in humans. Nature 2005; 435: 673–676.
McCullugh ME, Churchland PS, Mendez AJ . Problems with measuring peripheral oxytocin: can the data on oxytocin ad human behavior be trusted?. Neurosci Biobehav Rev 2013; 37: 1485–1492.
Israel S et al. The oxytocin receptor contributes to prosocial fund allocations in the dictator game and the social value orientations task. PLoS One 2009; 4: e5535.
Kogan A, Saslow LR, Impett EA, Oveis C, Keltner D, Rodrigues-Saturn S . Thin-slicing study of the oxytocin receptor (OXTR) gene and the evaluation and expression of the prosocial disposition. Proc Natl Acad Sci USA 2011; 108: 19189–19192.
Tost H, Kolachana B, Hakimi S, Lemaitre H, Verchinski BA, Mattay VS et al. A common allele in the oxytocin receptor gene (OXTR) impacts prosocial temperament and human hypothalamic-limbic structure and function. Proc Natl Acad Sci USA 2010; 107: 13936–13941.
Rodrigues SM, Saslow LR, Garcia N, John OP, Keltner D . Oxytocin receptor genetic variation relates to empathy and stress reactivity in humans. Proc Natl Acad Sci USA 2009; 106: 21437–21441.
Chen FS, Johnson SC . An oxytocin receptor gene variant predicts attachment anxiety in females and autism-spectrum traits in males. Soc Psychol Personal Sci 2011; 3: 93–99.
Bakermans-Kranenburg MJ, van Ijzendoorn MH . Oxytocin receptor (OXTR) and serotonin transporter (5-HTT) genes associated with observed parenting. Soc Cogn Affect Neurosci 2008; 3: 128–134.
Green L, Fein D, Modahl C, Feinstein C, Waterhouse L, Morris M . Oxytocin and autistic disorder: alterations in peptide forms. Biol Psychiatry 2001; 50: 609–613.
Guastella A, Einfeld SL, Gray KM, Rinehart NJ, Tonge BJ, Lambert TJ et al. Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biol Psychiatry 2010; 6: 692–694.
Andari E, Duhamel JR, Zalla T, Herbrecht E, Leboyer M, Sirigu A . Promoting social behavior with oxytocin in high-functioning autism spectrum disorders. Proc Natl Acad Sci USA 2010; 107: 4389–4394.
Skuse DH, Lori A, Cubells JF, Lee I, Conneely KN, Puura K et al. Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills. Proc Natl Acad Sci USA 2013; 111: 1987–1992.
Ylisaukko-oja T, Alarcón M, Cantor RM, Auranen M, Vanhala R, Kempas E et al. Search for autism loci by combined analysis of autism genetic resource exchange and finnish families. Ann Neurol 2006; 59: 145–155.
Wu S, Jia M, Ruan Y, Liu J, Guo Y, Shuang M, Gong X et al. Positive association of the oxytocin receptor gene (OXTR) with autism in the Chinese Han population. Biol Psychiatry 2005; 58: 74–77.
Jacob S, Brune C, Carter C, Leventhal B . Association of the oxytocin receptor gene OXTR in Caucasian children and adolescents with autism. Neurosci 2007; 417: 6–9.
Lerer E, Levi S, Salomon S, Darvasi A, Yirmiya N, Ebstein RP . Association between the oxytocin receptor (OXTR) gene and autism: relationship to Vineland Adaptive Behavior Scales and cognition. Mol Psychiatry 2007; 13: 980–988.
Yrigollen C, Han S, Kochetkova A, Babitz T . Genes controlling affiliative behavior as candidate genes for autism. Biol Psychiatry 2008; 63: 911–916.
Wermter AK, Kamp-Becker I, Hesse P, Schulte-Körne G, Strauch K, Remschmidt H . Evidence for the involvement of genetic variation in the oxytocin receptor gene (OXTR) in the etiology of autistic disorders on high-functioning level. Am J Med Genet B Neuropsychiatr Genet 2010; 153B: 629–639.
Liu X, Kawamura Y, Shimada T, Otowa T, Koishi S, Sugiyama T et al. Association of the oxytocin receptor (OXTR) gene polymorphisms with autism spectrum disorder (ASD) in the Japanese population. J Hum Genet 2010; 55: 137–141.
