Skip to main content

Birth weight interacts with a functional variant of the oxytocin receptor gene (OXTR) to predict executive functioning in children

  • Mark Wade (a1), Heather Prime (a1), Thomas J. Hoffmann (a2), Louis A. Schmidt (a3), Thomas G. O'Connor (a4) and Jennifer M. Jenkins (a1)...

Genetic variation in the oxytocin receptor gene (OXTR) is associated with several psychiatric conditions characterized by deficits in executive functioning (EF). A specific OXTR variant, rs2254298, has previously been associated with brain functioning in regions implicated in EF. Moreover, birth weight variation across the entire range is associated with individual differences in cortical structure and function that underlie EF. This is the first study to examine the main and interactive effect between rs2254298 and birth weight on EF in children. The sample consisted of 310 children from an ongoing longitudinal study. EF was measured at age 4.5 using observational tasks indexing working memory, cognitive flexibility, and inhibitory control. A family-based design that controlled for population admixture, stratification, and nongenomic confounds was employed. A significant genetic association between rs2254298 and EF was observed, with more copies of the major allele (G) associated with higher EF. There was also a significant interaction between rs2254298 and birth weight, such that more copies of the major allele in combination with higher birth weight predicted better EF. Findings suggest that OXTR may be associated with discrete neurocognitive abilities in childhood, and these effects may be modulated by intrauterine conditions related to fetal growth and development.

Corresponding author
Address correspondence and reprint requests to: Jennifer M. Jenkins, Department of Applied Psychology and Human Development, University of Toronto, 252 Bloor Street West, Toronto, ON M5S 1V6, Canada; E-mail:
Hide All

We are grateful to the families who give so generously of their time, to the Hamilton and Toronto Public Health Units for facilitating recruitment of the sample, and to Mira Boskovic for project management. The “Transactional Processes in Emotional and Behavioral Regulation: Individuals in Context” grant was awarded to Jennifer M. Jenkins and Michael Boyle from the Canadian Institutes of Health Research (CIHR Funding Reference 70334) and covered data collection. Mark Wade was also funded by a CIHR doctoral fellowship. The study team beyond the current authors includes Cathy Barr, Kathy Georgiades, Greg Moran, Michal Perlman, and Hildy Ross.

Hide All
Aarnoudse-Moens, C. S. H., Weisglas-Kuperus, N., van Goudoever, J. B., & Oosterlaan, J. (2009). Meta-analysis of neurobehavioral outcomes in very preterm and/or very low birth weight children. Pediatrics, 124, 717728. doi:10.1542/peds.2008-2816
Aguilar-Pardo, D., Martinez-Arias, R., & Colmenares, F. (2013). The role of inhibition in young children's altruistic behaviour. Cognitive Processing, 14, 301307. doi:10.1007/s10339-013-0552-6
Albin-Brooks, C. C., Nealer, C. A., Sabihi, S., Haim, A., & Leuner, B. (2017). The influence of offspring, parity, and oxytocin on cognitive flexibility during the postpartum period. Hormones and Behavior, 89, 130136. doi:10.1016/j.yhbeh.2016.12.015
Almli, L. M., Duncan, R., Feng, H., Ghosh, D., Binder, E. B., Bradley, B., … Epstein, M. P. (2014). Correcting systematic inflation in genetic association tests that consider interaction effects: Application to a genome-wide association study of posttraumatic stress disorder. JAMA Psychiatry, 71, 13921399. doi:10.1001/jamapsychiatry.2014.1339
Arnsten, A. F. (2011). Catecholamine influences on dorsolateral prefrontal cortical networks. Biological Psychiatry, 69, e89e99. doi:10.1016/j.biopsych.2011.01.027
