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Backgrounds: The influence of serotonin function on social phobia has been well-documented, yet the polygenic risk score of serotonergic polymorphisms for social phobia remains unclear., Methods: We assessed two aspects of social phobia (i.e., social interaction anxiety and social phobia scrutiny fear) and created a polygenic risk score of seven serotonergic polymorphisms in two independent samples., Results: The results from both samples indicated that a greater polygenic risk score, denoting a higher risk of anxiety, was associated with higher levels of social interaction anxiety and social phobia scrutinizing fear. Interestingly, the association between polygenic risk score and social interaction anxiety was mediated by interpersonal adaptability., Conclusion: These findings demonstrate the importance of serotonergic polymorphisms in social phobia and unveil a psychological pathway whereby interpersonal adaptability mediates the effect of serotonergic polymorphisms on social phobia., Competing Interests: Declaration of competing interest The authors declared that they had no conflicts of interest concerning their authorship or the publication of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: Social anxiety disorder (SAD) is a common disorder characterized by excessive fear of scrutiny and embarrassment, leading to severe distress and avoidance behaviors or dysfunctions. SAD and other relevant diseases have been reported to be associated with a higher risk of aging-related diseases, such as Alzheimer's disease, Parkinson's disease, and diabetes mellitus. Recently, epigenetic clock analysis, which measures biological aging based on comprehensive DNA methylation (DNAm) status, has been widely conducted. We conducted epigenetic clock analyses in patients with SAD and controls, examining various epigenetic age acceleration and DNAm-based predictive values of aging-related proteins (GrimAge components and GrimAge2 components), including leptin level., Methods: We used the publicly available DNAm dataset, GSE164056, which consists of 66 patients with SAD and 77 controls of Caucasian descent aged between 18 and 50 years. We conducted regression analyses investigating the association between SAD and various indices of epigenetic aging, using age and sex as covariates., Results: None of the epigenetic clocks showed significant differences in age acceleration. Of the DNAm-based predictive values of aging-related proteins, leptin level in GrimAge components (q = 0.0123) and GrimAge2 components (q = 0.0123) were significantly lower in patients with SAD than in controls., Conclusions: The results of this study suggested that leptin may be involved in SAD pathogenesis as an aging-related protein. Therefore, further studies with different designs are required., (© 2024 The Author(s). Neuropsychopharmacology Reports published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Society of Neuropsychopharmacology.)

Social anxiety disorder (SAD) and panic disorder (PD) are prevalent anxiety disorders characterized by a complex interplay of genetic and environmental factors. Both disorders share overlapping features and often coexist, despite displaying distinct characteristics. Childhood life adversity, overall stressful life events, and genetic factors contribute to the development of these disorders. DNA methylation, an epigenetic modification, has been implicated in the pathogenesis of these diseases. In this study, we investigated whether whole-genome DNA methylation risk scores (MRSs) for SAD risk, severity of social anxiety, childhood life adversity, PD risk, and overall stressful life events were associated with SAD or PD case‒control status. Preliminary epigenome-wide association studies (EWASs) for SAD risk, severity of social anxiety, and childhood life adversity were conducted in 66 SAD individuals and 77 healthy controls (HCs). Similarly, EWASs for PD risk and overall stressful life events were performed in 182 PD individuals and 81 HCs. MRSs were calculated from these EWASs. MRSs derived from the EWASs of SAD risk and severity of social anxiety were greater in PD patients than in HCs. Additionally, MRSs derived from the EWASs of overall stressful life events, particularly in PD individuals, were lower in SAD individuals than in HCs. In contrast, MRSs for childhood life adversity or PD risk were not significantly associated with PD or SAD case‒control status. These findings highlight the epigenetic features shared in both disorders and the distinctive epigenetic features related to social avoidance in SAD patients, helping to elucidate the epigenetic basis of these disorders., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Social anxiety disorder (SAD) is a common psychiatric disorder, often associated with avoidant temperament. Research studies have implicated a strong genetic architecture of SAD. We have conducted a systematic review on the genetics of SAD and yielded 66 articles. In general, prior research studies have focused on the serotonin transporter, oxytocin receptor, brain-derived neurotrophic factor and catechol-O-methyltransferase genes. Mixed and inconsistent results have been reported. Additional approaches and phenotypes have also been investigated, including pharmacogenetics of treatment response, imaging genetics and gene-environment interactions. Future directions warrant further international collaborative efforts, deep-phenotyping of clinical characteristics including consistent and reliable measurement-based symptom severity, and larger sample sizes to ensure sufficient power for stratification due to the heterogeneity of this chronic and often debilitating condition., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The purpose of the current article is to explore familial factors that influence the development of social anxiety disorder (SAD) in children and adolescents, including parenting, sibling relationships, and family environment. A multitude of interrelated genetic and familial factors have been found to cause and maintain SAD in children and adolescents. There are many challenges in diagnosing and treating the disorder. Knowledge and awareness of familial factors provide insight on targeted treatments that prevent or ameliorate SAD. [ Journal of Psychosocial Nursing and Mental Health Services, 59 (7), 23-34.].

