Convergent functional genomics of anxiety disorders: Translational identification of genes, biomarkers, pathways and mechanisms

Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Translational Psychiatry (Impact Factor: 5.62). 05/2011; 1(5):e9. DOI: 10.1038/tp.2011.9
Source: PubMed


Anxiety disorders are prevalent and disabling yet understudied from a genetic standpoint, compared with other major psychiatric disorders such as bipolar disorder and schizophrenia. The fact that they are more common, diverse and perceived as embedded in normal life may explain this relative oversight. In addition, as for other psychiatric disorders, there are technical challenges related to the identification and validation of candidate genes and peripheral biomarkers. Human studies, particularly genetic ones, are susceptible to the issue of being underpowered, because of genetic heterogeneity, the effect of variable environmental exposure on gene expression, and difficulty of accrual of large, well phenotyped cohorts. Animal model gene expression studies, in a genetically homogeneous and experimentally tractable setting, can avoid artifacts and provide sensitivity of detection. Subsequent translational integration of the animal model datasets with human genetic and gene expression datasets can ensure cross-validatory power and specificity for illness. We have used a pharmacogenomic mouse model (involving treatments with an anxiogenic drug--yohimbine, and an anti-anxiety drug--diazepam) as a discovery engine for identification of anxiety candidate genes as well as potential blood biomarkers. Gene expression changes in key brain regions for anxiety (prefrontal cortex, amygdala and hippocampus) and blood were analyzed using a convergent functional genomics (CFG) approach, which integrates our new data with published human and animal model data, as a translational strategy of cross-matching and prioritizing findings. Our work identifies top candidate genes (such as FOS, GABBR1, NR4A2, DRD1, ADORA2A, QKI, RGS2, PTGDS, HSPA1B, DYNLL2, CCKBR and DBP), brain-blood biomarkers (such as FOS, QKI and HSPA1B), pathways (such as cAMP signaling) and mechanisms for anxiety disorders--notably signal transduction and reactivity to environment, with a prominent role for the hippocampus. Overall, this work complements our previous similar work (on bipolar mood disorders and schizophrenia) conducted over the last decade. It concludes our programmatic first pass mapping of the genomic landscape of the triad of major psychiatric disorder domains using CFG, and permitted us to uncover the significant genetic overlap between anxiety and these other major psychiatric disorders, notably the under-appreciated overlap with schizophrenia. PDE10A, TAC1 and other genes uncovered by our work provide a molecular basis for the frequently observed clinical co-morbidity and interdependence between anxiety and other major psychiatric disorders, and suggest schizo-anxiety as a possible new nosological domain.

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    • "Comprehensive gene expression studies in brain and blood, with and without exposure to stress, were carried out in this animal model, generating additional candidate genes and blood biomarkers for bipolar disorder [Le-Niculescu et al., 2008]. Treatment studies in this model using omega-3 fatty acids led to a normalization of the phenotype [Le-Niculescu et al., 2011b]. Another genetic model, a knock-out of the circadian clock gene CLOCK, has been originally described to have a phenotype that mimics only the manic side of the illness [Roybal et al., 2007]. "
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    ABSTRACT: Human studies and animal model studies of psychiatric and other medical disorders are becoming increasingly integrated. Particularly for genomics, the convergence and integration of data across species, experimental modalities and technical platforms is providing a fit-to-disease way of extracting reproducible and biologically important signal, in contrast to the fit-to-cohort effect and limited reproducibility of human genetic analyses alone. With the advent of whole-genome sequencing and the realization that a major portion of the non-coding genome may contain regulatory variants, convergent functional genomics approaches are going to be essential to identify disease-relevant signal from the tremendous polymorphic variation present in the general population. Such work in psychiatry can provide an example of how to address other genetically complex disorders, and in turn will benefit by incorporating concepts from other areas, such as cancer, cardiovascular diseases, and diabetes. © 2013 Wiley Periodicals, Inc.
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    • "Other gene interactions are elusive to be functionally interpreted, GABBR1 [gamma-aminobutyric acid (GABA) B receptor 1] is expressed in the developing cortex and interacts with other GABA receptor in the placenta (GABRG2, GABA A receptor, gamma 2). GABBR1 has been associated with anxiety (Le-Niculescu et al., 2011), autism (Fatemi et al., 2009), schizophrenia (Hegyi, 2013), and epilepsy (Peters et al., 1998), but there are not reports about brain development implications. EDN (endothelin 3) is an endothelium-derived vasoactive peptide expressed in the placenta, involved in a variety of biological functions and interacting with EDNRA (endothelin receptor type A), which is expressed in the developing cortex and upregulated after hypoxic preconditioning in the immature brain (Gustavsson et al., 2007). "
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