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Additive effects of oxytocin receptor gene polymorphisms on reward circuitry in youth with autism

Abstract

Several common alleles in the oxytocin receptor gene (OXTR) are associated with altered brain function in reward circuitry in neurotypical adults and may increase risk for autism spectrum disorders (ASD). Yet, it is currently unknown how variation in the OXTR relates to brain functioning in individuals with ASD, and, critically, whether neural endophenotypes vary as a function of aggregate genetic risk. Here, for we believe the first time, we use a multi-locus approach to examine how genetic variation across several OXTR single-nucleotide polymorphisms (SNPs) affect functional connectivity of the brain’s reward network. Using data from 41 children with ASD and 41 neurotypical children, we examined functional connectivity of the nucleus accumbens (NAcc) – a hub of the reward network – focusing on how connectivity varies with OXTR risk-allele dosage. Youth with ASD showed reduced NAcc connectivity with other areas in the reward circuit as a function of increased OXTR risk-allele dosage, as well as a positive association between risk-allele dosage and symptom severity, whereas neurotypical youth showed increased NAcc connectivity with frontal brain regions involved in mentalizing. In addition, we found that increased NAcc-frontal cortex connectivity in typically developing youth was related to better scores on a standardized measure of social functioning. Our results indicate that cumulative genetic variation on the OXTR impacts reward system connectivity in both youth with ASD and neurotypical controls. By showing differential genetic effects on neuroendophenotypes, these pathways elucidate mechanisms of vulnerability versus resilience in carriers of disease-associated risk alleles.

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Acknowledgements

This work was supported by the National Institute of Child Health and Human Development grant P50 HD055784 (to SYB), National Institute of Mental Health grant RO1 MH100028 (to SYB), National Institute of Mental Health grant T32 MH073526-08 (to LMH), National Research Service Awards F32 MH105167-01 (to SAG) and F31 DA038578-01A1 (to LES). We are grateful for the generous support from the Brain Mapping Medical Research Organization, Brain Mapping Support Foundation, Pierson-Lovelace Foundation, The Ahmanson Foundation, Capital Group Companies Charitable Foundation, William M. and Linda R. Dietel Philanthropic Fund, and Northstar Fund. Research reported in this publication was also partially supported by the National Center for Research Resources and by the Office of the Director of the National Institutes of Health under award numbers C06RR012169, C06RR015431 and S10OD011939. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Hernandez, L., Krasileva, K., Green, S. et al. Additive effects of oxytocin receptor gene polymorphisms on reward circuitry in youth with autism. Mol Psychiatry 22, 1134–1139 (2017). https://doi.org/10.1038/mp.2016.209

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