Social anxiety disorder (SAD) is a psychiatric disorder characterized by extensive fear in social situations. Multiple genetic and environmental factors are known to contribute to its pathogenesis. One of the main environmental risk factors is early life adversity (ELA). Evidence is emerging that epigenetic mechanisms such as DNA methylation might play an important role in the biological mechanisms underlying SAD and ELA. To investigate the relationship between ELA, DNA methylation, and SAD, we performed an epigenome-wide association study for SAD and ELA examining DNA from whole blood of a cohort of 143 individuals using DNA methylation arrays. We identified two differentially methylated regions (DMRs) associated with SAD located within the genes SLC43A2 and TNXB. As this was the first epigenome-wide association study for SAD, it is worth noting that both genes have previously been associated with panic disorder. Further, we identified two DMRs associated with ELA within the SLC17A3 promoter region and the SIAH3 gene and several DMRs that were associated with the interaction of SAD and ELA. Of these, the regions within C2CD2L and MRPL28 showed the largest difference in DNA methylation. Lastly, we found that two DMRs were associated with both the severity of social anxiety and ELA, however, neither of them was found to mediate the contribution of ELA to SAD later in life. Future studies are needed to replicate our findings in independent cohorts and to investigate the biological pathways underlying these effects.

Social Anxiety Disorder (SAD) is characterized by emotional and attentional biases as well as distorted negative self-beliefs. According this, we proposed to identify the brain structures and hub genes involved in SAD. An analysis in Pubmed and TRANSFAC was conducted and 72 genes were identified. Using Microarray data, from Allen Human Brain Atlas, it was possible to identify three modules of co-expressed genes from our gene set (R package WGCNA). Higher mean gene expression was found in cortico-medial group, basomedial nucleus, ATZ in amygdala and in head and tail of the caudate nucleus, nucleus accumbens and putamen in striatum. Our enrichment analysis identified the followed hub genes: DRD2, HTR1A, JUN, SP1 and HDAC4. We suggest that SAD is explained by delayed extinction of circuitry for conditioned fear. Caused by reduced activation of the dopaminergic and serotonergic systems,due diminished expectation of reward during social interactions., Competing Interests: Declaration of Competing Interest We have no conflicts of interest to disclose., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Social anxiety symptoms (SAS) are among the most common mental health problems during adolescence, and it has been shown that parenting influences the adolescent's level of social anxiety. In addition, it is now widely assumed that most mental health problems, including social anxiety, originate from a complex interplay between genes and environment. However, to date, gene-environment (G × E) interactions studies in the field of social anxiety remain limited. In this study, we have examined how 274 genes involved in different neurotransmission pathways interact with five aspects of perceived parenting as environmental exposure (i.e., support, proactive control, psychological control, punitive control, and harsh punitive control) to affect SAS during adolescence., Methods: We have applied an analytical technique that allows studying genetic information at the gene level, by aggregating data from multiple single-nucleotide-polymorphisms within the same gene and by taking into account the linkage disequilibrium structure of the gene. All participants were part of the STRATEGIES cohort of 948 Flemish adolescents (mean age = 13.7), a population-based study on the development of problem behaviors in adolescence. Relevant genes were preselected based on prior findings and neurotransmitter-related functional protein networks., Results: The results suggest that genes involved in glutamate (SLC1A1), glutathione neurotransmission (GSTZ1), and oxidative stress (CALCRL), in association with harsh punitive parenting, may contribute to social anxiety in adolescence. Isolated polymorphisms in these genes have been related to anxiety and related disorders in earlier work.Conclusions: Taken together, these findings provide new insights into possible biological pathways and environmental risk factors involved in the etiology of social anxiety symptoms' development., Conclusions: Taken together, these findings provide new insights into possible biological pathways and environmental risk factors involved in the etiology of social anxiety symptoms' development.

