The present results extend previous work on OXTR sequence variants’ role in predicting facets of human behavior. Under the assumption of sexually dimorphic effects, an association was observed for two substitutions and Harm Avoidance, with female carriers of the minor alleles scoring highest.
The possible implications of this observation are three-fold:
From an evolutionary perspective, oxytocin control of Harm Avoidance in humans is relevant to parental care and related behaviors. According to Cloninger, harm avoidant reaction patterns have arisen from multifactorial phylogenetic mechanisms which in their 'optima' are advantageous to the adaptation and survival of the individual [20
]. Human offspring require more intense care and protection from hazards in early life than other species. Both the fine-tuning of appraisal mechanisms that detect potential threats to the offspring and the initiation of alarm responses in parents are key to averting hazards. There is a growing concern, however, that high levels of anxiety or excessive harm avoidant behavior in parents may be counter-productive and, in some age-groups, may even augment childrens' levels of anxiety [21
]. Oxytocin exerts anxiolytic effects that can balance and optimize maternal defense. Consistent with this view, breast-feeding women show lower systolic blood pressure reactivity to aggressive encounters than do formula-feeding women [22
]. Similar observations have been made during lactation using cold pressor and mental arithmetic stressor tasks [23
]. Provided that OXTR are involved in these functionalities, and provided the present association is genuine, women carrying the minor OXTR
alleles could be less susceptible to the anxiety-attenuating effects of oxytocin than subjects carrying only wild-type alleles and, possibly, more prone to responding aggressively to detected threats. While a certain measure of heightened reactivity to stressful stimuli should benefit the defense of offspring, excessive emotional lability is liable to interfere with sensitive parenting [24
]. Sex-specific responses to oxytocin could be one reason why HA is gender-sensitive [25
]. Until this is confirmed, the absence of a main effect of genotype on HA scores in men cautions against overrating the predictive role of OXTR
in shaping personality traits.
From a more general point of view, the gene encoding OXTR has been implicated in the responsiveness to social support as a buffer against stress [26
]. This extends the reciprocal interaction between serotonin and social behavior to the oxytocinergic system [24
]. To specifically evaluate gene x environment interactions of the SNPs examined, however, more work is needed in a context of psychosocial stress exposure. Theoretically, a putative loss of OXTR function could be mediated either by the T alleles, or by mutations that are in linkage disequilibrium with these alleles. Of the two variants addressed here, rs237900 is intronic, and its functionality is uncertain. Rs237902 stands for a synonymous substitution at residue 230 and has the potential to interfere with gene expression, e.g. by disrupting motifs recognized by transcription factors, or by affecting post-transcriptional regulatory mechanisms. Confirmatory investigations in larger samples are still required, together with an elucidation of the mechanism by which the endocrine response is altered.
In contrast to the results described earlier for rs53576 [11
], we failed to identify significant genetic effects on the personality dimension of Reward Dependence. This could be due to a difference in sample size, or to using different markers. Others have shown that rs237902 and rs53576 map to two different haplotype blocks in the Caucasian population [2
]. Balancing of Harm Avoidance and Reward Dependence would appear to facilitate response selection mechanisms in parental care. On the one hand, sources of reward trigger heightened distress when the attachment object is being threatened. Thus reward-related reactivity of mothers to images of infants (as measured by activation of the ventral striatum) varies with cues of potential harm [28
]. On the other hand, reward responses are believed to buffer otherwise deleterious levels of heightened anxiety and stress [30
]. On these grounds, common OXTR
variants could serve to predict Harm Avoidance and Reward Dependence, depending on the markers used, and on the assumptions made in the respective models. It is noteworthy that sexually dimorphic effects of OXTR
variants are emerging in the sensitivity to pain [7
], a composite trait integrating, in turn, measures of Harm Avoidance and Reward Dependence [31
Finally, identification of a novel A217T mutation in a highly harm avoidant subject may be a chance finding. Whether a putative loss of receptor function is aggravated any further by this rare substitution is unresolved. Its location in a highly conserved region argues against a neutral effect on the OXTR protein and should therefore justify inclusion in future investigations of target phenotypes.