Bakermans-Kranenburg, M., & van IJzendoorn, M. (2013). Sniffing around oxytocin: Review and meta-analyses of trials in healthy and clinical groups with implications for pharmacotherapy. Translational Psychiatry, 3, e258. doi:10.1038/tp.2013.34
Bartz, J. A., Zaki, J., Bolger, N., & Ochsner, K. N. (2011). Social effects of oxytocin in humans: Context and person matter. Trends in Cognitive Sciences, 15, 301309. doi:10.1016/j.tics.2011.05.002
Benson, J. E., Sabbagh, M. A., Carlson, S. M., & Zelazo, P. D. (2013). Individual differences in executive functioning predict preschoolers’ improvement from theory-of-mind training. Developmental Psychology, 49, 1615. doi:10.1037/a0031056
Bernier, A., Carlson, S. M., Deschênes, M., & Matte-Gagné, C. (2012). Social factors in the development of early executive functioning: A closer look at the caregiving environment. Developmental Science, 15, 1224. doi:10.1111/j.1467-7687.2011.01093.x
Brüne, M. (2012). Does the oxytocin receptor polymorphism (rs2254298) confer “vulnerability” for psychopathology or “differential susceptibility”? Insights from evolution. BMC Medicine, 10, 38. doi:10.1186/1741-7015-10-38
Bush, G., Luu, P., & Posner, M. I. (2000). Cognitive and emotional influences in anterior cingulate cortex. Trends in Cognitive Sciences, 4, 215222. doi:10.1016/s1364-6613(00)01483-2
Chini, B., Leonzino, M., Braida, D., & Sala, M. (2014). Learning about oxytocin: Pharmacologic and behavioral issues. Biological Psychiatry, 76, 360366. doi:10.1016/j.biopsych.2013.08.029
Clausson, B., Lichtenstein, P., & Cnattingius, S. (2000). Genetic influence on birthweight and gestational length determined by studies in offspring of twins. British Journal of Obstetrics and Gynaecology, 107, 375381. doi:10.1111/j.1471-0528.2000.tb13234.x
Cost, K. T., Unternaehrer, E., Plamondon, A., Steiner, M., Meaney, M., Atkinson, L., … Fleming, A. S. (2016). Thinking and doing: The effects of dopamine and oxytocin genes and executive function on mothering behaviours. Genes, Brain and Behavior. Advance online publication. doi:10.1111/gbb.12337
Cuthbert, B. N. (2014). Translating intermediate phenotypes to psychopathology: The NIMH Research Domain Criteria. Psychophysiology, 51, 12051206. doi:10.1111/psyp.12342
Feldman, R., Monakhov, M., Pratt, M., & Ebstein, R. P. (2016). Oxytocin pathway genes: Evolutionary ancient system impacting on human affiliation, sociality, and psychopathology. Biological Psychiatry, 79, 174184. doi:10.1016/j.biopsych.2015.08.008
Feldman, R., Rosenthal, Z., & Eidelman, A. I. (2014). Maternal-preterm skin-to-skin contact enhances child physiologic organization and cognitive control across the first 10 years of life. Biological Psychiatry, 75, 5664. doi:10.1016/j.biopsych.2013.08.012
Feldman, R., Weller, A., Zagoory-Sharon, O., & Levine, A. (2007). Evidence for a neuroendocrinological foundation of human affiliation: Plasma oxytocin levels across pregnancy and the postpartum period predict mother-infant bonding. Psychological Science, 18, 965970. doi:10.1111/j.1467-9280.2007.02010.x
Friedman, N. P., Miyake, A., Robinson, J. L., & Hewitt, J. K. (2011). Developmental trajectories in toddlers' self-restraint predict individual differences in executive functions 14 years later: A behavioral genetic analysis. Developmental Psychology, 47, 14101430. doi:10.1037/a0023750
Friedman, N. P., Miyake, A., Young, S. E., DeFries, J. C., Corley, R. P., & Hewitt, J. K. (2008). Individual differences in executive functions are almost entirely genetic in origin. Journal of Experimental Psychology: General, 137, 201225. doi:10.1037/0096-3445.137.2.201