Background: Correct prediction of treatment response is a central goal of precision psychiatry. Here, we tested the predictive accuracy of a variety of pre-treatment patient characteristics, including clinical, demographic, molecular genetic, and neuroimaging markers, for treatment response in patients with social anxiety disorder (SAD)., Methods: Forty-seven SAD patients (mean±SD age 33.9 ± 9.4 years, 24 women) were randomized and commenced 9 weeks' Internet-delivered cognitive behavior therapy (CBT) combined either with the selective serotonin reuptake inhibitor (SSRI) escitalopram (20 mg daily [10 mg first week], SSRI+CBT, n = 24) or placebo (placebo+CBT, n = 23). Treatment responders were defined from the Clinical Global Impression-Improvement scale (CGI-I ≤ 2). Before treatment, patients underwent functional magnetic resonance imaging and the Multi-Source Interference Task taxing cognitive interference. Support vector machines (SVMs) were trained to separate responders from nonresponders based on pre-treatment neural reactivity in the dorsal anterior cingulate cortex (dACC), amygdala, and occipital cortex, as well as molecular genetic, demographic, and clinical data. SVM models were tested using leave-one-subject-out cross-validation., Results: The best model separated treatment responders (n = 24) from nonresponders based on pre-treatment dACC reactivity (83% accuracy, P = 0.001). Responders had greater pre-treatment dACC reactivity than nonresponders especially in the SSRI+CBT group. No other variable was associated with clinical response or added predictive accuracy to the dACC SVM model., Limitations: Small sample size, especially for genetic analyses. No replication or validation samples were available., Conclusions: The findings demonstrate that treatment outcome predictions based on neural cingulate activity, at the individual level, outperform genetic, demographic, and clinical variables for medication-assisted Internet-delivered CBT, supporting the use of neuroimaging in precision psychiatry., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

Social anxiety disorder (SAD) runs in families, but the neurobiological pathways underlying the genetic susceptibility towards SAD are largely unknown. Here, we employed an endophenotype approach, and tested the hypothesis that amygdala hyperreactivity to faces conditioned with a social-evaluative meaning is a candidate SAD endophenotype. We used data from the multiplex, multigenerational Leiden Family Lab study on Social Anxiety Disorder (eight families, n = 105) and investigated amygdala activation during a social-evaluative conditioning paradigm with high ecological validity in the context of SAD. Three neutral faces were repeatedly presented in combination with socially negative, positive or neutral sentences. We focused on two endophenotype criteria: co-segregation of the candidate endophenotype with the disorder within families, and heritability. Analyses of the fMRI data were restricted to the amygdala as a region of interest, and association analyses revealed that bilateral amygdala hyperreactivity in response to the conditioned faces co-segregated with social anxiety (SA; continuous measure) within the families; we found, however, no relationship between SA and brain activation in response to more specific fMRI contrasts. Furthermore, brain activation in a small subset of voxels within these amygdala clusters was at least moderately heritable. Taken together, these findings show that amygdala engagement in response to conditioned faces with a social-evaluative meaning qualifies as a neurobiological candidate endophenotype of social anxiety. Thereby, these data shed light on the genetic vulnerability to develop SAD., Competing Interests: Declaration of Competing Interest The authors report no conflicts of interest., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Social anxiety disorder (SAD) is a mental illness with a complex, partially genetic background. Differences in characteristics of white matter (WM) microstructure have been reported in patients with SAD compared to healthy controls. Also, WM characteristics are moderately to highly heritable. Endophenotypes are measurable characteristics on the road from genotype to phenotype, putatively reflective of genetically based disease mechanisms. In search of candidate endophenotypes of SAD we used a unique sample of SAD patients and their family members of two generations to explore microstructure of WM tracts as candidate endophenotypes. We focused on two endophenotype