Anxiety disorders (ADs) are a significant global health concern, ranking as the ninth most prevalent health-related cause of disability. Affecting approximately 285 million people worldwide, or 3.8% of the global population, ADs are characterized by moderate heritability (32–67%) and substantial familial aggregation. This familial tendency, especially among first-degree relatives of AD-affected individuals, indicates a strong genetic component in the development of various AD subtypes.
These studies have identified mutations in several genes, providing insights into the etiology of anxiety. For instance, genes like RGS2, PKP1, TMEM132D, and BDKRB2 have been associated with the diagnosis of panic disorder, as defined by the Diagnostic and Statistical Manual of Mental Disorders (DSM).
THBS2 has been linked to generalized anxiety disorder, and GLRB to agoraphobia. Other genes, such as SLC6A4, COMT, HTR1B, and HTR2A, are associated with responses to drug/psychotherapy. Further, genes like PDE4B, NTRK2, and NPSR1 relate to the DSM-guided binary diagnosis of anxiety and/or composite anxiety measures, CRHR1 is connected to neuroticism (an AD-associated personality trait), and NPY to neural activation patterns in response to anxiety-inducing stimuli.
Despite these findings, the exact contribution of these genes to the development and manifestation of ADs remains a subject of ongoing research. To complement genetic studies, physiological research using functional magnetic resonance imaging (fMRI) and positron emission tomography (PET) has identified specific frontal-limbic-midbrain circuits involved in AD symptoms. Similarly, microstimulation studies in rhesus macaques have pinpointed specific neural circuits causally linked to AD symptoms. However, it is not yet clear whether the spatial distribution of AD-associated genes corresponds to these identified neural circuits.
This gap in understanding led researchers to hypothesize that the regional specificities of AD-associated genes might align with the functional organization of AD neurocircuitry as identified in physiological experiments. To test this hypothesis, an integrated approach was adopted, involving the analysis of more than 200 AD-associated genes from GWAS across four AD subtypes. This genetic information was mapped onto microarray-based, spatiotemporal transcriptomic data extracted from over 200 brain structures of normal human brains, as available from the Allen Brain Atlas.
The results of this integrative study are revealing. The AD-associated genes were found to cluster into two distinct groups, each showing unique spatial expression profiles in cerebral nuclei, the limbic system, and the midbrain. These clusters are thought to underlie different neural systems of anxiety, involved in specific behaviors, signaling pathways, region-specific gene networks, and cell types.
Interestingly, these clusters exhibited negatively correlated temporal expression patterns. Crucially, the spatial distribution patterns of these gene clusters corresponded with the AD-associated neurocircuitry identified in physiological experiments. This finding bridges the gap between genetic and neural circuitry perspectives in understanding AD-associated behavior, offering a more comprehensive view of the underlying mechanisms of anxiety disorders.
Discussion
The study delves deeper into the complexities of the relationship between genetic predispositions and neural circuitry in anxiety disorders (ADs). The researchers address a significant gap in previous studies: the need to understand if AD-associated genes exhibit spatial distribution patterns that align with neural circuits implicated in AD symptoms.
Prior studies often focused on single AD subtypes or used rodent models, which do not fully capture the human context of AD. This study, however, utilized a comprehensive approach by examining the spatial expression patterns of genes associated with four AD subtypes. The findings revealed that regions such as the cerebral nuclei, midbrain, and limbic system are enriched for AD-associated genes across all subtypes. This suggests a preferential bias in gene expression patterns corresponding to specific brain structures linked to anxiety in physiological studies.
A novel discovery from this research is the bifurcation of AD-associated genes based on their differential expression in the cerebral nuclei, limbic, and midbrain regions. This led to the identification of two distinct gene clusters, each related to specific neural circuits and behaviors. These clusters were shown to be involved in different aspects of state and trait anxiety, with connections to behaviors such as threat sensitivity, behavioral inhibition, and stress responses. The study further explored the links between these gene clusters and specific neural systems, signaling pathways, and cell types.
Interestingly, the study also examined the relationships between different AD subtypes. Using co-expression analysis, moderate correlations between various AD subtypes were observed, providing insights into their clinical comorbidities and shared traits. For example, a positive correlation was found between panic disorder (PD) and social anxiety disorder (SAD) genes, reflecting their clinical comorbidity. On the other hand, generalized anxiety disorder (GAD) genes showed a different pattern of correlations and enrichment in specific brain regions, highlighting the distinct genetic and neural underpinnings of different AD subtypes.
The research also identified distinct signaling pathways associated with the two spatial clusters, pointing to a dichotomy in the neurophysiology of AD symptoms. One cluster was involved in Glu receptor signaling, while the other was associated with 5-HT and DAergic signaling. This finding aligns with regional and AD subtype specificities, emphasizing the role of neurotransmitter systems in AD pathology.
Additionally, the study presented evidence that specific cell types might be selectively vulnerable to AD-associated gene perturbations, suggesting potential targets for therapeutic interventions. The genetic data also provided insights into the temporal aspects of AD development, indicating that AD mechanisms might be regulated during critical developmental stages.
Despite these advancements, the study acknowledges its limitations and the need for further research. In conclusion, this comprehensive analysis has significantly enhanced the understanding of the genetic, functional, and temporal dimensions of ADs, offering a foundation for future studies in this field.
reference link : https://www.nature.com/articles/s41398-023-02693-y#Sec11
