Who's afraid of anxiety genetics?

r a d ( ( “ s a i u l p T i p d d ( t d a r t i p 6 h t a c h o R esearch on the genetics of anxiety disorders ought to be a hotbed. All the ingredients are there. Twin studies have shown that anxiety disorders are heritable. We know more bout the neurocircuitry and molecular basis of anxiety than we do bout most psychiatric phenotypes. There are well-validated anial models that provide opportunities for discovering and validatng candidate genes. And the public health importance of anxiety isorders is enormous: taken together, they represent the most ommon class of psychiatric disorders and account for more days of isability than mood disorders and substance use disorders (1). But compared with the explosion of large-scale genetic research on other mental disorders—autism, attention-deficit/hyperactivity disorder, schizophrenia, bipolar disorder, depression— genetic studies of anxiety disorders have been relatively scarce. Some of this might be due to disparities in funding and advocacy, but a more fundamental reason might have to do with the complexity of the phenotype itself. Anxiety is a universal human experience, and the line between normal and pathological anxiety can be difficult to draw. In addition, comorbidity is the rule, and the boundaries among the anxiety disorders themselves are fuzzy. These complexities might have fostered a “fear of anxiety genetics” that has kept some investigators and funding agencies from pursuing research on the genetic determinants of anxiety. But the public health burden and limited treatment options for anxiety disorders make the importance of defining their etiology undeniable. The good news is that genetic research on anxiety is beginning to flourish, and those pursuing this research can now benefit from insights and advances in other areas of psychiatric and medical genetics. Two studies in this issue of Biological Psychiatry illustrate emerging directions for such genetic studies: the role of regulatory RNAs, and the contribution of rare variants (2,3). Muinos-Gimeno et al. (2) examined whether variants in genes encoding microRNAs (miRNAs) are associated with anxiety disorders. The miRNAs are a class of small noncoding RNAs whose importance has only recently been appreciated. They are a crucial part of a puzzle that emerged with the sequencing of the human genome: how can only 21,000 genes account for the remarkable diversity of biological functions required to build and maintain human life? The answer has much to do with the symphony of regulatory mechanisms that modulate gene expression, including miRNAs and epigenetic modifications. The miRNAs act predominantly by binding to messenger RNAs of other genes and interfering with their translation or accelerating their degradation. Taken together, the hundreds of different miRNAs encoded by the genome regulate up to 50% of protein-coding genes (4). Muinos-Gimeno et al. asked whether miRNAs contribute to the risk for anxiety disorders by examining variation across 325 miRNA genes. In a case–control analysis that included 203 patients with panic disorder (PD), they found moderate evidence of association for single nucleo-