criteria: co-segregation with social anxiety within the families, and heritability., Methods: Participants (n = 94 from 8 families genetically vulnerable for SAD) took part in the Leiden Family Lab Study on Social Anxiety Disorder (LFLSAD). We employed tract-based spatial statistics to examine structural WM characteristics, being fractional anisotropy (FA), axial diffusivity (AD), mean diffusivity (MD) and radial diffusivity (RD), in three a-priori defined tracts of interest: uncinate fasciculus (UF), superior longitudinal fasciculus (SLF) and inferior longitudinal fasciculus (ILF). Associations with social anxiety symptoms and heritability were estimated., Results: Increased FA in the left and right SLF co-segregated with symptoms of social anxiety. These findings were coupled with decreased RD and MD. All characteristics of WM microstructure were estimated to be at least moderately heritable., Conclusion: These findings suggest that alterations in WM microstructure in the SLF could be candidate endophenotypes of SAD, as they co-segregated within families genetically vulnerable for SAD and are heritable. These findings further elucidate the genetic susceptibility to SAD and improve our understanding of the overall etiology., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Social anxiety disorder (SAD) is an incapacitating disorder running in families. Previous work associated social fearfulness with a failure to habituate, but the habituation response to neutral faces has, as of yet, not been investigated in patients with SAD and their family members concurrently. Here, we examined whether impaired habituation to neutral faces is a putative neurobiological endophenotype of SAD by using data from the multiplex and multigenerational Leiden Family Lab study on SAD., Methods: Participants (n = 110; age, 9.2 - 61.5 years) performed a habituation paradigm involving neutral faces, as these are strong social stimuli with an ambiguous meaning. We used functional magnetic resonance imaging data to investigate whether brain activation related to habituation was associated with the level of social anxiety within the families. Furthermore, the heritability of the neural habituation response was estimated., Results: Our data revealed a relationship between impaired habituation to neutral faces and social anxiety in the right hippocampus and right amygdala. In addition, our data indicated that this habituation response displayed moderate - to-moderately high heritability in the right hippocampus., Conclusion: The present results provide support for altered habituation as a candidate SAD endophenotype; impaired neural habitation cosegregrated with the disorder within families and was heritable. These findings shed light on the genetic susceptibility to SAD., (© 2019 The Authors. Depression and Anxiety Published by Wiley Periodicals, Inc.)

Background: Little is known about adolescent mental health problems, including social phobia, as risk factors for future work incapacity. The aim of this study was to investigate the association between social phobia in adolescence and unemployment and sickness absence (SA) in early adulthood, also evaluating the role of familial factors (genetics and shared environment)., Methods: A sample of 2845 Swedish twins born in 1985-86 in Sweden was followed longitudinally in the population-based and prospective Twin study of CHild and Adolescent Development. Information on twins' social phobia was collected at ages 13-4, 16-7 and 19-20 years. Logistic regression providing odds ratios (OR) with 95% confidence intervals (95% CI) was used to analyze the associations between social phobia, unemployment and SA during the follow-up 2006-12. The influence of familial factors was evaluated by conditional logistic regression., Results: Presence of social phobia during adolescence was associated with increased odds for unemployment and SA in young adulthood. For unemployment, the highest OR was at the age of 13-4 years (1.58 [95% CI: 1.22-2.06]), and the associations became null after adjusting for familial factors. For SA, the highest OR was at the age of 19-20 years (1.73 [95% CI: 1.13-2.65]), and the estimates changed slightly after adjusting for familial factors., Conclusions: : Results suggest that social phobia experienced in adolescence contribute to early adulthood unemployment and SA. Familial factors seemed to explain the association between social phobia and unemployment., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Public Health Association. All rights reserved.)

