**Background: characteristics, course and treatment of Social Anxiety Disorder; Key question of project.** ------------------------------------------------------------------------ Social anxiety (SA), an intense fear of social interactions and social evaluation, is a relatively common problem. The life-time prevalence of social anxiety disorder (SAD), the severe form of SA including avoidance behavior and disturbance of general functioning, as described in the Diagnostic and Statistical Manual (DSM IV, 1994), is between 7 and 13% in Western societies (Furmark, 2002; Rapee and Spence, 2004). The year prevalence in the Netherlands is 3.8%, the life-time prevalence is 9.3% (de Graaf et al., 2012). SA with a sub-threshold level below the DSM-IV diagnostic threshold of SAD and with subclinical levels of social anxiety symptoms shows a life-time prevalence rate up to 25% in the general population (Ruscio et al., 2008; Wittchen and Fehm, 2003; Wittchen et al., 1999). SAD patients show a high rate of impairment of social functioning, working- and family-life and close relationships (Lampe et al., 2003; Wong et al., 2012). In addition, patients with SAD are less likely to be in a relationship or marriage (Dingemans et al., 2001; Lampe et al., 2003). SAD is also associated with early leave of school (Stein and Kean, 2000), lower level of education (Dingemans et al., 2001; Wittchen et al., 1999), a higher risk of being unemployed (Dingemans et al., 2001; Lampe et al., 2003) and engagement in jobs below the level of qualification (Dingemans et al., 2001; Katzelnick and Greist, 2001). In addition, the economic costs of SAD are relatively high (Acarturk et al., 2008). Longitudinal studies indicate that SAD grows out of subclinical SA. The growing fear of social interactions and social evaluation often goes unnoticed or is noticed only after a long period of time, because socially anxious individuals shy away from social situations or stay in the background. In contrast with externalizing behavior, socially anxious persons are not an obvious burden on society, another reason why this problem often goes unnoticed. Generally, the age of onset of SAD is during late childhood or adolescence (Rapee and Spence, 2004). SAD is a life-long disease with a low likelihood of spontaneous remission and intervention studies show that SAD is resistant to treatment in comparison with other anxiety disorders. SAD shows a high rate of comorbidity with other anxiety disorders, depression and substance use disorders, with in general SAD preceding the other disorders (Wittchen and Fehm, 2003). In order to reduce the development of SAD, to minimize individual suffering and to reduce the substantial economic costs, it is imperative to develop preventive interventions (Acarturk et al., 2008). Preventive interventions, focused on subjects with increased SA or subclinical SAD, are called indicated prevention. Until now, such interventions have not been developed and studied in persons with SA, but only in adult populations with subclinical panic attacks (Meulenbeek et al., 2010) and in children with increased anxiety (Kendall, 1994). Insight into the risks and protective factors that play a role in the development and maintenance of SAD forms the basis for developing such preventive interventions. **Intergenerational transmission of SAD** ------------------------------------- Family studies have shown that SAD runs in families. Stein et al. showed that first-degree relatives of individuals with generalized SAD were 10 times more likely to have SAD than relatives of individuals without SAD (Stein et al., 1998). This increased risk of SAD was particularly found for the generalized type of SAD and not for specific SAD (Mannuzza et al., 1995). Furthermore, Lieb and colleagues (Lieb et al., 2000) demonstrated that 9.6% of the children of parents with SAD met the criteria of SAD, whereas 2.1% of the children of parents with no psychiatric disorder had SAD. In contrast, there appears to be no significant association between spouses, indicating a random mating for social anxious persons (Distel et al., 2008). Behavior-genetic research (e.g., twin studies) supports both a hereditary and an environmental contribution to the development of social phobia. Twin studies yield heritability estimates of 20-50% (Distel et al., 2008; Kendler, 1992; Middeldorp et al., 2005; Nelson et al., 2000) and investigations of genetics (e.g., Genome Wide Association studies) contributed to the determination of a SAD-specific genetic background (Gelernter et al., 2004). However, it remains unclear which genes are specifically involved in SAD. Likewise, most environmental correlates of SAD seem to be risk factors for internalizing disorders in general (see (Rapee and Spence, 2004)). Few specific environmental effects have been identified and these effects are rather modest. Recently, it has been argued that the investigation of gene-environment interactions is crucial for a better understanding of the involvement of both genetic and environmental factors in the development of psychopathology (Beauchaine et al., 2008). In addition, a special issue of European Archives of Psychiatry and Clinical Neuroscience emphasized the importance of studying gene-environment interactions in anxiety disorders such as SAD (Poulton et al., 2008). However, in order to investigate these gene-environment interactions, it is imperative to understand SAD at the level of its endophenotypes. Allegedly, endophenotypes have a simpler genetic architecture than that of the disorder, and this should enhance the power to discover genes that are specific to the development of SAD (Walters and Owen, 2007). Profiling endophenotypes for SAD is therefore the purpose of the present project; a successful delineation of endophenotypes will facilitate the investigation of gene-environment interactions in subsequent studies on SAD. **Profiling Endophenotypes of SAD** ------------------------------- The SAD phenotype may be linked to the genotype through endophenotypes, which refer to genetic trait markers of the disorder. Complementary to traditional diagnostics, profiling endophenotypes of SAD will advance our understanding of the genetic architecture of this disorder and reveal its neurobiological and neurocognitive abnormalities (Ritsner, 2009). The characterization of SAD specific endophenotypes is of both clinical and scientific relevance. Endophenotypes (1) help to improve diagnostic criteria, which are difficult to interpret when signs and symptoms overlap with other disorders; (2) may supplement psychiatric diagnosis solely based on signs and symptoms; (3) are by definition present before the onset of an illness and can be used to identify persons who are at elevated risk for becoming ill and for the delivery of preventive interventions; (4) may help to identify a biological subtype of SAD, individualizing treatment and predicting therapeutic response; and (5) may aid in the search for more precise genetic and environmental determinants of the disorder (Ritsner, 2009). For a marker to be considered an endophenotype, “it has to (1) be associated with the phenotype (formal diagnosis), (2) be independent of clinical state, (3) be highly heritable, and (4) the impairment must co-segregate with the illness within a family, with non-affected family members showing impairment relative to the general population” (Glahn et al., 2007). This calls for a multigenerational family study that examines the affected individual with SAD, his or her siblings and children, as well as the partners of each family member. It is hypothesized that the SAD relevant trait characteristics of the patient will also be observable in family members, however, in a milder form. In addition, it is anticipated that these observed SAD traits will not be evident in non-relatives (partners). The present project is the first comprehensive study on SAD endophenotypes. **Key question** ------------ The key question addressed in this project is whether the psychophysiological and neurocognitive abnormalities often reported in SAD patients are heritable, and can thus be found in family members of SAD patients. Determination of genetic kinship of these neurocognitive deficiencies is essential for endophenotyping (Ritsner, 2009) and will result in a better understanding of the constellation of trait markers that, together, will determine whether an individual will develop social anxiety. EEG and MRI will be used to investigate brain reactivity during tasks relevant to SAD symptomatology. Resting-state data and several structural MRI scans (including Diffusion Tensor Imaging, DTI) will also be acquired. 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