European Psychiatry The role of schizotypal traits and the OXTR www.cambridge.org/epa gene in theory of mind in schizophrenia: A family-based study M. Giralt-López1,2, S. Miret3,4, J. Soler4,5, S. Campanera3, M. Parellada4,6, Research Article L. Fañanás4,5 and M. Fatjó-Vilas4,5,7 Cite this article: Giralt-López M, Miret S, Soler J, Campanera S, Parellada M, Fañanás L, 1 Servei de Psiquiatria, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; 2Departament de Psiquiatria i Fatjó-Vilas M (2020). The role of schizotypal traits and the OXTR gene in theory of mind in Medicina Legal, Universitat Autònoma de Barcelona (UAB), Bellaterra, Spain; 3Centre de Salut Mental d'Adults de Lleida, schizophrenia: A family-based study. European Servei de Psiquiatria, Salut Mental i Addiccions, Hospital Universitari Santa Maria, Lleida, Spain; 4Centro de Investigación Psychiatry, 63(1), e15, 1–8 Biomédica en Red de Salud Mental (CIBERSAM), Instituto de Salud Carlos III, Madrid, Spain; 5Departament de Biologia https://doi.org/10.1192/j.eurpsy.2019.17 Evolutiva, Ecologia i Ciències Ambientals, Facultat de Biologia, Universitat de Barcelona, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Barcelona, Spain; 6Departamento de Psiquiatría del Niño y del Adolescente, Hospital Received: 10 July 2019 General Universitario Gregorio Marañón, Universidad Complutense, Madrid, Spain and 7FIDMAG Germanes Revised: 05 December 2019 Hospitalàries Research Foundation, Barcelona, Spain Accepted: 06 December 2019 Key words: Abstract Family-based study; OXTR gene; schizophrenia; schizotypy; theory of mind Background. There is consistent evidence that theory of mind (ToM) is impaired in schizo- phrenia (SZ); however, it remains unclear whether such deficits are trait- or state-dependent. We Author for correspondence: evaluated ToM in patients with schizophrenia spectrum disorders (SSDs), their healthy first- Mar Fatjó-Vilas and Salvador Miret degree relatives, and controls to test its suitability as an endophenotypic marker. We also studied E-mails: mfatjo-vilas@fidmag.com, the modifying effect of markers of clinical and genetic liability to SZ (schizotypy and genetic smiret@gss.scs.es variability in the oxytocin receptor gene: OXTR) on ToM in healthy individuals. Methods. The sample included 38 stable SSD patients, 80 unaffected first-degree relatives, and 81 controls. ToM was assessed using the Hinting Task (HT) and schizotypy via the Schizotypal Personality Questionnaire-Brief (SPQ-B), which generates interpersonal (SPQ-IP), cognitive- perceptual (SPQ-CP), and disorganization (SPQ-D) scores. The polymorphism rs53576 of OXTR was genotyped. Results. Patients presented poorer HT performance than relatives and controls (p = 0.003 and p < 0.001). High SPQ-IP and SPQ-CP scores correlated with poorer ToM performance in relatives (p = 0.010 and p = 0.030), but not in controls. OXTR was not associated with HT scores, but it showed a modifying effect within controls; high SPQ-CP was related to HT poorer performance conditional to GG genotype (p = 0.007). Conclusions. ToM deficits were present in patients but not in unaffected relatives or controls. However, our data indicate the usefulness of clinical and genetic liability markers to characterize differences in ToM abilities within healthy individuals. Then, the observed link between ToM and SZ liability suggests the putative role of ToM as an endophenotypic marker. Nevertheless, new analyses in larger samples are needed. Introduction Schizophrenia (SZ) is a prevalent and severe psychiatric disorder with a complex etiology involving environmental and genetic factors (heritability ffi 80%). The high degree of disability, prevalence, chronicity, and financial costs place an enormous burden on patients with SZ, their families, and society as a whole. This burden warrants efforts to identify predictors directly applicable to prevention, diagnosis, and therapy. Research into these predictors has produced growing evidence that social cognition deficits are an important predictor of outcome, even more so than neurocognition [1]. Social cognition refers to a wide range of skills that allow people to perceive, interpret and process social stimuli, and that guide social interactions. One of its multiple components is theory of mind (ToM), that is, the ability to infer mental states, such © The Author(s) 2020. This is an Open Access as beliefs, intentions, desires, and emotions, in other people [2]. article, distributed under the terms of the Creative Commons Attribution licence (http:// ToM impairments are being increasingly reported in SZ [3–5]. Although some studies have creativecommons.org/licenses/by/4.0/), which interpreted ToM deficits as a state marker