Guided by a developmental psychopathology framework, research has increasingly focused on the interplay of genetics and environment as a predictor of different forms of psychopathology, including social anxiety. In these efforts, the polygenic nature of complex phenotypes such as social anxiety is increasingly recognized, but studies applying polygenic approaches are still scarce. In this study, we applied Principal Covariates Regression as a novel approach to creating polygenic components for the oxytocin system, which has recently been put forward as particularly relevant to social anxiety. Participants were 978 adolescents (49.4% girls; M age T 1  = 13.8 years). Across 3 years, questionnaires were used to assess adolescent social anxiety symptoms and multi-informant reports of parental psychological control and autonomy support. All adolescents were genotyped for 223 oxytocin single nucleotide polymorphisms (SNPs) in 14 genes. Using Principal Covariates Regression, these SNPs could be reduced to five polygenic components. Four components reflected the underlying linkage disequilibrium and ancestry structure, whereas the fifth component, which consisted of small contributions of many SNPs across multiple genes, was strongly positively associated with adolescent social anxiety symptoms, pointing to an index of genetic risk. Moreover, significant interactions were found with this polygenic component and the environmental variables of interest. Specifically, adolescents who scored high on this polygenic component and experienced less adequate parenting (i.e., high psychological control or low autonomy support) showed the highest levels of social anxiety. Implications of these findings are discussed in the context of individual-by-environment models.

Objectives: Social anxiety disorder (SAD) is a serious and prevalent psychiatric condition, with a heritable component. However, little is known about the characteristics that are associated with the genetic component of SAD, the so-called "endophenotypes". These endophenotypes could advance our insight in the genetic susceptibility to SAD, as they are on the pathway from genotype to phenotype. The Leiden Family Lab study on Social Anxiety Disorder (LFLSAD) is the first multiplex, multigenerational study aimed to identify neurocognitive endophenotypes of social anxiety., Methods: The LFLSAD is characterized by a multidisciplinary approach and encompasses a variety of measurements, including a clinical interview, functional and structural magnetic resonance imaging and an electroencephalography experiment. Participants are family members from 2 generations, from families genetically enriched for SAD., Results: The sample (n = 132 participants, from 9 families) was characterized by a high prevalence of SAD, in both generations (prevalence (sub)clinical SAD: 38.3%). Furthermore, (sub)clinical SAD was positively related to self-reported social anxiety, fear of negative evaluation, trait anxiety, behavioral inhibition, negative affect, and the level of depressive symptoms., Conclusions: By the multidimensional character of the measurements and thorough characterization of the sample, the LFLSAD offers unique opportunities to investigate candidate neurocognitive endophenotypes of SAD., (© 2018 The Authors International Journal of Methods in Psychiatric Research Published by John Wiley & Sons Ltd.)

