ASD and Genetic Associations with Receptors for Oxytocin and Vasopressin—AVPR1A, AVPR1B, and OXTR

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) in AVPR1B and OXTR, and microsatellites in AVPR1A were 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 of OXTR SNPs (i.e., rs53576-rs2254298-rs2268493) were also analyzed due to previously published associations.Results: Using the additive inheritance model in FBAT we found associations between AVPR1B SNPs (rs28632197, p = 0.005, rs35369693, p = 0.025) and diagnosis. As in other studies, OXTR rs2268493 (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 analyze AVPR1A microsatellites (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, only AVPR1B SNPs 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 and AVPR1B SNPs. Understanding of genotype-phenotype relationships may be helpful in the development of pharmacological interventions for the OT/AVP system.

Oxytocin and vasotocin receptor variation sheds light into the evolution of human prosociality

“…Carriers of the MHS C allele displayed more stress-related vocal symptoms (dysphonia, muscle tension, frequency changes) and higher cortisol levels 62 . The MHS allele rs2258493(T) has been linked to ASD subphenotypes 63 and diagnosi 41, 64, 65 , negative scores in social performance, perception and mentalizing tasks in schizophrenia patients 66 , ADHD patients 67 and depressive temperament (as part of a haplotype block) 19 . Carriers of this allele also showed reduced mesolimbic reward system activation, a result that might point towards the neurobiological basis of the aforementioned phenotypic effects of this SNP 68 .…”

“…Concerning AVPR1B, rs28676508(T) has been claimed to be involved in child onset aggression 94 . The missense (arginine to histidine, position 364) variant rs28632197(T) has been associated with ASD diagnosis 63 and panic disorder 95 . Finally, the G allele of rs33985287 protects against depressive moods in female children 96 .…”

NMDA receptor in vasopressin 1b neurons is not required for short-term social memory, object memory or aggression

“…Recent data indicate that variation in Avpr1b signaling may have maladaptive impacts on human social behavior. Avpr1b SNP variants are positively correlated with autism diagnoses (Francis, Kim et al 2016) and with increased emotional aggression (Luppino, Moul et al 2014). Similarly, life-long disruption of Avpr1b signaling through genetic removal in knockout (KO) mice results in altered social aggression and social memory performance (Wersinger, Ginns et al 2002), while leaving spatial and object memory performance and olfactory discrimination intact, indicating a special role in the social aspect of memory (Wersinger, Ginns et al 2002, Wersinger, Kelliher et al 2004, Wersinger, Caldwell et al 2007, Caldwell, Wersinger et al 2008).…”

Epigenetic dysregulation of Oxtr in Tet1-deficient mice has implications for neuropsychiatric disorders

“…The involvement of DNA methylation in regulating the expression of OXTR has been suggested, but the exact mechanism mediating this process remains largely unknown (9)(10)(11). Epigenetic studies in humans have found altered DNA methylation in the 5′ CpG island of OXTR in a wide spectrum of morbid behaviors and neuropsychiatric disorders, such as autism spectrum disorder (ASD), schizophrenia, bipolar, depression, obsessive-compulsive disorders (OCD), and anxiety (12)(13)(14)(15)(16)(17)(18). Similar correlations between DNA methylation and behavior are also reported in other species, such as dog and nonhuman primates (19,20).…”