associated with symptoms in the active phase of the permits unrestricted re-use, distribution, and disease [6] or with the severity of negative symptoms [7], the majority have reported ToM reproduction in any medium, provided the impairment to be a trait marker, still present in remission [8,9] and found to be stable after a original work is properly cited. longitudinal 3-year follow-up design [10]. Several studies also indicate that ToM deficits are present in first-episode psychosis and in high-risk individuals (unmedicated prodromal subjects) [4,11]. Family-based study designs are suitable for establishing whether ToM is a trait feature when the defect is also seen in healthy family members (in a higher prevalence than in controls). Although large samples of well-characterized families are difficult to recruit, these studies have 2 Maria Giralt-López et al. the advantage of controlling for certain confounder factors, as individuals with a greater number of G alleles present better family members have a shared genetic background and tend to be empathic ability [28]. Interestingly, Rodrigues et al. [29] linked the more homogeneous with respect to exposure to environmental lower empathy exhibited by A allele carriers of this SNP with a higher factors. physiological stress reactivity as compared to GG individuals. Meta-analytic data on social cognition in unaffected relatives of Furthermore, OXTR polymorphic variants (rs53576 and others) patients with SZ have reported their decreased performance when have been associated with the risk for SZ and with other neurode- compared to healthy controls [12] and that the social cognition velopmental disorders (reviewed in [17]). abilities in relatives lie somewhere between the levels seen in Neuroimaging studies have provided evidence to support the probands and in healthy non-relatives [4]. rs53576 association with brain structure and activity, mainly in All of the above, in addition to the fact that some social cognitive healthy subjects. For instance, Tost et al. [30] described that A impairment are heritable (28–37% for emotion recognition) [13], allele carriers of rs53576 show the lowest amygdala activation and account for the interest in social cognition as a candidate endophe- an increased coupling of the hypothalamus and the amygdala notype. when processing social information. Data also suggest that To explain the heterogeneous results in the relative group and to rs53576 influences striatal dopamine availability and modulates detect healthy relatives with a potentially higher genetic loading for the interactions between the oxytocinergic and dopaminergic SZ, a useful strategy would be to study the association between the systems. In a study based on single-photon emission-computed endophenotypic marker and other known vulnerability markers in tomography (SPECT), striatal dopamine transporter availability SZ such as schizotypy, family history, and specific genetic factors. in G carriers (AG/GG) was lower than in the AA group, and G Schizotypy is a set of personality traits that encompasses behaviors, carriers showed a negative correlation between dopamine trans- cognitions, and emotions, and resembles the signs and symptoms of porter availability and OXT level [31]. Then, despite rs53576 is a SZ in the general population. It has been associated with ToM silent polymorphism and that the pathophysiological significance impairment [14,15]. of its association with brain phenotypes remains to be elucidated, As regards the biological underpinnings of ToM, the most accumulated evidence suggest that this SNP could be a marker of extensively studied neuropeptide to date is oxytocin (OXT). On the role of the OXTR in the neural mechanism that links the the one hand, several functional neuroimaging studies have shown differences in the oxytocinergic system to individual differences that OXT has significant modulatory effects on “social brain,” in social cognition. which refers to the brain systems that govern social cognition, social In line with the above, our study first aimed to explore ToM in behavior, and affect regulation [16]. For example, acute OXT schizophrenia-spectrum disorder (SSD) patients, healthy first- administration in healthy subjects has been shown to modulate degree relatives, and healthy controls to test whether ToM deficits amygdala activity as well as other regions (e.g., prefrontal areas, may be a putative endophenotypic marker of SZ. We hypothesized superior temporal sulcus, and fusiform gyrus) and to enhance the that ToM deficits would show a trait marker pattern with first- functional connectivity of the amygdala with other brain regions degree relatives showing intermediate scores between patients