PMID- 27843152 OWN - NLM STAT- MEDLINE DCOM- 20171113 LR - 20181113 IS - 1476-5578 (Electronic) IS - 1359-4184 (Print) IS - 1359-4184 (Linking) VI - 22 IP - 8 DP - 2017 Aug TI - Additive effects of oxytocin receptor gene polymorphisms on reward circuitry in youth with autism. PG - 1134-1139 LID - 10.1038/mp.2016.209 [doi] AB - 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. FAU - Hernandez, L M AU - Hernandez LM AD - Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, USA. AD - Interdepartmental Neuroscience Program, University of California, Los Angeles, Los Angeles, CA, USA. FAU - Krasileva, K AU - Krasileva K AD - Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, USA. AD - Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. FAU - Green, S A AU - Green SA AD - Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, USA. AD - Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA. FAU - Sherman, L E AU - Sherman LE AD - Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, USA. AD - Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA. FAU - Ponting, C AU - Ponting C AD - Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, USA. AD - Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA. FAU - McCarron, R AU - McCarron R AD - Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, USA. AD - Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA. FAU - Lowe, J K AU - Lowe JK AD - Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. FAU - Geschwind, D H AU - Geschwind DH AD - Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA. AD - Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA. AD - Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA. FAU - Bookheimer, S Y AU - Bookheimer SY AD - Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA. FAU - Dapretto, M AU - Dapretto M AD - Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, USA. AD - Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA. LA - eng GR - F31 DA038578/DA/NIDA NIH HHS/United States GR - T32 MH073526/MH/NIMH NIH HHS/United States GR - F32 MH105167/MH/NIMH NIH HHS/United States GR - K08 MH112871/MH/NIMH NIH HHS/United States GR - U54 HD087101/HD/NICHD NIH HHS/United States GR - C06 RR012169/RR/NCRR NIH HHS/United States GR - R01 MH100028/MH/NIMH NIH HHS/United States GR - S10 OD011939/OD/NIH HHS/United States GR - P50 HD055784/HD/NICHD NIH HHS/United States GR - C06 RR015431/RR/NCRR NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20161115 PL - England TA - Mol Psychiatry JT - Molecular psychiatry JID - 9607835 RN - 0 (Receptors, Oxytocin) RN - 50-56-6 (Oxytocin) SB - IM MH - Adolescent MH - Alleles MH - Autism Spectrum Disorder/*genetics MH - Autistic Disorder/genetics MH - Brain MH - Case-Control Studies MH - Child MH - Female MH - Frontal Lobe MH - Gene Dosage/genetics MH - Gene Frequency/genetics MH - Genetic Variation MH - Humans MH - Male MH - Neuroimaging/methods MH - Nucleus Accumbens/physiopathology MH - Oxytocin/metabolism MH - Polymorphism, Single Nucleotide/genetics MH - Receptors, Oxytocin/*genetics/metabolism MH - Reward MH - Social Behavior PMC - PMC5991611 MID - NIHMS970818 COIS- CONFLICT OF INTEREST The authors declare no conflict of interest. EDAT- 2016/11/16 06:00 MHDA- 2017/11/14 06:00 PMCR- 2018/06/07 CRDT- 2016/11/16 06:00 PHST- 2016/07/19 00:00 [received] PHST- 2016/08/30 00:00 [revised] PHST- 2016/10/04 00:00 [accepted] PHST- 2016/11/16 06:00 [pubmed] PHST- 2017/11/14 06:00 [medline] PHST- 2016/11/16 06:00 [entrez] PHST- 2018/06/07 00:00 [pmc-release] AID - mp2016209 [pii] AID - 10.1038/mp.2016.209 [doi] PST - ppublish SO - Mol Psychiatry. 2017 Aug;22(8):1134-1139. doi: 10.1038/mp.2016.209. Epub 2016 Nov 15.