Furman, D. J., Chen, M. C., & Gotlib, I. H. (2011). Variant in oxytocin receptor gene is associated with amygdala volume. Psychoneuroendocrinology, 36, 891897. doi:10.1016/j.psyneuen.2010.12.004
Garon, N., Bryson, S. E., & Smith, I. M. (2008). Executive function in preschoolers: A review using an integrative framework. Psychological Bulletin, 134, 3160. doi:10.1037/0033-2909.134.1.31
Gottesman, I. I., & Gould, T. D. (2003). The endophenotype concept in psychiatry: Etymology and strategic intentions. American Journal of Psychiatry, 160, 636645. doi:10.1176/appi.ajp.160.4.636
Guastella, A. J., Einfeld, S. L., Gray, K. M., Rinehart, N. J., Tonge, B. J., Lambert, T. J., & Hickie, I. B. (2010). Intranasal oxytocin improves emotion recognition for youth with autism spectrum disorders. Biological Psychiatry, 67, 692694. doi:10.1016/j.biopsych.2009.09.020
Haukvik, U. K., Rimol, L. M., Roddey, J. C., Hartberg, C. B., Lange, E. H., Vaskinn, A., … Agartz, I. (2013). Normal birth weight variation is related to cortical morphology across the psychosis spectrum. Schizophrenia Bulletin, 40, 410419. doi:10.1093/schbul/sbt005
Hunter, D. J. (2005). Gene-environment interactions in human diseases. Nature Reviews Genetics, 6, 287298. doi:10.21775/cimb.010.025
Inoue, H., Yamasue, H., Tochigi, M., Abe, O., Liu, X., Kawamura, Y., … Rogers, M. A. (2010). Association between the oxytocin receptor gene and amygdalar volume in healthy adults. Biological Psychiatry, 68, 10661072. doi:10.1016/j.neures.2010.07.2479
Jack, A., Connelly, J. J., & Morris, J. P. (2012). DNA methylation of the oxytocin receptor gene predicts neural response to ambiguous social stimuli. Frontiers in Human Neuroscience, 6, 280. doi:10.3389/fnhum.2012.00280
Kumsta, R., & Heinrichs, M. (2013). Oxytocin, stress and social behavior: Neurogenetics of the human oxytocin system. Current Opinion in Neurobiology, 23, 1116. doi:10.1016/j.conb.2012.09.004
Laird, N. M., & Lange, C. (2008). Family-based methods for linkage and association analysis. Advances in Genetics, 60, 219252. doi:10.1016/s0065-2660(07)00410-5
Landry, S. H., Smith, K. E., Swank, P. R., Zucker, T., Crawford, A. D., & Solari, E. F. (2012). The effects of a responsive parenting intervention on parent-child interactions during shared book reading. Developmental Psychology, 48, 969. doi:10.1037/a0026400
Lange, C., DeMeo, D. L., & Laird, N. M. (2002). Power and design considerations for a general class of family-based association tests: Quantitative traits. American Journal of Human Genetics, 71, 13301341. doi:10.1086/344696
Levine, A., Zagoory-Sharon, O., Feldman, R., & Weller, A. (2007). Oxytocin during pregnancy and early postpartum: Individual patterns and maternal–fetal attachment. Peptides, 28, 11621169. doi:10.1016/j.peptides.2007.04.016
LoParo, D., & Waldman, I. D. (2015). The oxytocin receptor gene (OXTR) is associated with autism spectrum disorder: A meta-analysis. Molecular Psychiatry, 20, 640646. doi:10.1038/mp.2014.77
Luna, B., Doll, S. K., Hegedus, S. J., Minshew, N. J., & Sweeney, J. A. (2007). Maturation of executive function in autism. Biological Psychiatry, 61, 474481. doi:10.1155/2012/146132
Manuck, S. B., & McCaffery, J. M. (2014). Gene-environment interaction. Annual Review of Psychology, 65, 4170. doi:10.1146/annurev-psych-010213-115100
Meyer-Lindenberg, A., Domes, G., Kirsch, P., & Heinrichs, M. (2011). Oxytocin and vasopressin in the human brain: Social neuropeptides for translational medicine. Nature Reviews Neuroscience, 12, 524538. doi:10.1038/nrn3044
Michalopoulou, P. G., Averbeck, B. B., Kalpakidou, A. K., Evans, S., Bobin, T., Kapur, S., & Shergill, S. S. (2015). The effects of a single dose of oxytocin on working memory in schizophrenia. Schizophrenia Research, 162, 6263. doi:10.1016/j.schres.2014.12.029