and [17,18]. Also, animal models of psychosis have shown that OXT healthy controls. Second, to understand the ToM variability, we administration reduces dopaminergic hyperactivity in the striatum aimed to investigate whether ToM is modified by: (i) clinical and nucleus accumbens [19] in a similar manner to antipsychotic liability to SZ in healthy individuals (schizotypy) and (ii) the medications [20,21]. OXT receptor gene (OXTR). We hypothesized that the polymor- On the other hand, some studies in healthy subjects have shown phism rs53576 at the OXTR would modify the association between the enhancing effect of intranasal OXT administration on social schizotypy and ToM, and that the allelic variants would cognition [22] and specifically on ToM [23] and that this is an age- co-segregate with ToM performance within families. independent effect [24]. A meta-analysis based on neurodevelop- mental disorders (SZ and autism spectrum disorders) also reported the age-independent intranasal OXT improvement effect on ToM Methods across these disorders [23]. Accordingly, it has been suggested that Sample both the anatomy and functional physiology of the human nervous system may be shaped by OXT signaling pathways (and their The sample comprised 199 individuals: 38 patients with a diagnosis interaction with dopaminergic ones), leading to the idea that their of a SSD, 80 healthy first-degree relatives of these patients variability may contribute to individual differences in social (22 fathers, 30 mothers, and 28 siblings), and 81 unrelated controls behavior and cognition by modulating the neural circuits involved with no psychiatric history (Table 1). All participants were of in processing socio-affective information [25,26]. Caucasian origin. All were recruited at the Centre de Salut Mental Importantly, the behavioral effects of OXT depend on the d’Adults de Lleida and evaluated by the same clinician (S.M.), and distribution and expression of its receptor (OXTR). OXT receptors were assessed when they were clinically stable. are present in numerous limbic and reward-related regions of the Patients’ DSM-IV-TR diagnoses were: SZ (n = 32) and psychotic human brain; mainly in (but not restricted to) the amygdala, the disorder not otherwise specified (n = 6). Patients’ mean age at onset hippocampus and the nucleus accumbens, and also in cortical was 22.12 (SD = 3.83) and the mean duration of illness was 26.40 regions (such as the anterior cingulate cortex) [27]. The receptor months (SD = 24.44). is coded by the OXTR gene and its polymorphic variability All patients were treated with antipsychotic monotherapy: may contribute to individual differences in social behavior and 94.7% with second-generation antipsychotic (24 risperidone, cognition [25]. 5 olanzapine, 3 amisulpride, 2 ziprasidone, 2 clozapine) and 5.3% General population-based studies have highlighted the influence with haloperidol. of this gene on many facets of social cognition including ToM. The The exclusion criteria for relatives included any psychotic spec- most intensively examined single nucleotide polymorphism (SNP) trum disorder and any major affective disorder. Controls had no in OXTR is rs53576, and a recent meta-analysis showed that personal or family history of psychiatric disorders or treatment. European Psychiatry 3 Table 1. Sample description and statistical comparisons among patients, first-degree relatives, and controls Patients (n = 38) First-degree relatives (n = 80) Controls (n = 81) ANOVA F/χ2 (p) Post hoc significant differences Male (%) 73.68 41.25 45.68 11.54 (0.003) P > C, P > R Age at interview 24.92 (3.90) 44.74 (13.43) 34.77 (12.53) 38.46 (<0.001) R>C>P Years of education 13.43 (3.12) 11.42 (4.83) 15.23 (3.82) 16.59 (<0.001) C > R, P > R IQ 90.03 (15.23) 94.97 (15.26) 107.98 (11.96) 27.67 (<0.001) C > R, C > P PANSS positive 10.63 (3.36) – – PANSS negative 20.37 (4.01) – – PANSS general 32.58 (7.32) – – PANSS “lack of insight” 2.50 (0.80) – – Proportion (%) or mean scores (SD). Only significant differences in post hoc comparisons are given (all p-values were <0.001). Abbreviations: C, controls; P, patients; R, first-degree relatives. Other exclusion criteria common to all groups were any major or odd beliefs), interpersonal dimension (i.e., suspiciousness, inap- medical illness that could affect brain function, neurological con- propriate, or constricted affect), and disorganization dimension ditions, and history of head trauma with loss of consciousness. (i.e., odd thinking/speech/behavior/appearance). In order to select All participants provided written consent after being informed a subgroup of carriers of higher-vulnerability SPQ subscales, raw of the study procedures and implications. The