Bringing a developmental perspective to anxiety genetics.

Despite substantial recent advancements in psychiatric genetic research, progress in identifying the genetic basis of anxiety disorders has been limited. We review the candidate gene and genome-wide literatures in anxiety, which have made limited progress to date. We discuss several reasons for this hindered progress, including small samples sizes, heterogeneity, complicated comorbidity profiles, and blurred lines between normative and pathological anxiety. To address many of these challenges, we suggest a developmental, multivariate framework that can inform and enhance anxiety phenotypes for genetic research. We review thepsychiatric andgeneticepidemiological evidencethat supportssuch aframework, includingtheearlyonsetandchroniccourse of anxiety disorders, shared genetic risk factors among disorders both within and across time, and developmentally dynamic genetic influences. We propose three strategies for developmentally sensitive phenotyping: examination of early temperamental risk factors, use of latent factors to model underlying anxiety liability, and use of developmental trajectories as phenotypes. Expanding the range of phenotypic approaches will be important for advancing studies of the genetic architecture of anxiety disorders. Many excellent papers in this Special Issue address the ways in which genetic and genomic sciences are informing our understanding of developmental psychopathology. Here, we take a complementary approach in which we explore the ways that developmental science can contribute to more informative genetic studies. We focus specifically on anxiety disordersand argue thatadevelopmental approach tothephenotype will be particularly important, given the early onset and high prevalence of anxiety disorders in children. We cover fourmaintopics:thecurrentstateof the candidate gene and genome-wide association literatures in anxiety disorders; current obstacles to gene finding in anxiety genetics; the psychiatricand genetic epidemiologyof anxietydisorders with a specific focus on data that can guide developmental, multivariate approaches to phenotype definition; and strategies for developmentally sensitive phenotyping that could be used in existing samples and in future study designs. Wenotehereaclarificationofouruseofthebroadtermanxiety disorders. DSM-IV-TR lists 13 separate anxiety disorders, butwewillfocuson the most commonly diagnosed, idiopathic anxiety disorders: generalized anxiety disorder (GAD), panic disorder (PD) with and without agoraphobia, agoraphobia without a history of PD, separation anxiety disorder, social phobia, and specific phobia. Although the DSM-IV-TR includes obsessive–compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) in the anxiety category, there is also evidence that these disorders have partly distinct etiologic and neurobiological underpinnings (Eleyet al., 2003; Graybiel & Rauch, 2000; Heim & Nemeroff, 2009; Tambs et al., 2009). For this reason, this paper will not include OCD and PTSD, an approach that is consistent with the new DSM-5 proposal for theanxietydisorderscategory.Wealsoacknowledgethestrong