Genetics of anxiety disorders: Complexities and opportunities

By the latest estimates, anxiety disorders are the most common psychiatric disorders in the United States, affecting 3 of every 10 Americans over a lifetime [Kessler et al., 2005]. The direct and indirect costs of these illnesses exceed $40 billion annually [Greenberg et al., 1999]. Disability associated with these disorders also exceeds that attributable to other psychiatric disorders and most chronic medical conditions, including lung disease, cardiovascular disease, gastrointestinal diseases and cancer [Merikangas et al., 2007]. Effective treatments for anxiety disorders exist in the form of pharmacotherapy (antidepressants and benzodiazepines) and psychosocial treatments (especially, cognitive-behavioral therapy). However, for a substantial proportion of affected individuals, the disorders follow a chronic course and are inadequately treated. For most of the past 40 years, pharmacologic therapies have targeted two classes of neurotransmitters: monoamines and GABA. The development of more effective strategies for treatment and prevention will depend on a more detailed understanding of the underlying etiology of anxiety disorders. Of the known risk factors for anxiety disorders, the most well-validated is family history. Thus, genetic research offers a potentially crucial window into the pathogenesis of these disorders and, as a consequence, the basis for improving their treatment and prevention. As reviewed in several of the articles that follow, genetic epidemiologic studies have clearly documented that all of the anxiety disorders aggregate in families and that this familiality is primarily due to genetic factors. First degree relatives of probands with the major anxiety disorders (panic disorder, social anxiety disorder, specific phobias, obsessive-compulsive disorder) have a fourto sixfold increased risk of the index disorder compared to relatives of unaffected probands [Hettema et al., 2001]. Heritability estimates from twin studies of the anxiety disorders have ranged from approximately 0.20–0.40 [Scherrer et al., 2000; Kendler et al., 2001; Hettema et al., 2005]. It is clear, then, that genes contribute to pathologic anxiety. As with other psychiatric and medical disorders, such findings have motivated efforts to identify the specific genes involved. We now live in a scientific era where the tools of genetic research enable sophisticated and high-throughput interrogation of the genome. These techniques have been used aggressively and successfully to implicate specific loci for a variety of psychiatric and medical disorders. However, the progress for anxiety disorders has been less impressive. Indeed, much less attention has been directed toward genetic research on anxiety disorders in comparison with other major psychiatric disorders. Figure 1 shows the number of articles published on the genetics of a variety of psychiatric disorders over the 5-year period from January 1, 2002 to January 1, 2007. As is clear from the figure, the literature on the genetics of anxiety disorders has lagged far behind that of other major psychiatric disorders such as autism, schizophrenia, bipolar disorder, and depression. What accounts for this relative neglect? One possibility is that the low heritability of anxiety disorders has discouraged further genetic research. The answer may also lie in the phenotype [Smoller and Tsuang, 1998]. The nosology of anxiety disorders is arguably more complex than that of many other psychiatric disorders. Anxiety and fear are normal human emotions that have survival value and the distinction between normal and pathologic degrees of anxiety can be difficult to define. In addition, the anxiety disorder diagnoses have evolved substantially over the past 30 years. The current constellation of anxiety diagnoses did not enter the official canon of psychiatric classification until 1980, with the publication of DSM-III. Whereas DSM-II included brief and relatively nonspecific disorders (e.g., anxiety neurosis, phobic neurosis, obsessional neurosis) spanning two pages of text, the number of anxiety disorders swelled to 13 in DSM-IV, covering more than 50 pages of description. Anxiety neurosis was split into panic disorder (PD) and generalized anxiety disorder (GAD) and the definition of these Jordan W. Smoller, M.D., ScD, Psychiatric Genetics Program in Mood and Anxiety Disorders, Department of Psychiatry; Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts. Stephen V. Faraone, Departments of Psychiatry and of Neuroscience & Physiology, SUNY Upstate Medical University, Syracuse, New York. *Correspondence to: Jordan W. Smoller, M.D., ScD, Center for Human Genetic Research, Simches Research Building, 185 Cambridge St., Boston, MA 02114. E-mail: jsmoller@hms.harvard. edu DOI 10.1002/ajmg.c. 30167