study was performed scores were dichotomized using the SPSS visual binning method in in accordance with the guidelines of the institutions involved and each group to define high/low scorers for each SPQ subscale. approved by the local research ethics committees. All procedures Intellectual quotient (IQ) was estimated using the Block Design were carried out in accordance with the latest version of the and Vocabulary or Information WAIS-III subtests. Declaration of Helsinki. Family history was assessed with the Family Interview for Genetic Studies. Following broad SZ spectrum criteria [39], families were Assessments classified as having a positive family history when patients had at least one first- or second-degree relative with SZ, affective or non- The patients were diagnosed according to DSM-IV-TR criteria and affective psychosis, or schizotypal or paranoid personality disorder. interviewed by means of the Comprehensive Assessment of Symp- toms and History [32]. Molecular analysis Symptom severity and prevalence of positive or negative symp- toms were assessed by means of The Positive and Negative Syn- Genomic DNA was extracted from peripheral blood cells or buccal drome Scale (PANSS) [33]. It is a 30-item scale designed to obtain a mucosa using standard methods, that is, the Real Extraction DNA measure of positive, negative, and general psychopathology symp- Kit (Durviz S.L.U., Valencia, Spain) or the BuccalAmp DNA toms in patients with SZ. The scores for these scales are arrived at by Extraction Kit (Epicenter Biotechnologies, Madison, WI). summation of ratings across component items. In addition to these The OXTR gene on chromosome 3p25 spans ~19 kbp and con- measures, a Composite Scale is scored by subtracting the negative tains four exons and three introns. Genotyping of the intronic SNP score from the positive score. This yields a bipolar index, which is rs53576 in the OXTR gene was performed using a fluorescence-based essentially a difference score reflecting the degree of predominance allelic discrimination procedure (TaqMan 50 exonuclease assays; of one syndrome (positive or negative) in relation to the other. Applied Biosystems). Standard conditions were observed. The gen- Based on the previously reported association between insight otyping call rate was higher than 86%. After randomly regenotyping and social cognition [34], the PANSS item “lack of insight” was also 10% of the sample, 100% of the genotyping results were confirmed. independently used to test such association. The SNP was in Hardy–Weinberg equilibrium. Due to the low Social cognition, specifically ToM, was assessed by means of the frequency of individuals homozygous for the allele A, the genotype Spanish version of the Hinting Task (HT) [35,36], a test that variable was dichotomized in GG versus A allele carriers (AA+AG). consists of 10 brief stories involving two people in a conversation. The task is to infer what a person is implying indirectly. In each Statistical analyses item, a correct answer gives 2 points (for a total of 20 points). In case of an incorrect answer, an additional hint is given, after which a All data were processed using SPSS 22.0 software (SPSS IBM, correct answer gives 1 point. Armonk, NY). The task has good validity for patients with SZ and has proven Sociodemographic and clinical data were compared between sensitive to ToM difficulties in a number of studies to date [37]. groups by means of analysis of variance (ANOVA) tests or a chi- Schizotypy assessment was carried out by means of the Schizo- squared test when appropriate. typal Personality Questionnaire-Brief (SPQ-B) [38]. SPQ-B is a The effect of age, years spent in education, and IQ on HT 22-item self-report; each item presents a statement or question to performance for each group was tested using the Pearson correla- the respondent, who then circles “yes” or “no.” Each affirmative tion test. Within groups, differences on HT performance according response counts as one point toward the total score, which ranges to sex or family history were tested using Student’s t-test. From all from 0 to 22, with higher scores indicating higher levels of self- these analyses, age and sex showed a trend toward or significant reported schizotypy. Items were created to measure three schizotypal effect in relatives (p = 0.059 and p = 0.001, respectively), so they dimensions: cognitive-perceptual dimension (i.e., ideas of reference were added as covariates in the subsequent analyses. 