Genetic predisposition of behavioral response

We Are Who We Meet

As humans, we understand that our behavior and the relationships we form throughout life are manifestations of our positive and negative experiences of social interaction. However, the notion that the evolution of our behavioral response is solely shaped by the events themselves is challenged by studies that highlight how interindividual differences in social perception and response to social cues may be determined by underlying genetic predisposed. These studies are establishing that our DNA contains heritable variants that contribute to subtle differences in social cognition. These sequence variants are contained within genes that not only play a role in the relationship that parents may have with their offspring but also how we recognize or react to one another (1, 2). In PNAS, Skuse et al. (3) investigate the signaling pathways of neuropeptides oxytocin (OT) and arginine-vasopressin (AVP) to identify DNA polymorphisms that might explain interindividual differences in response to social cues. The authors genotyped a series of SNPs from the OT and AVP receptor regions to identify SNPs that account for variation in response to tests of social cognition in autism spectrum disorder (ASD) families.

Coalescing Discrete Deficits

Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development that includes core deficits in language development, patterns of repetitive behaviors and/or restricted interests, and core deficits in social interaction. The authors hypothesized that there may be a genetic component driving the deficits in the latter of these core ASD components. Thus, they used three tests of social cognition, the facial emotion recognition task (ERT-fear), the facial recognition memory test (FMRT), and the eye gaze monitoring task (GMT), within the general population to standardize the scores across age and sex, and then within ASD families, and correlated these scores with SNP genotypes from the neuropeptide receptors. The ASD cases represented a cohort that has known deficits and a wider response to social cues, whereas the families permitted the authors to assess the heritability of the variants from the OT receptor (OXTR) and AVP receptor (AVPR1a).

The OT and AVP signaling pathways have long been known to play important prosocial roles influencing social behavior and cognitive

Skuse et al. investigate the signaling pathways of neuropeptides oxytocin and argininevasopressin to identify DNA polymorphisms that might explain interindividual differences in response to social cues.

function in a species-specific manner (4, 5); however, these functions have sexually dimorphic roles in brain function and behavior (6), which is of particular relevance to autism because of the disproportionate number of affected males. The aberrant regulation of OT signaling has already been shown to play a role in the development in high functioning autism spectrum disorder (7–9). Functionally, children with autism have been shown to contain higher OT precursor levels in their plasma (10) but have significantly lower plasma OT levels (11), suggesting impaired OT biosynthesis. Genetic and epigenetic data also support a role of the OT signaling pathway in the etiology of autism via OXTR based on genetic linkage (12), genetic association (13–15), and epigenetic data (16). Additionally, sequence variation in the AVRP1a promoter repeat region, RS3, has been implicated in variance associated with primate personality (17), maternal behavior (18), and pair bonding (19).

The Behavior of Social Cues

Ultimately, the investigators identified a modest statistical association with a variant, rs237887, in intron 3 of OXTR with FMRT. The SNP was associated in their cohort of almost 200 ASD patients, mothers, fathers, and unaffected siblings from UK discovery and Finnish replication populations. Interestingly, the association, which survived testing for multiple comparisons, was most significant when calculated with all family members and was independent of affection status and intelligence quotient. Further, the level of facial recognition was dependent on the number of inherited alleles; for example, individuals who had the AA genotype from the A/G SNP had the worst facial recognition score. In toto, these data are interesting because they identify a genetic component to one of the core deficits of ASD and, by doing so, support the notion that ASD develops because of a constellation of individual heritable components, i.e., de novo risk alleles/genomic rearrangements, etc., to a multifaceted disorder.

Nonetheless, the authors need to establish how this genetically associated, noncoding SNP may regulate the function of the OXTR and how it modulates the signaling of its intriguing ligand, OT. This work contributes yet another piece of the OT-ASD puzzle. Most recently, Gordon et al. demonstrated in PNAS (20) that administration of OT as a nasal spray to a small number of high-functioning children with autism resulted in increased activity in the right amygdala and orbitofrontal cortex during social vs. nonsocial judgments. This region-specific brain response may result from epigenetic regulation OXTR gene expression as indicated by a recent study (21). Together, these data provide yet further support for a role of these social peptides in the etiology of a heritable component in the spectrum of autism disorders.