title: ASD and Genetic Associations with Receptors for Oxytocin and Vasopressin-AVPR1A, AVPR1B, andOXTR.
abstract: Background:There are limited treatments available for autism spectrum disorder (ASD). Studies have reported significant associations between the receptor genes of oxytocin (OT) and vasopressin (AVP) and ASD diagnosis, as well as ASD-related phenotypes. Researchers have also found the manipulation of these systems affects social and repetitive behaviors, core characteristics of ASD. Consequently, research involving the oxytocin/vasopressin pathways as intervention targets has increased. Therefore, further examination into the relationship between these neuropeptides and ASD was undertaken. In this study, we examined associations between variants in the receptor genes of vasopressin (AVPR1A, AVPR1B), oxytocin (OXTR), and ASD diagnosis along with related subphenotypes.Methods:Probands were assessed using Autism Diagnostic Interview-Revised, Autism Diagnostic Observation Schedule, and clinical DSM-IV-TR criteria. Single nucleotide polymorphisms (SNPs) inAVPR1BandOXTR, and microsatellites inAVPR1Awere genotyped in ~200 families with a proband with ASD. Family-based association testing (FBAT) was utilized to determine associations between variants and ASD. Haplotypes composed ofOXTRSNPs (i.e., rs53576-rs2254298-rs2268493) were also analyzed due to previously published associations.Results:Using the additive inheritance model in FBAT we found associations betweenAVPR1BSNPs (rs28632197,p= 0.005, rs35369693,p= 0.025) and diagnosis. As in other studies,OXTRrs2268493 (p= 0.050) was associated with diagnosis. rs2268493 was also associated with ASD subphenotypes of social withdrawal (p= 0.013) and Insistence on Sameness (p= 0.039). Further analyses demonstrated that the haplotype, rs2254298-rs2268493 was found to be significantly associated with diagnosis (A-T;p= 0.026). FBAT was also used to analyzeAVPR1Amicrosatellites (RS1 and RS3). Both length variants were found to be associated with restrictive, repetitive behaviors, but not overall diagnosis. Correction for multiple comparisons was performed for SNPs tested in each gene region, onlyAVPR1BSNPs remained significantly associated with ASD diagnosis.Conclusions:Autism is a heterogeneous disorder with many genes and pathways that contribute to its development. SNPs and microsatellites in the receptor genes of OT and AVP are associated with ASD diagnosis and measures of social behavior as well as restricted repetitive behaviors. We reported a novel association with ASD andAVPR1BSNPs. Understanding of genotype-phenotype relationships may be helpful in the development of pharmacological interventions for the OT/AVP system.
authors.affiliation: Department of Psychiatry, University of Minnesota Minneapolis, MN, USA.
authors.forename: Sunday M
authors.initials: SM
authors.lastname: Francis
authors.affiliation: Department of Psychiatry and Behavioral Sciences, University of Washington WA, USA.
authors.forename: Soo-Jeong
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Biostatistics Shared Resource, Hollings Cancer Center, Medical University of South Carolina Charleston, SC, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Kistner-Griffin
authors.affiliation: Department of Psychiatry, Institute of Juvenile Research, University of Illinois at Chicago Chicago, IL, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Guter
authors.affiliation: Department of Psychiatry, Institute of Juvenile Research, University of Illinois at Chicago Chicago, IL, USA.
authors.forename: Edwin H
authors.initials: EH
authors.lastname: Cook
authors.affiliation: Department of Psychiatry, University of Minnesota Minneapolis, MN, USA.
authors.forename: Suma
authors.initials: S
authors.lastname: Jacob
keywords: neuropeptides; oxytocin; receptors; repetitive behaviors; social behaviors; vasopressin