4 Maria Giralt-López et al. The association between HT performance and clinical charac- severity or insight as measured with PANSS, no association was teristics (PANSS) within patients was tested with linear regressions detected. Thus, these clinical variables were not considered in the (adjusted for age and sex). following analyses. HT performance differences between patients and their first- degree relatives were assessed by means of linear mixed models Analysis of ToM performance in SSD patients relative to their (LMMs) with total HT as the dependent variable, family member first-degree relatives and healthy individuals (patients/first-degree relative) as the fixed-effect factor, sex and age as fixed-effect covariates, and family as the random effect (subjects A comparison of HT performance between patients and first-degree nested within families). When the analyses included nonrelated relatives and between patients and controls showed significant group groups (patients vs. controls and relatives vs. controls), the same effects (F = 8.96, p = 0.003 and F = 17.64, p < 0.001, respectively). models were used for the comparison without including the family Patients presented lower scores than relatives (estimated mean dif- random effect. ference = 2.27) and controls (estimated mean difference = 2.44). The association between HT performance and schizotypy These results remained significant after including IQ as a covariate within healthy relatives and controls was tested with linear regres- (p = 0.007 and p = 0.025, respectively). The scores of relatives and sion (adjusted for age, sex, and family history). controls did not differ significantly. To test the putative effect of the OXTR gene as a mediator of the relationship between HT performance and schizotypy, the geno- Association between HT performance and schizotypy in healthy type (GG vs. A allele carriers) was added to these analyses. relatives and controls In addition, a family-based association test between rs53576 and the HT scores was conducted with PLINK v1.07 by means of the We tested whether ToM performance in healthy individuals is quantitative transmission disequilibrium test (qTDT). Since modulated by schizotypy, a marker of liability to SSD. PLINK does not allow covariates to be included in qTDT analyses, A linear regression analysis (adjusted for age, sex, and family the analyses were performed in two steps. First, lineal regressions history) showed that being a high scorer for Schizotypal Personality between HT scores and each schizotypy factor (covaried by age and Questionnaire-interpersonal (SPQ-IP; β = 0.277, p = 0.010, Radj2 = sex) were conducted. Second, the residuals from these regressions 22.2%) and Schizotypal Personality Questionnaire cognitive- were used to conduct the qTDT. perceptual (SPQ-CP; β = 0.243, p = 0.030, Radj2 = 20%) was related to poorer ToM performance in relatives. Results for SPQ-IP remained significant when the IQ was included as a covariate (p = Results 0.025). No such relationship was observed in the controls. Sample characteristics Association between OXTR gene (rs53576) and ToM performance Tables 1 and 2 show the main sociodemographic and clinical data of the sample. The proportion of males was higher in the patients group For the OXTR SNP, the genotype distribution is shown in Table 3. (73.7% male) than in the relatives (41.3%) or controls (45.7%) The qTDT analysis showed no association between the OXTR groups. Relatives had spent less time in education than patients or gene and HT performance within families. controls. Such a difference was mainly attributable to parents (mean The rs53576 (GG vs. A allele carriers) did not show a significant years of education [SD] = 9.46 (4.05) and not to siblings (mean years association with HT performance but showed a modifying effect on of education [SD] = 14.93 (4.12)]. IQs were higher in the control the relationship between schizotypy and HT in controls. When sample than in the relatives or patients. A total of 21.1% of patients including the OXTR variability in the model (see “Association and 17.5% of relatives had a family history of psychotic disorders. between Hinting Task performance and schizotypy in healthy Within the family group, there were no significant differences in relatives and controls” section) being a high scorer for SPQ-CP HT or SPQ-B scores between siblings and parents (data not shown); turned to be related to poorer ToM performance in controls for this reason, they were considered a single group in all analyses. (β = 0.307, p = 0.030, Radj2 = 13.8%). Accordingly, within GG According to the PANSS Composite Scale, all patients showed subjects (17 SPQ-CP low scorers and 12 high scorers), the effect of more prevalent negative than positive symptoms. When we tested SPQ-CP on HT performance was statistically significant (β = 0.468, whether ToM performance in patients is modulated by clinical p = 0.007, Radj2 = 30.1%), while it was