•Microstructure of white matter tracts is altered in social anxiety disorder.•Endophenotypes could be used to investigate neurobiological vulnerability to SAD•Altered microstructure of the SLF is a ...promising candidate endophenotype for SAD. SAD
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.
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.
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.
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.
Background: Social Anxiety Disorder (SAD) is a disabling psychiatric disorder, associated with high co-morbidity. Previous research on structural brain alterations associated with SAD has yielded ...inconsistent results concerning changes in gray matter (GM) in various brain regions, as well as on the relationship between GM and SAD-symptomatology. These heterogeneous findings are possibly due to limited sample sizes. Multi-site imaging offers new possibilities to investigate SAD-related GM changes in larger samples.
Methods: An international multi-center mega-analysis on the largest database of SAD brain scans to date was performed to compare GM volumes of SAD-patients (n=174) and healthy participants (n=213) using voxel-based morphometry. A hypothesis-driven region of interest (ROI) approach was used, focusing on the basal ganglia, amygdala-hippocampal complex, prefrontal cortex and parietal cortex.
Results: SAD-patients had larger GM volume in the dorsal striatum when compared to healthy participants. This increase correlated positively with the level of social anxiety symptoms. No SAD-related differences in GM volume were present in the other ROIs.
Conclusions: The results suggest a role for the dorsal striatum in SAD, but previously reported SAD-related changes in GM in the amygdala, hippocampus, precuneus, prefrontal cortex and parietal regions were not replicated. Thereby, our findings indicate that sample size matters and stress the need for meta-analyses like those performed by the Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium and its working groups. Actually, the collaborative effort for this work has resulted in the start of the ENIGMA-Anxiety workgroup.
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•Social Anxiety Disorder (SAD) is a complex disorder with a genetic component.•The endophenotype (EP) approach could shed light on this genetic vulnerability.•Potential neuroimaging ...EPs for SAD are qualitatively reviewed.•We found evidence for several promising candidate EPs.•Future research is needed to investigate whether all criteria for EPs are met.
Social anxiety disorder (SAD) is a disabling psychiatric disorder with a complex pathogenesis. Studies indicate a genetic component in the development of SAD, but the search for genetic mechanisms underlying this vulnerability is complicated. A focus on endophenotypes instead of the disorder itself may provide a fruitful path forward. Endophenotypes are measurable characteristics related to complex psychiatric disorders and reflective of genetically-based disease mechanisms, and could shed light on the ways by which genes contribute to the development of SAD. We review evidence for candidate MRI endophenotypes of SAD and discuss the extent to which they meet the criteria for an endophenotype, focussing on the amygdala, the medial prefrontal cortex, whole-brain functional connectivity and structural-anatomical changes. Strongest evidence is present for the primary endophenotype criterion of association between the candidate endophenotypes and SAD, while the other criteria, involving trait-stability, heritability and co-segregation of the endophenotype with the disorder within families, warrant further investigation. We highlight the potential of neuroimaging endophenotypes and stress the need for family studies into SAD endophenotypes.
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