represent the higher. Factor analytic approaches had also failed to show discontinuity between autistic spectrum disorders and autistic-like traits (Constantino et al., 2004) and in two twin studies no genetic or environmental thresholds could be discerned, which also indicates a continuum of symptoms (Ronald et al., 2006; Lundstrom et al., 2012). Additionally, a series of studies demonstrated that the same common genetic variants associated with autism are associated with differences in social ability in the normal population, which includes processing of social information (Tops et al., 2011), personality traits (Rodrigues et al., 2009) and different brain anatomy and activity during social tasks (Tost et al., 2010). Among these genetic variants, three of the most studied are the SNPs rs53576 and rs2254298 of the OXTR and rs3796863 of the CD38 gene. For these SNPs, several studies indicate an association between risk alleles and impairments on social behavior in the general population (Lucht et al., 2009; Bakermans-Kranenburg et al., 2008; Kim et al., 2010; Feldman et al., 2012; Sauer et al., 2012) and at least three studies pointed out that the critical alleles of these SNPs are overtransmitted in ASD
(Wu et al., 2005; Munesue et al., 2010; Lerer et al., 2010). However, the investigation of these genetical variants as determinants of autistic traits as measured by scales such as the Autism-spectrum Quotient (Baron-Cohen et al., 2001) and Social Responsiveness Scale (Constantino et al., 2003a) in the general population has not been a focus of attention of many studies. If the autistic traits are normally distributed in the general population and these genetical variants associated with autism are also associated with social deficits in the same population, it is presumed that these genetical variants may also be associated with the presence of autistic traits in individuals without a diagnosis of a mental disorder.
Among the different traits and deficits that an individual with autism can exhibit, three of them were systematically investigated in the general population by Baron-Cohen et al.: Empathizing, Systemizing and specific traits of autism (Wheelwright et al., 2006).
Empathizing is one such specific component of social cognition and is defined as the drive to identify another person’s emotion and thoughts, and to respond to these with an appropriate emotion. Empathy consists of an
affective and cognitive component, which respectively includes an observer’s emotional response to the affective state of another and a “theory of mind”
(attribution of a mental state and prediction of behaviors and feelings of someone else) (Baron-Cohen &
Wheelwright, 2004). Systematizing is defined as the drive to analyze, understand, predict, control and construct rule-based systems, which is higher prevalent in autistic probands and in men. In contrary, females score higher on empathy while autistic probands have the lowest score (Wheelwright et al., 2006). Finally, specific autistic traits of autism can be understood as those traits that are important to the definition and diagnosis of the disorder, i.e. the criteria in the diagnose manuals. They include traits like attention to details and deficits in social skills, communication, attention switching and imagination (Baron-Cohen et al., 2001). Of interest is the fact that men tend to have a higher prevalence of specific autistic traits than women, which in association with the higher prevalence of autism in males, lead some authors to consider autism as an extreme expression of a “male brain” phenotype (Baron-Cohen, 2002). This extreme
male brain phenotype is normally characterized as a higher prevalence of specific autistic traits, higher tendency to systematizing and lower levels of empathy, which in fact, described the phenotype observed in ASD.
Whether these heritable phenotypes, which are characterized by being extremes of a continuum in a given population, are determined by the SNPs rs3796863, rs2254298 and rs53576, has not been a subject of any study. The only genetic-wide association study of autistic traits in the general population, using a dimensional measure of autistic-like behaviors, (Ronald et al., 2010) found an association of three SNPs with autistic behaviors but none of them are directly related to oxytocin and linkage disequilibrium was not described in one autistic sample. The interaction of both SNPs in the determination of social behavior has not also been studied until this moment. Regarding the cited studies, it is plausible to assume that critical alleles of both SNPs are associated with the presence of autistic traits in a
“dose-dependent” manner and that the interaction between them has a significant effect.
Furthermore, animal studies show that a variety of stressful circumstances are associated with the activation of oxytocinergic neurons in the hypothalamus and with oxytocin release in the blood circulation (Onaka, 2004).
The experience of traumatic events is also associated with alterations in oxytocin secretion in humans (Pierrehumbert et al., 2010; Heim et al., 2009). In conjunction these findings led to the confirmed hypothesis that oxytocin is also involved in the regulation of the physiological stress response.
Some animal studies show that oxytocin, when administered for some days, can inhibit the activity of the HPA and the release of ACTH and corticosterone (Windle et al., 1997; Windle et al., 2004). In humans, oxytocin regulates the stress response and its intranasal administration reduces the release of cortisol and anxiety (Ditzen et al., 2009; Heinrichs et al., 2003; Quirin et al., 2011). It is well accepted that oxytocin release is one of the ways by which social support modulates the magnitude of the stress reaction and exerts a protective role. Carriers of the critical allele A of the SNPs rs53576 have higher physiological and dispositional stress
reactivity and do not benefit from social contact as a protective factor during stress tests. Unlike GG homozygotes, a suppressive effect of social support on the stress reaction (i.e. lower cortisol levels) has not been indentified (Rodrigues et al., 2009; Chen et al., 2011).
Considering the suppressive effect of oxytocin on the HPA, it is also plausible that an effect of the critical alleles on the SNPs rs3796863, rs2254298 and rs53576 on the modulation of the HPA and sympathetic activity can be demonstrated during participation in a social stress test. Presumably, if the polymorphisms have additive effects, an effect of their interaction will be also observed. In this respect, carriers of the critical alleles would present a relatively intense stress reaction, which would be demonstrated by higher levels of cortisol and alpha-amylase, and report of negative emotions.
The purpose of this thesis is to investigate the effect that the SNPs rs3796863, rs2254298 and rs53576 have in the prevalence of autistic traits in a sample of healthy adults, and the individual differences on the stress response during a standardized stress test in male participants. As a secondary objective, the impression that the participants
cause on blind raters will also be investigated. Regarding this, the main hypotheses of this thesis can be so formulated:
H1: Critical alleles (rs53576A, rs2254298A and rs3796863C) have a dose-dependent effect on the prevalence of autistic traits and on the empathy and systematizing quotients.
H2: Homozygotes for the OXTR rs53576 (GG) and rs2254298 (GG) have an attenuated HPA and sympathetic response to social stress when compared with critical allele carriers (AA/AG).
H3: Homozygotes for the CD38 rs3796863 (CC) critical alleles have an enhanced HPA and sympathetic response to social stress in comparison with carriers of the A allele (AC/AA).
H4: There are differences in the intensity of the emotional states evoked by the Trier Social Stress Test associated with different genotype groups mentioned above, in which critical alleles carriers may report more
negative emotions like anxiety or anger and less positive emotions like joy.
H5: Carriers of critical alleles cause a worse impression on blind raters during public speaking.
H6: The selected SNPs interact in an additive manner to determine the mentioned behavioral phenotypes, in which a larger number of critical alleles is associated with worse social abilities.
H7: The selected SNPs interact to determine the magnitude of the HPA and sympathetic response to social stress in the same manner reported on H6.