not within A carriers. Table 2. ToM and schizotypy (SPQ-B) scores in patients (P), their first-degree relatives (R), and controls (C) Patients First-degree relatives Controls a HT 15.74 (4.07) 17.88 (2.16) 18.46 (1.64) Low scorers High scorers Low scorers High scorers Low scorers High scorers SPQ-CPb 0.91 (0.81) 4.15 (1.41) 0 (0) 2.00 (1.11) 0 (0) 2.00 (1.11) b SPQ-IP 2.38 (1.50) 6.55 (1.13) 1.60 (1.01) 4.96 (1.19) 1.05 (0.83) 4.03 (1.15) SPQ-Db 0 (0) 2.24 (1.48) 0 (0) 1.63 (0.92) 0 (0) 1.39 (0.72) Schizotypy scores for each dimension were dichotomized in low and high scorers. Mean scores (SD). Abbreviations: HT, Hinting Task; SPQ-CP, Schizotypal Personality Questionnaire-cognitive-perceptual; SPQ-D, Schizotypal Personality Questionnaire-disorganization; SPQ-IP, Schizotypal Personality Questionnaire-interpersonal. a Available for 39 patients, 82 relatives, and 81 controls. b Available for 36 patients, 76 relatives, and 68 controls. European Psychiatry 5 Table 3. Genotype frequencies for the single nucleotide polymorphism rs53576 at the OXTR gene and HT mean scores within each group Patients (n = 37) Relatives (n = 76) Controls (n = 56) GG GA AA GG GA AA GG GA AA Genotype frequencies 21 (56.8%) 15 (40.5%) 1 (2.7%) 43 (56.6%) 31 (40.8%) 2 (2.6%) 31 (55.4%) 21 (37.5%) 4 (7.1%) HT mean score (SD) 15.24 (4.83) 16.20 (3.03) 16.00 17.77 (2.40) 17.97 (1.96) 19.50 (0.71) 18.58 (1.61) 18.38 (1.80) 18.00 (1.63) In relatives, the association between SPQ and HT remained had minimal contextual information, but not when the task significant while the genotype did not show an effect per se. had enriched contextual information. Another element to consider when explaining the heterogeneity of ToM capacities in the healthy relatives’ group is the variability in clinically defined liability. As regards to the selection of schizotypy, Discussion it is a clinical liability marker that has shown to be useful in the In our study, SZ patients showed impairments in inferring the mental identification of families with a higher genetic loading for SZ states of others (i.e., intentions) via indirect speech such as hints, [51]. In this respect, our study shows that high levels of positive measured with the HT, in comparison to controls. This result is and negative schizotypy (cognitive-perceptual and interpersonal consistent with previous studies that have used the same task [40–42] dimensions) are related to poorer ToM performance in relatives but and others that have used different tools for assessing ToM [3,5,8,11]. not in controls. Within the general population, ToM has been To further investigate the properties of ToM as an endopheno- extensively studied in relation to schizotypy. Several studies have typic marker, we looked at how healthy relatives behave in relation detected ToM impairments associated with high levels of total to patients and controls. In our study, the mean score of healthy schizotypy [14,15]. In line with our results, other studies have failed relatives in the HT fell somewhere between the scores of the other to identify this association in controls [52,53], but some have two groups, but the differences between relatives and controls were reported that poorer social cognition is a function of specific not significant. In line with our findings, other studies that have schizotypy traits such as positive schizotypy [54,55]. assessed ToM aspects have also observed no differences in relatives Overall, the mixed findings associated with schizotypy and ToM compared to controls [43,44]. In contrast, other studies have sug- performance in healthy controls may be due to the fact that indi- gested a genetic liability effect with relatives demonstrating impair- viduals with positive and negative schizotypy display poor ToM ments in advanced ToM ability [4,45,46]. A recent study that performances for different reasons. Frith [56] asserted that indi- included several different measurements reported mixed results viduals with positive symptoms of SZ show deficits in ToM tasks across tasks [9]. due to inaccurate representations of the intentions of others, This heterogeneity of results could be explained by different whereas individuals with negative symptoms of SZ display ToM factors including the sample sizes of studies and the different tasks deficits due to a lack of experience of or interest in social interac- used to evaluate ToM. tions. It may also be that different aspects of social cognition are First-order false belief or deception tasks test the ability to differentially affected by positive and negative schizotypy. understand that someone can have an inaccurate mental represen- Another fact that could explain the heterogeneity is the different tation of events based