Association of oxytocin receptor (OXTR) gene variants with multiple phenotype domains of autism spectrum disorder

Abstract

Autism spectrum disorder (ASD) is characterized by core deficits in social behavior, communication, and behavioral flexibility. Several lines of evidence indicate that oxytocin, signaling through its receptor (OXTR), is important in a wide range of social behaviors. In attempts to determine whether genetic variations in the oxytocin signaling system contribute to ASD susceptibility, seven recent reports indicated association of common genetic polymorphisms in the OXTR gene with ASD. Each involved relatively small sample sizes (57 to 436 families) and, where it was examined, failed to identify association of OXTR polymorphisms with measures of social behavior in individuals with ASD. We report genetic association analysis of 25 markers spanning the OXTR locus in 1,238 pedigrees including 2,333 individuals with ASD. Association of three markers previously implicated in ASD susceptibility, rs2268493 (P = 0.043), rs1042778 (P = 0.037), and rs7632287 (P = 0.016), was observed. Further, these genetic markers were associated with multiple core ASD phenotypes, including social domain dysfunction, measured by standardized instruments used to diagnose and describe ASD. The data suggest association of OXTR genetic polymorphisms with ASD, although the results should be interpreted with caution because none of the significant associations would survive appropriate correction for multiple comparisons. However, the current findings of association in a large independent cohort are consistent with previous results, and the biological plausibility of participation of the oxytocin signaling system in modulating social disruptions characteristic of ASD, suggest that functional polymorphisms of OXTR may contribute to ASD risk in a subset of families.

Oxytocin receptor gene ( OXTR ) is related to psychological resources

“…The association of variation in intron 3 of the OXTR with psychological resources and depressive symptomatology is consistent with an emerging body of evidence associating variation in this region with similar psychological phenotypes (35,50), psychological responses in experimental studies (33,34,37), and neural reactivity to emotional stimuli (38). Although the precise molecular mechanisms responsible for these associations are unclear, intron 3 is emerging as an important region in the regulation of OXTR expression.…”

Developmental Perspectives on Oxytocin and Vasopressin

“…In combination with an enriched social-sensory developmental environment, this enhanced developmental expression of neocortical OXTR should lead to enhanced social expertise in adulthood because of more facile neural computation of sensory input as adults (Figure 4). Atypical neocortical multisensory processing is a proposed etiological factor in autism, indicating that this mechanism may help explain some of the gene association studies implicating OXTR in autism (Wu et al, 2005;Jacob et al, 2007;Israel et al, 2008;Lerer et al, 2008;Liu et al, 2010;Campbell et al, 2011), and also that it may be difficult to detect the effect of OXTR alleles on autism risk (Tansey et al, 2010) without controlling for social and sensory environment in early life. As sensory systems are exceptionally tractable experimental targets in human neuroscience research, exploring the interaction between oxytocin and neocortical function should be a highly informative research area in the near term.…”

Integrative Approaches Utilizing Oxytocin to Enhance Prosocial Behavior: From Animal and Human Social Behavior to Autistic Social Dysfunction

“…Prairie voles, in particular, have been useful in revealing OT's role in human sociality largely because they share with humans the tendency toward forming selective preferences for familiar conspecifics (Williams et al, 1992). In the context of mating and reproduction, this tendency is expressed as a selective preference to spend time with a bonded mate over an unfamiliar conspecific (Williams et al, 1992;Carter and Keverne, 2002).…”

“…Prairie voles, in particular, have been useful in revealing OT's role in human sociality largely because they share with humans the tendency toward forming selective preferences for familiar conspecifics (Williams et al, 1992). In the context of mating and reproduction, this tendency is expressed as a selective preference to spend time with a bonded mate over an unfamiliar conspecific (Williams et al, 1992;Carter and Keverne, 2002). Biological adaptations that facilitate selective social preference likely arise because they offer adaptive benefits, helping individuals efficiently overcome the many stressors and challenges associated with survival and reproduction throughout the lifespan (Carter, 1998;Porges, 2003a).…”