Michels, K. B., Harris, H. R., & Barault, L. (2011). Birthweight, maternal weight trajectories and global DNA methylation of LINE-1 repetitive elements. PLOS ONE, 6, e25254. doi:10.1371/journal.pone.0025254
Miller, G. A., & Rockstroh, B. (2013). Endophenotypes in psychopathology research: Where do we stand? Annual Review of Clinical Psychology, 9, 177213. doi:10.1146/annurev-clinpsy-050212-185540
Minzenberg, M. J., Laird, A. R., Thelen, S., Carter, C. S., & Glahn, D. C. (2009). Meta-analysis of 41 functional neuroimaging studies of executive function in schizophrenia. Archives of General Psychiatry, 66, 811822. doi:10.1001/archgenpsychiatry.2009.91
Mizumoto, Y., Kimura, T., & Ivell, R. (1997). A genomic element within the third intron of the human oxytocin receptor gene may be involved in transcriptional suppression. Molecular and Cellular Endocrinology, 135, 129138. doi:10.1016/s0303-7207(97)00195-0
Moerkerke, B., Vansteelandt, S., & Lange, C. (2010). A doubly robust test for gene-environment interaction in family-based studies of affected offspring. Biostatistics, 11, 213225. doi:10.1093/biostatistics/kxp061
Mur, M., Portella, M. J., Martínez-Arán, A., Pifarré, J., & Vieta, E. (2007). Persistent neuropsychological deficit in euthymic bipolar patients: Executive function as a core deficit. Journal of Clinical Psychiatry, 68, 10781086. doi:10.4088/jcp.v68n0715
Niendam, T. A., Laird, A. R., Ray, K. L., Dean, Y. M., Glahn, D. C., & Carter, C. S. (2012). Meta-analytic evidence for a superordinate cognitive control network subserving diverse executive functions. Cognitive, Affective, & Behavioral Neuroscience, 12, 241268. doi:10.3758/s13415-011-0083-5
Phua, D. Y.-L., Rifkin-Graboi, A., Saw, S.-M., Meaney, M. J., & Qiu, A. (2012). Executive functions of six-year-old boys with normal birth weight and gestational age. PLOS ONE, 7, e36502. doi:10.1371/journal.pone.0036502
Raznahan, A., Greenstein, D., Lee, N. R., Clasen, L. S., & Giedd, J. N. (2012). Prenatal growth in humans and postnatal brain maturation into late adolescence. Proceedings of the National Academy of Sciences, 109, 1136611371. doi:10.1073/pnas.1203350109
Reed, M. A., Pien, D. L., & Rothbart, M. K. (1984). Inhibitory self-control in preschool children. Merrill-Palmer Quarterly, 30, 131147.
Rutter, M., Kim-Cohen, J., & Maughan, B. (2006). Continuities and discontinuities in psychopathology between childhood and adult life. Journal of Child Psychology and Psychiatry, 47, 276295. doi:10.1111/j.1469-7610.2006.01614.x
Schlotz, W., & Phillips, D. I. (2009). Fetal origins of mental health: Evidence and mechanisms. Brain, Behavior, and Immunity, 23, 905916. doi:10.1016/j.bbi.2009.02.001
Takahashi, K., Diamond, F., Bieniarz, J., Yen, H., & Burd, L. (1980). Uterine contractility and oxytocin sensitivity in preterm, term, and postterm pregnancy. American Journal of Obstetrics and Gynecology, 136, 774779. doi:10.1016/0002-9378(80)90455-X
Tomeo, C. A., Rich-Edwards, J. W., Michels, K. B., Berkey, C. S., Hunter, D. J., Frazier, A. L., … Buka, S. L. (1999). Reproducibility and validity of maternal recall of pregnancy-related events. Epidemiology, 10, 774776. doi:10.1097/00001648-199911000-00022
Tost, H., Kolachana, B., Verchinski, B. A., Bilek, E., Goldman, A. L., Mattay, V. S., … Meyer-Lindenberg, A., (2011). Neurogenetic effects of OXTR rs2254298 in the extended limbic system of healthy Caucasian adults. Biological Psychiatry, 70, e37e39. doi:10.1016/j.biopsych.2011.06.034
Umbach, D. M., & Weinberg, C. R. (2000). The use of case-parent triads to study joint effects of genotype and exposure. American Journal of Human Genetics, 66, 251261. doi:10.1086/302707