on incomplete knowledge. In a second-order ways of quantifying schizotypy levels. Some studies have used a false belief or deception task, participants have to infer the (false) continuous variable, while others have used median splits or the top beliefs of one character about the (false) beliefs of a second and bottom 5 or 10% in an attempt to emphasize the qualitative character [47,48]. differences between groups. We were not able to use this method More complex ToM includes the comprehension of indirect due to the limited size of our sample. speech, such as irony, metaphors, faux pas, and hints, assessed using In contrast to the results for the control group, data from the the Strange Stories Task [49] or the HT. This is based on the notion subgroup of healthy relatives of SZ-spectrum patients suggest that that understanding indirect speech requires an understanding of high levels of cognitive-perceptual and interpersonal dimensions another person’s mental state. are related to poorer ToM performance. To the best of our knowl- It has been reported that ToM abilities might decline at edge, only three studies have tested this association in a sample of different times over the course of SZ. This is consistent with healthy relatives of SZ patients. Two found no significant correla- Brüne’s developmental model, which posits that ToM abilities tions between ToM and schizotypy scores in the relative sample decline in the reverse order of acquisition [5]. Therefore, deteri- [57,58]. However, SPQ mean scores and ranges in these samples oration is first detected in complex ToM tasks, while the decline were somewhat low. in first-order ToM tasks is observed later. This theory is consis- Irani et al. [59] used the Revised Eyes Test and reported a trend tent with studies that have observed a deficit in second-order whereby relatives were more accurate than patients and less accu- mentalizing questions, but not in first-order inference items, in rate than controls in the ToM task, although these differences only patients experiencing a first episode of psychosis [50]. Thus, it became significant when the SPQ social-interpersonal subscale can be deduced that tasks assessing higher-order forms of ToM scores were included. This is consistent with the hypothesis that could be more sensitive and especially appropriate for detecting these social-interpersonal features are the best differentiators ToM impairment in nonclinical samples such as healthy relatives. between relatives and controls, and might be the most important Also, there could be other factors intrinsic to the task that schizotypal traits associated with genetic vulnerability for SZ conditions its sensitivity to changes in social cognition abilities [60]. Despite the fact that the relatives in our sample showed higher performance. For instance, Grainger et al. [24] detected that schizotypy levels than controls on the social-interpersonal subscale, intranasal OXT administration improved ToM when the task differences were not significant. 6 Maria Giralt-López et al. In our study, schizotypy symptoms in healthy first-degree On the other hand, even though the sample size is comparable to relatives seem to put individuals at an increased risk of these previous studies and that one of the main disadvantages of family- ToM deficits, thus suggesting that some social cognition functions based designs is the challenge associated with recruiting large might be sensitive to subthreshold psychotic symptoms. These samples of well-characterized families, the size of our sample results are similar to those reported by Johnson et al. [61], in which represents the main limitation of the study. In line with this, the the relationship between schizotypy and other measures of cogni- family-based design is intrinsically associated with differences in tion was mediated by SZ genetic risk. sample sizes of the subgroups (more relatives than patients), which Finally, regarding the role of the OXTR gene in ToM, our study could represent a bias when conducting subgroups comparison did not report a family-based association. However, despite not analyses. Moreover, although ToM is an important area of social having an effect per se on HT, the genotype showed a modifying cognition, other areas, such as emotion processing and social effect of the association between schizotypy and HT in controls. knowledge, were not studied. Also, according to some recent data Then, while the genotype did not change the significant relationship showing that antipsychotic treatment can improve social cognition observed between schizotypy and HT within relatives, in controls, performance [69,70], the non-inclusion of the treatment data in our this association