Genetics of Panic Disorder

Abstract

The molecular genetic research on panic disorder (PD) has grown tremendously in the past decade. To date, several hundreds of candidate genes have been examined in association studies, but most of the results have been negative, inconsistent or awaiting replication. Perhaps most intriguing have been findings involving the genes of biological systems known to be pertinent to anxiety phenotypes, such as serotonin, cholecystokinin and adenosine. An array of other genes related to hormonal, neurotrophic and intracellular systems has also been implicated in disposition to PD. The recent advances in bioinformatics and genotyping technologies, including genome‐wide association and gene expression methods, promise more comprehensive discovery in PD. Preliminary findings point to a number of novel gene targets with still unknown pathogenetic relationship to PD. The progress in clinical and neurobiological concepts of PD may further guide genetic research through the current ambiguity to more definitive findings. Key Concepts: The linkage and candidate gene association studies have so far showed only weak success to identify reliable and replicated evidence for the genetic substrate of PD. The genetic research in PD to date has been mostly restricted to small phenotypically and ethnically diverse datasets with genotyping of limited numbers of SNPs. An improved understanding of neurobiological pathways of PD could contribute to a more effective identification of candidate genes. Novel conceptual and analytic approaches, such as pathways‐based analyses, may help to advance GWA studies in PD. Laboratory panic challenge models may provide clues to genetic predisposition to PD. The understanding of genetic underpinnings of PD will not be of full value without a conceptual integration of the clinical phenomena of PD with psychological models and neurobiological or molecular substrates underlying its development and course. The course of PD may depend on the balance between pathogenetic and compensatory or recovery processes, accompanied by activation or inhibition of relevant genes. PD might exist in many distinct genetic forms, each with a different set of genes, but also in one form with certain genes reflecting broader vulnerability to panicogenesis. The heterogeneity in PD phenotypes, age of onset, subtypes and severity of panic attacks, gender and familial aggregation were not sufficiently accounted for in most of published studies and should be more carefully addressed in further analyses. Other comprehensive genetic approaches, including GWA, the analysis of copy number variants and the study of regulatory small noncoding RNAs, may lead to uncovering new genomic mechanisms of PD.