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A bioinformatic study revealed serotonergic neurons are involved in the etiology and therapygenetics of anxiety disorders.

ABSTRACT: Genetic factors contribute to the susceptibility of anxiety disorders (ADs) and responses to associated cognitive-behavioral therapy (CBT). However, the type of brain cell affected by the related genes remains unclear. Previous studies have indicated various important brain neurons associated with psychiatric disorders, highlighting the necessity to study the cellular basis of anxiety. We assembled 37 AD-related genes and 23 CBT-related genes from recent large-scale genome-wide association studies, and then investigated their cell-type specificity in single-cell transcriptome data via an expression weighted cell type enrichment method. Additionally, to investigate the cellular differences between ADs and other psychiatric disorders, we excluded the genes associated with major depressive disorder, bipolar disorder, and neuroticism, resulting in 29 AD-specific genes. Remarkably, results indicate that serotonergic neurons are significantly associated with both AD-related and CBT-related genes, despite the two gene sets showing no overlap. These observations provide evidence that serotonergic neurons are involved in the etiology and therapygenetics of ADs. Moreover, results also showed that serotonergic neurons are associated with AD-specific genes, providing a supplementary finding that is in opposition to previous studies that found no evidence for the association between serotonergic neurons and psychiatric disorders via the same strategy. In summary, the current study found that serotonergic neurons are involved in the etiology and therapygenetics of ADs, providing insights into their genetic and cellular basis. Further, this cellular difference study may deepen our understanding of ADs and other psychiatric disorders.

SUBMITTER: Liu HK

PROVIDER: S-EPMC8134630 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:There is ample evidence that genetic factors play an important role in anxiety disorders. In support, human genome-wide association studies have implicated several novel candidate genes. However, illumination of such genetic factors involved in anxiety disorders has not resulted in novel drugs over the past decades. A complicating factor is the heterogeneous classification of anxiety disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) and diverging operationalization of anxiety used in preclinical and clinical studies. Currently, there is an increasing focus on the gene × environment (G × E) interaction in anxiety as genes do not operate in isolation and environmental factors have been found to significantly contribute to the development of anxiety disorders in at-risk individuals. Nevertheless, extensive research on G × E mechanisms in anxiety has not resulted in major breakthroughs in drug discovery. Modification of individual genes in rodent models has enabled the specific study of anxiety in preclinical studies. In this context, two extensively studied neurotransmitters involved in anxiety are the gamma-aminobutyric acid (GABA) and 5-HT (5-hydroxytryptamine) system. In this review, we illustrate the complex interplay between genes and environment in anxiety processes by reviewing preclinical and clinical studies on the serotonin transporter (5-HTT), 5-HT1A receptor, 5-HT2 receptor, and GABAA receptor. Even though targets from the serotonin and GABA system have yielded drugs with known anxiolytic efficacy, the relation between the genetic background of these targets and anxiety symptoms and development of anxiety disorders is largely unknown. The aim of this review is to show the vast complexity of genetic and environmental factors in anxiety disorders. In light of the difficulty with which common genetic variants are identified in anxiety disorders, animal models with translational validity may aid in elucidating the neurobiological background of these genes and their possible role in anxiety. We argue that, in addition to human genetic studies, translational models are essential to map anxiety-related genes and to enhance our understanding of anxiety disorders in order to develop potentially novel treatment strategies.

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A bioinformatic study revealed serotonergic neurons are involved in the etiology and therapygenetics of anxiety disorders.

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