Background: Social anxiety disorder (SAD) is characterized by an extreme and intense fear and avoidance of social situations. In this two-generation family study we examined delta-beta correlation during a social performance task as candidate endophenotype of SAD., Methods: Nine families with a target participant (diagnosed with SAD), their spouse and children, as well as target's siblings with spouse and children performed a social performance task in which they gave a speech in front of a camera. EEG was measured during resting state, anticipation, and recovery. Our analyses focused on two criteria for endophenotypes: co-segregation within families and heritability., Results: Co-segregation analyses revealed increased negative delta-low beta correlation during anticipation in participants with (sub)clinical SAD compared to participants without (sub)clinical SAD. Heritability analyses revealed that delta-low beta and delta-high beta correlation during anticipation were heritable. Delta-beta correlation did not differ between participants with and without (sub)clinical SAD during resting state or recovery, nor between participants with and without SAD during all phases of the task., Limitations: It should be noted that participants were seen only once, they all performed the EEG tasks in the same order, and some participants were too anxious to give a speech., Conclusions: Delta-low beta correlation during anticipation of giving a speech might be a candidate endophenotype of SAD, possibly reflecting increased crosstalk between cortical and subcortical regions. If validated as endophenotype, delta-beta correlation during anticipation could be useful in studying the genetic basis, as well as improving treatment and early detection of persons at risk for developing SAD., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Social anxiety is a form of anxiety characterized by continuous fear of one or more social or performance situations. Although multiple treatment modalities (cognitive behavioral therapy, selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors, benzodiazepines) exist for social anxiety, they are effective for only 60% to 70% of patients. Thus, researchers have looked for other candidates for social anxiety treatment. Our review focuses on the peptide oxytocin as a potential therapeutic option for individuals with social anxiety. Animal research both in nonprimates and primates supports oxytocin's role in facilitation of prosocial behaviors and its anxiolytic effects. Human studies indicate significant associations between social anxiety and oxytocin receptor gene alleles, as well as social anxiety and oxytocin plasma levels. In addition, intranasal administration of oxytocin in humans has favorable effects on social anxiety symptomology. Other disorders, including autism, schizophrenia, and anorexia, have components of social anxiety in their pathophysiology. The therapeutic role of oxytocin for social dysfunction in these disorders is discussed.

Social anxiety is a neurobehavioral trait characterized by fear and reticence in social situations. Twin studies have shown that social anxiety has a heritable basis, shared with neuroticism and extraversion, but genetic studies have yet to demonstrate robust risk variants. We conducted genomewide association analysis (GWAS) of subjects within the Army Study To Assess Risk and Resilience in Servicemembers (Army STARRS) to (i) determine SNP-based heritability of social anxiety; (ii) discern genetic risk loci for social anxiety; and (iii) determine shared genetic risk with neuroticism and extraversion. GWAS were conducted within ancestral groups (EUR, AFR, LAT) using linear regression models for each of the three component studies in Army STARRS, and then meta-analyzed across studies. SNP-based heritability for social anxiety was significant (h 2 g  = 0.12, P = 2.17 × 10 -4 in EUR). One meta-analytically genomewide significant locus was seen in each of EUR (rs708012, Chr 6: BP 36965970, P = 1.55 × 10 -8 ; beta = 0.073) and AFR (rs78924501, Chr 1: BP 88406905, P = 3.58 × 10 -8 ; beta = 0.265) samples. Social anxiety in Army STARRS was significantly genetically correlated (negatively) with extraversion (r g  = -0.52, se = 0.22, P = 0.02) but not with neuroticism (r g  = 0.05, se = 0.22, P = 0.81) or with an anxiety disorder factor score (r g  = 0.02, se = 0.32, P = 0.94) from external GWAS meta-analyses. This first GWAS of social anxiety confirms a genetic basis for social anxiety, shared with extraversion but possibly less so with neuroticism. © 2017 Wiley Periodicals, Inc., (© 2017 Wiley Periodicals, Inc.)