Campbell DB, Datta D, Jones ST, Batey Lee E, Sutcliffe JS, Hammock EA et al. Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder. J Neurodev Disord 2011; 3: 101–112.
Chakrabarti B, Dudbridge F, Kent L, Wheelwright S, Hill-Cawthorne G, Allison C et al. Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger Syndrome. Autism Res 2009; 2: 157–177.
Walum H, Lichtenstein P, Neiderhiser JM, Reiss D, Ganiban JM, Spotts EL et al. Variation in the oxytocin receptor gene is associated with pair-bonding and social behavior. Biol Psychiatry 2012; 71: 419–426.
Luo L, Peng G, Zhu Y, Dong H, Amos CI, Xiong M . Genome-wide gene and pathway analysis. Eur J Hum Genet 2010; 18: 1045–1053.
Lord C, Rutter M, Couteur A . Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Neurodev Disord 1994; 24: 659–685.
Lord C, Risi S, Lambrecht L, Cook EH Jr, Leventhal BL, DiLavore PC et al. The autism diagnostic observation schedule-generic: a standard measure of social and communication deficits associated with the spectrum of autism. J Autism Neurodev Disord 2000; 30: 205–223.
Schopler E, Reichler RJ, DeVillis RF, Daly K . Toward objective classification of childhood autism: Childhood Autism Rating Scale (CARS). J Autism Neurodev Disord 1980; 10: 91–103.
Skuse D, Warrington R, Bishop D, Chowdhury U, Lau J, Mandy W et al. The Developmental, Dimensional and Diagnostic Interview (3di): A novel computerized assessment for autism spectrum disorders. J Am Acad Child Adolesc Psychiatry 2004; 45: 548–558.
Han B, Eskin E . Random-effects model aimed at discovering associations in meta-analysis of genome-wide association studies. Am J Hum Genet 2011; 88: 586–598.
Li MX, Sham PC, Cherny SS, Son YQ . A knowledge-based weighting framework to boost the power of genome-wide association studies. PLoS One 2010; 5: e14480.
Li MX, Gui HS, Kwan JS, Sham PC . GATES: a rapid and powerful gene-based association test using extended Simes procedure. Am J Hum Genet 2011; 88: 283–293.
Ge D . 2009 MetaP [Software]. Available from http://compute1.lsrc.duke.edu/softwares/MetaP/metap.php.
Egger M, Smith GD, Schneider M, Minder C . Bias in meta-analysis detected by a simple, graphical test. Brit Med J 1997; 315: 629–634.
Ioannidis JPA, Trikalinos TA . An exploratory test for an excess of significant findings. Clin Trials 2007; 4: 245–253.
Anney R, Klei L, Pinto D, Regan R, Conroy J, Magalhaes TR et al. A genome-wide scan for common alleles affecting risk for autism. Hum Mol Genet 2010; 19: 4072–4082.
Wu N, Li Z, Su Y . The association between oxytocin receptor gene polymorphism (OXTR) and trait empathy. J Affect Disord 2012; 138: 468–472.
Chen FS, Barth ME, Johnson SL, Gotlib IH, Johnson SC . Oxytocin receptor (OXTR) polymorphisms and attachment in human infants. Front Psychol 2011; 2: 200.
Feldman R, Zagoory-Sharon O, Weisman O, Schneiderman I, Gordon I, Maoz R et al. Sensitive parenting is associated with plasma oxytocin and polymorphisms in the OXTR and CD38 genes. Biol Psychiatry 2012; 72: 175–18.
Ronald A, Happé F, Bolton P, Butcher LM, Price TS, Wheelwright S et al. Genetic heterogeneity between the three components of the autism spectrum: a twin study. J Am Acad Child Psy 2006; 45: 691–699.
Mazefsky CA, Williams DL, Minshew NJ . Variability in adaptive behavior in autism: Evidence for the importance of family history. J Abnorm Child Psych 2008; 36: 591–599.
The authors declare no conflict of interest.
About this article
Cite this article
LoParo, D., Waldman, I. The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: a meta-analysis. Mol Psychiatry 20, 640–646 (2015). https://doi.org/10.1038/mp.2014.77
Signal Transduction and Targeted Therapy (2022)
Translational Psychiatry (2022)
Molecular Psychiatry (2022)
Journal of Autism and Developmental Disorders (2022)
Science China Life Sciences (2022)