microRNA-Mediated Regulation and the Genetic Susceptibility to Anxiety Disorders

Investigation of how genetic variation within complex gene regulatory networks results in phenotypic alterations may represent a useful approach towards the understanding of human evolution and disease. In this regard, genetic studies can contribute to the identification of genes and pathways underlying the susceptibility to psychiatric disorders including anxiety disorders. However, this has shown to be difficult due to the complexity of both, the genetics and the phenotypes of these disorders. In fact, even though the estimated heritability of psychiatric disorders is high, most genetic risk alleles for these disorders have still not been identified, leading to the conclusion that either major risk alleles are scarce or that they increase risks only marginally, that is to say that their associated Odds Ratio is low. Genetic heterogeneity for complex disorders is widely accepted and, in addition, it has been suggested that non-standard factors, such as epigenetic or regulatory changes or combinations of various of these elements could be involved in the aetiology of psychiatric disorders (Burmeister et al., 2008). Accordingly, increasing evidence at a population and experimental level indicates that genetic variation at regulatory regions underlies differences in gene expression and could be a major contributor to phenotypic diversity in human populations (Buckland et al., 2005; Knight, 2005; Rockman and Wray, 2002). This may be particularly true in the case of psychiatric disorders, where changes in regulatory elements leading to small variations in the dosage of proteins involved in neuronal pathways may disrupt the fine-tuned equilibrium of complex brain functions and contribute to the development of the disease. In this respect, even though the search for susceptibility genes for anxiety disorders has led to the finding of positive associations, most of these studies have produced results that are inconsistent or not clearly replicated, indicating that the genetic basis of anxiety disorders requires further investigation using alternative approaches. Stress has also been shown to have a critical role in the development of anxiety disorders (Lupien et al, 2009), at least partially, through mechanisms related to neural plasticity. Synaptic connections in the brain undergo experience-dependent functional or morphological changes through complex pathways that are not yet fully understood, but for which microRNAs (miRNAs) might have a critical role (Kosik et al., 2006). miRNAs are endogenous small non-coding RNAs that regulate gene expression by means of partial