Background: Williams syndrome (WS), a genetic disorder resulting from hemizygous microdeletion of chromosome 7q11.23, has emerged as a model for identifying the genetic architecture of socioemotional behavior. Common polymorphisms in GTF2I, which is found within the WS microdeletion, have been associated with reduced social anxiety in the general population. Identifying neural phenotypes affected by these polymorphisms would help advance our understanding not only of this specific genetic association but also of the broader neurogenetic mechanisms of variability in socioemotional behavior., Methods: Through an ongoing parent protocol, the Duke Neurogenetics Study, we measured threat-related amygdala reactivity to fearful and angry facial expressions using functional magnetic resonance imaging, assessed trait personality using the Revised NEO Personality Inventory, and imputed GTF2I rs13227433 from saliva-derived DNA using custom Illumina arrays. Participants included 808 non-Hispanic Caucasian, African American, and Asian university students., Results: The GTF2I rs13227433 AA genotype, previously associated with lower social anxiety, predicted decreased threat-related amygdala reactivity. An indirect effect of GTF2I genotype on the warmth facet of extraversion was mediated by decreased threat-related amygdala reactivity in women but not men., Conclusions: A common polymorphism in the WS gene GTF2I associated with reduced social anxiety predicts decreased threat-related amygdala reactivity, which mediates an association between genotype and increased warmth in women. These results are consistent with reduced threat-related amygdala reactivity in WS and suggest that common variation in GTF2I contributes to broader variability in socioemotional brain function and behavior, with implications for understanding the neurogenetic bases of WS as well as social anxiety., (Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Behavioral symptoms and traits have been proposed as early markers in neurodegenerative diseases. The aim of this study was to evaluate social anxiety and autism in FMR1 premutation carriers using the Social Phobia Inventory (SPIN) and the Autism-Spectrum Quotient (AQ) questionnaires. Fifty-nine premutation carriers were compared with 50 controls. The SPIN test showed statistically significant differences between female but not male carriers. The AQ questionnaire found statistically significant differences between premutation carriers and controls in the total AQ as well as in the social skills and attention switching subdomains. A gender effect was only observed for the social skills subdomain. Spearman's correlation analysis revealed a moderately positive correlation with the total AQ scores as well as the social skills and communication subdomains. Our results show that fragile X-associated tremor/ataxia syndrome (FXTAS) patients have higher AQ scores. Moreover, this is the first study to find statistically significant differences between FXTAS and no-FXTAS premutation carriers in the communication and the imagination subdomains, suggesting that FXTAS patients present a broader autistic phenotype than premutation carriers without FXTAS. Based on our results, a wide range of behavioral/psychiatric traits should be included within the broader phenotypic presentation of individuals with the FMR1 premutation., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Female-emitted pheromonal inputs possess an intrinsic rewarding value for conspecific males, promoting approach and investigation of the potential mating partner. In mice these inputs are detected mainly by the vomeronasal organ (VNO) and the main olfactory epithelium (MOE). We investigated the role of VNO-mediated inputs in experience-dependent plasticity of reproductive responses. We applied a sex-specific conditioned odor aversion (COA) paradigm on adult, wild-type (WT) male mice and on male mice impaired in VNO-mediated signal transduction (TrpC2 -/- ). We found that WT males, which underwent COA to female-soiled bedding, lost their innate preference to female odors and presented lower motivation to approach a sexually receptive female. COA also abolished the testosterone surge normally seen following exposure to female odors. Moreover, the conditioned males displayed impairments in copulatory behaviors, which lasted for several weeks. Surprisingly, these males also exhibited phobic behaviors towards receptive females, including freezing and fleeing responses. In contrast, WT males which underwent COA specifically to male pheromones showed no change in olfactory preference and only a marginally significant elevation in intermale aggression. Finally, we show that TrpC2 -/- males were able to acquire aversion to female-soiled bedding and presented similar behavioral alterations following COA in their responses to female cues. Our results demonstrate that the intrinsic rewarding value of female pheromones can be overridden through associative olfactory learning, which occurs independently of VNO inputs, probably through MOE signaling., (© 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.)

