title: 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.
authors.affiliation: Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, USA.|Interdepartmental Neuroscience Program, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: L M
authors.initials: LM
authors.lastname: Hernandez
authors.affiliation: Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, USA.|Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Krasileva
authors.affiliation: Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, USA.|Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: Green
authors.affiliation: Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, USA.|Department of Psychology, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: L E
authors.initials: LE
authors.lastname: Sherman
authors.affiliation: Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, USA.|Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Ponting
authors.affiliation: Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, USA.|Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: R
authors.initials: R
authors.lastname: McCarron
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: J K
authors.initials: JK
authors.lastname: Lowe
authors.affiliation: Department of Neurology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.|Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA.|Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: D H
authors.initials: DH
authors.lastname: Geschwind
authors.affiliation: Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: S Y
authors.initials: SY
authors.lastname: Bookheimer
authors.affiliation: Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles, Los Angeles, CA, USA.|Department of Psychiatry and Biobehavioral Sciences, University of California, Los Angeles, Los Angeles, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Dapretto
mesh_terms: D000293:Adolescent; D000483:Alleles; D000067877:Autism Spectrum Disorder / Q000235:genetics*; D001321:Autistic Disorder / Q000235:genetics; D001921:Brain; D016022:Case-Control Studies; D002648:Child; D005260:Female; D005625:Frontal Lobe; D018628:Gene Dosage / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D014644:Genetic Variation; D006801:Humans; D008297:Male; D059906:Neuroimaging / Q000379:methods; D009714:Nucleus Accumbens / Q000503:physiopathology; D010121:Oxytocin / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018045:Receptors, Oxytocin / Q000235:genetics* / Q000378:metabolism; D012201:Reward; D012919:Social Behavior
chemical_list: D018045:Receptors, Oxytocin; D010121:Oxytocin