Plasma oxytocin concentrations and OXTR polymorphisms predict social impairments in children with and without autism spectrum disorder

Abstract

The neuropeptide oxytocin (OXT) and its receptor (OXTR) regulate social functioning in animals and humans. Initial clinical research suggests that dysregulated plasma OXT concentrations and/or OXTR SNPs may be biomarkers of social impairments in autism spectrum disorder (ASD). We do not know, however, whether OXT dysregulation is unique to ASD or whether OXT biology influences social functioning more generally, thus contributing to, but not causing, ASD phenotypes. To distinguish between these possibilities, we tested in a child ASD cohort, which included unaffected siblings and unrelated neurotypical controls (ages 3-12 y; n = 193), whether plasma OXT concentrations and OXTR SNPs (i) interact to produce ASD phenotypes, (ii) exert differential phenotypic effects in ASD vs. non-ASD children, or (iii) have similar phenotypic effects independent of disease status. In the largest cohort tested to date, we found no evidence to support the OXT deficit hypothesis of ASD. Rather, OXT concentrations strongly and positively predicted theory of mind and social communication performance in all groups. Furthermore, OXT concentrations showed significant heritability between ASD-discordant siblings (h 2 = 85.5%); a heritability estimate on par with that of height in humans. Finally, carriers of the "G" allele of rs53576 showed impaired affect recognition performance and carriers of the "A" allele of rs2254298 exhibited greater global social impairments in all groups. These findings indicate that OXT biology is not uniquely associated with ASD, but instead exerts independent, additive, and highly heritable influences on individual differences in human social functioning, including the severe social impairments which characterize ASD. T he neuropeptide oxytocin (OXT) and its receptor (OXTR) regulate affiliative motivation, social bonding, and social recognition in animals (1, 2). Preclinical research likewise has shown that individual differences in OXT biology (e.g., OXT concentrations, OXTR distribution in key brain regions) are associated with individual differences in social functioning (3-6). At the extreme, experimental manipulations that diminish OXT peptide and/or receptor signaling produce a variety of social deficits in animal models (7,8).Translation of this animal research to neurotypical populations has confirmed that OXT administration enhances social functioning in humans (9, 10). Individual differences in endogenous OXT concentrations are also positively correlated with social behavior measures (11, 12), such that lower OXT concentrations are frequently associated with diminished social functioning even within neurotypical cohorts. This research has led to the hypothesis that abnormalities in OXT peptide biology may be directly related to social impairments observed in clinical populations, particularly in people with autism spectrum disorder (ASD), who exhibit core deficits in social interactions and preferences, eye contact, facial recognition, empathy, and social communication.Several studies have begun to exp...

Perception of Facial Aging and Its Relationship to Two Single Nucleotide Polymorphisms (OXTR rs53576, CD38 rs3796863)

“…Such "allele flips" (i.e., study-to-study variations in indicating which allele is associated with risk) are not uncommon across different association studies of oxytocinergic genes (Michalska et al, 2014;Parker et al, 2014) and are thought to arise due to genetic heterogeneity between the sampled populations (e.g., diverging haplotypes, differing allele frequencies) as well as discordant environmental factors between populations (Clarke & Cardon, 2010). It is unclear to what extent our sample may have differed from previous studies along these parameters and we cannot exclude their potential impact upon our assignment of allele risk.…”

Autism-Like Behavior in BTBR Mice Is Improved by Electroconvulsive Therapy

“…Oxytocin promotes social behavior, while its deficiency (e.g., oxytocin or oxytocin receptor gene polymorphism) has been implicated in mechanisms of autism [11][12][13]. Oxytocin and oxytocin receptor knockout mice present with autism-like abnormalities [14,15], whereas exogenously administered oxytocin improves autism-like behavior in mice of the BALB/cByJ and C58/J strains [16].…”

“…Oxytocin is a Bsocialĥ ormone, and its deficiency has been implicated in mechanisms of autism in both clinical and experimental studies. Clinical studies connected autism to the decreased plasma oxytocin levels, as well as to oxytocin receptor gene polymorphism [11][12][13]. In the laboratory setting, oxytocin receptor knockout mice presented with autism-like behavioral impairments [14,15].…”

Introducing Therioepistemology: the study of how knowledge is gained from animal research

“…But this bizarre "Stepford Experiment" is exactly what we aspire to in an animal study. In human work, not only do we recognize the richness of individual diversity, but we actively study it 17,18,40,[107][108][109] . More advanced experimental designs and analyses that either study individual variation or spontaneous disease within the animal population 54 , or which deliberately introduce variability in a controlled manner [26][27][28] as we do in real human trials, offer several advantages.…”

“…In human trials it is considered best practice to register an analysis plan, to specify primary outcome measures, and in general to formally state both a null hypothesis and how it will be tested. There is a clear understanding that the more rigorously defined an analysis is before its performance, the more likely a significant result is to be true, for a variety of reasons 22 , not least the avoidance of p-hacking 107 . Contrast this with animal trials that often have multiple stages of confirmation, which is not hypothesis testing.…”