became significant when the polymorphism was analyses could limit the interpretation of our results. Then, if we included. This suggests that in controls (with less liability load than had excluded the treatment effect, the patients’ performance on relatives) high schizotypy would be related to a poorer performance ToM could be potentially worse and could show larger differences on ToM conditional to GG genotype. This result is consistent with with relatives and healthy controls. Finally, although one of the other studies that observed the role of this polymorphism on differ- most studied polymorphisms in the OXTR gene is rs53576, the ent social cognition domains in healthy subjects [25–27], nonetheless analysis of a single SNP does not represent the whole variability the comparison is not straightforward as previous studies were based gamut of OXTR. In addition, like many human competencies, ToM on different social cognition dimensions or scales and none has is a complex trait influenced by multiple genes, future research analyzed the role of OXTR gene jointly with schizotypy. In all, these should screen the polymorphic variability along the OXTR gene and results should be treated with caution, as the sample size limits the other OXT signaling pathway-related genes. statistical power of our study and replication is needed in larger In conclusion, our study initially shows that ToM deficits are samples in order to confirm such effect. greater in patients with SSDs as compared to healthy relatives and Given the well-documented role of OXT in mammalian social controls; however, when clinical and genetic liability markers such behavior, and the previously mentioned effects of OXT adminis- as schizotypy and OXTR gene in healthy subjects are considered, our tration on social abilities in humans, it is not surprising that OXTR data indicate the putative role of ToM as a trait marker. Our study gene variability has been studied with a range of social phenotypes does not report the role of the polymorphism rs53576 at the OXTR [62]. In this regard, some studies have provided evidence that gene on ToM abilities within families; however, new studies in larger OXTR polymorphisms are associated with different dimensions family-based samples are needed. of social cognition in healthy individuals [63,64] and also with the risk for SZ and poorer performance in ToM measurements in Acknowledgment. We are deeply grateful to all participants, whose generosity SZ, while others have failed to find such an association [17,65,66]. made this work possible. Focusing on the family-based approach, despite the design being particularly robust for controlling widespread confounds such as Financial Support. This study was funded by: (i) Fundació La Marató de TV3, (ii) Fundación Alicia Koplowitz, (iii) ERA-NET NEURON admixture and stratification [67], we are aware of only one previous (PIM2010ERN-00642), (iv) the Instituto de Salud Carlos III through project study with a similar approach as ours. In that study, Wade et al. [67] PI15/01420 (co-funded by the European Regional Development Fund/Euro- reported the association of another polymorphism at intron 3 of pean Social Fund “Investing in your future”), (v) the Comissionat per a Uni- OXTR (rs11131149) with social cognition in 18 months old chil- versitats i Recerca del DIUE, of the Generalitat de Catalunya regional authorities dren. Interestingly, the same authors also reported the interaction (2017SGR1577 and 2017SGR1271), (vi) Ajuts de Personal Investigador Predoc- between OXTR and parenting behavior on 4 years old children’s toral en Formació (APIF-Universitat de Barcelona) awarded to J.S., and (vii) a ToM [68], suggesting a nature–nurture interaction with regard to Sara Borrell contract (Instituto de Salud Carlos III) awarded to M. Fatjó-Vilas ToM in early development. Therefore, our results add to the (CD16/00264). variability and discrepancies observed in the limited body of liter- The funding sources played no role in the design of the study, the collection, ature in relation to SZ, which are likely related to several factors analysis or interpretation of data, or the decision to submit this manuscript for such as the diversity of genotypes across studies, the variation in publication. participants’ ancestry and limited sample sizes. Also, for the under- Conflict of Interest. The authors declare no conflict of interest. standing of heterogeneity across studies, our data and other family- based studies indicate the need of considering environmental and developmental factors. References To interpret our data, it is important to consider the strengths and limitations of the study. 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