It is disputed whether anxiety disorders, like social anxiety disorder, are characterized by serotonin over- or underactivity. Here, we evaluated whether our recent finding of elevated neural serotonin synthesis rate in patients with social anxiety disorder could be reproduced in a separate cohort, and whether allelic variation in the tryptophan hydroxylase-2 (TPH2) G-703T polymorphism relates to differences in serotonin synthesis assessed with positron emission tomography. Eighteen social anxiety disorder patients and six healthy controls were scanned during 60 minutes in a resting state using positron emission tomography and 5-hydroxy-L-[β -(11)C]tryptophan, [(11)C]5-HTP, a substrate of the second enzymatic step in serotonin synthesis. Parametric images were generated, using the reference Patlak method, and analysed using Statistical Parametric Mapping (SPM8). Blood samples for genotyping of the TPH2 G-703T polymorphism were obtained from 16 social anxiety disorder patients (T carriers: n=5, GG carriers: n=11). A significantly elevated [(11)C]5-HTP accumulation rate, indicative of enhanced decarboxylase activity and thereby serotonin synthesis capacity, was detected in social anxiety disorder patients compared with controls in the hippocampus and basal ganglia nuclei and, at a more lenient (uncorrected) statistical threshold, in the amygdala and anterior cingulate cortex. In patients, the serotonin synthesis rate in the amygdala and anterior cingulate cortex was significantly elevated in TPH2 T carriers in comparison with GG homozygotes. Our results support that social anxiety disorder entails an overactive presynaptic serotonergic system that, in turn, seems functionally influenced by the TPH2 G-703T polymorphism in emotionally relevant brain regions., (© The Author(s) 2016.)

Conflicting reports exist on the direction of the relationship between social anxiety (SA) and alcohol/cigarette use (AU/CU) and alcohol/nicotine dependence (AD/ND), with both positive and negative associations reported. A prospective, longitudinal sample of Finnish twins (n = 1,906) was used to test potential explanations for these discrepancies. Specifically, this study used peer, parent, and teacher ratings of SA, and a clinical interview screening item for social anxiety disorder (SAD-Sc) to examine associations between SA and AU/CU and AD/ND from early adolescence into young adulthood. Peer-rated SA was negatively associated with AU, CU, and AD from age 14 through age 22, implying a protective effect (β = -0.01 to -.03). Teacher- and parent-rated SA associations were in the same directions but weaker or nonsignificant, indicating that aspects of SA that are recognizable by peers may be most relevant to AU/CU. Self-reported SAD-Sc was also negatively associated with AU, but positively associated with AD symptoms in young adulthood (β = 0.38). Our findings partially support the existence of different associations between SA and AU versus AD, but only in the context of SAD-Sc rather than trait SA. Neither trait SA nor SAD-Sc significantly predicted ND symptoms, although SAD-Sc was associated with both cigarette abstinence and daily smoking. These findings suggest that adolescent SA is modestly associated with lower AU/CU, although there may be some individuals with more severe SA who develop alcohol problems later in life. There was little evidence of a common underlying liability contributing to both SA and alcohol/cigarette use. (PsycINFO Database Record, ((c) 2016 APA, all rights reserved).)

Social anxiety disorder (SAD) and avoidant personality disorder (AvPD) are frequently co-occurring psychiatric disorders with symptomatology related to fear of social situations. It is uncertain to what degree the 2 disorders reflect the same genetic and environmental risk factors. The current study addresses the stability and co-occurrence of SAD and AvPD, the factor structure of the diagnostic criteria, and genetic and environmental factors underlying the disorders at 2 time points. SAD and AvPD were assessed in 1,761 young adult female twins at baseline and 1,471 of these approximately 10 years later. Biometric models were fitted to dimensional representations of SAD and AvPD. SAD and AvPD were moderately and approximately equally stable from young to middle adulthood, with increasing co-occurrence driven by environmental factors. At the first wave, approximately 1 in 3 individuals with AvPD had SAD, increasing to 1 in 2 at follow-up. The diagnostic criteria for SAD and AvPD had a two-factor structure with low cross-loadings. The relationship between SAD and AvPD was best accounted for by a model with separate, although highly correlated (r = .76), and highly heritable (.66 and .71) risk factors for each disorder. Their genetic and environmental components correlated .84 and .59, respectively. The finding of partially distinct risk factors indicates qualitative differences in the etiology of SAD and AvPD. Genetic factors represented the strongest time-invariant influences, whereas environmental factors were most important at the specific points in time., ((c) 2016 APA, all rights reserved.)