Unternaehrer, E., Bolten, M., Nast, I., Staehli, S., Meyer, A. H., Dempster, E., … Meinlschmidt, G. (2016). Maternal adversities during pregnancy and cord blood oxytocin receptor (OXTR) DNA methylation. Social Cognitive and Affective Neuroscience, 11, 14601470. doi:10.1093/scan/nsw051
Uzefovsky, F., Shalev, I., Israel, S., Edelman, S., Raz, Y., Mankuta, D., … Ebstein, R. (2015). Oxytocin receptor and vasopressin receptor 1a genes are respectively associated with emotional and cognitive empathy. Hormones and Behavior, 67, 6065. doi:10.1016/j.yhbeh.2014.11.007
Vansteelandt, S., DeMeo, D. L., Lasky-Su, J., Smoller, J. W., Murphy, A. J., McQueen, M., … Silverman, E. K. (2008). Testing and estimating gene-environment interactions in family-based association studies. Biometrics, 64, 458467. doi:10.1111/j.1541-0420.2007.00925.x
Vetter, N. C., Altgassen, M., Phillips, L., Mahy, C. E., & Kliegel, M. (2013). Development of affective theory of mind across adolescence: Disentangling the role of executive functions. Developmental Neuropsychology, 38, 114125. doi:10.1080/87565641.2012.733786
Wade, M., Browne, D., Madigan, S., Plamondon, A., & Jenkins, J. (2014). Normal birth weight variation and children's neuropsychological functioning: Links between language, executive functioning, and theory of mind. Journal of the International Neuropsychological Society, 20, 909919. doi:10.1017/s1355617714000745
Wade, M., Hoffmann, T. J., & Jenkins, J. M. (2014). Association between the arginine vasopressin receptor 1A (AVPR1A) gene and preschoolers’ executive functioning. Brain and Cognition, 90, 116123. doi:10.1016/j.bandc.2014.06.002
Wade, M., Hoffmann, T. J., & Jenkins, J. M. (2015). Gene-environment interaction between the oxytocin receptor (OXTR) gene and parenting behaviour on children's theory of mind. Social Cognitive and Affective Neuroscience, 10, 17491757. doi:10.1093/scan/nsv064
Walhovd, K. B., Fjell, A. M., Brown, T. T., Kuperman, J. M., Chung, Y., Hagler, D. J., … Akshoomoff, N. (2013). Long-term influence of normal variation in neonatal characteristics on human brain development. Proceedings of the National Academy of Sciences, 109, 2008920094. doi:10.1073/pnas.1208180109
Wang, J., Braskie, M. N., Hafzalla, G. W., Faskowitz, J., McMahon, K. L., de Zubicaray, G. I., & Thompson, P. M. (2017). Relationship of a common OXTR gene variant to brain structure and default mode network function in healthy humans. NeuroImage, 147, 500506. doi:10.1016/j.neuroimage.2016.12.062
Weisman, O., Pelphrey, K. A., Leckman, J. F., Feldman, R., Lu, Y., Chong, A., … Ebstein, R. P. (2015). The association between 2D: 4D ratio and cognitive empathy is contingent on a common polymorphism in the oxytocin receptor gene (OXTR rs53576). Psychoneuroendocrinology, 58, 2332. doi:10.1016/j.psyneuen.2015.04.007
Willcutt, E. G., Doyle, A. E., Nigg, J. T., Faraone, S. V., & Pennington, B. F. (2005). Validity of the executive function theory of attention-deficit/hyperactivity disorder: A meta-analytic review. Biological Psychiatry, 57, 13361346. doi:10.1016/j.biopsych.2005.02.006
Yamasue, H., Suga, M., Yahata, N., Inoue, H., Tochigi, M., Abe, O., … Takei, K. (2011). Reply to: Neurogenetic effects of OXTR rs2254298 in the extended limbic system of healthy Caucasian adults. Biological Psychiatry, 70, e41e42. doi:10.1016/j.biopsych.2011.07.021
Zelazo, P. D. (2006). The Dimensional Change Card Sort (DCCS): A method of assessing executive function in children. Nature Protocols, 1, 297301. doi:10.1038/nprot.2006.46
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Development and Psychopathology
  • ISSN: 0954-5794
  • EISSN: 1469-2198
  • URL: /core/journals/development-and-psychopathology
Please enter your name
Please enter a valid email address
Who would you like to send this to? *


Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed