Genome-wide associantion studies of anxiety spectrum phenotypes: The PGC Anxiety Disorders working group
Although anxiety disorders are widespread and being estimated to represent the sixth leading cause of global disability, the knowledge about their genetic underpinnings lags behind that of most psychiatric conditions. Proven to serve as a powerful tool to identify novel loci for genetic susceptibility factors, genome-wide association studies (GWAS) have already been applied successfully to a wide range of disorders including psychiatric illnesses. However, only few GWAS have been conducted focussing on primary anxiety disorders so far, although there is evidence for a genetic component of these disorders. Assuming multiple small effects of different genes are acting in concert to disease susceptibility presupposes the use of large sample sizes which provide sufficient statistical power for a successful identification of these genetic variants.
Since 2007, the Psychiatric Genomics Consortium (PGC), a collaborative confederation of researchers in the field of psychiatric genetics, has published several meta- and mega-analyses of genome-wide genomic data for various psychiatric disorders. To date, the PCG is the largest consortium in the field, comprises over 800 investigators worldwide, and has more than 900,000 samples in analysis. The recently established Anxiety Workgroup (ANX) within the PGC aims at elucidating the genetic background of anxiety disorders within large samples. Representing the so far largest and most comprehensive study for any single or multiple anxiety disorders, this project promises an innovative and powerful investigation of the genetic variants underlying susceptibility to lifetime anxiety-spectrum psychopathology. Further, anxiety disorders possess substantial lifetime comorbidity with each other and with other psychiatric conditions, most notably, the mood disorders. The data gained by ANX hence is used to test the hypotheses that anxiety disorders share molecular genetic risk variants with other anxiety spectrum phenotypes. While evolving formulations of DSM have described anxiety disorders with an increasing specificity of symptomatic criteria, a growing body of research has suggested that these conditions share more of their risk factors and underlying neurobiology than would be predicted by clinical nosology alone. In contrast to the common approach of analysing disorders one-by-one using case-control comparisons derived from clinical diagnoses, sometimes followed by exploratory analyses of their possible genetic relationship, in this project empirically-based psychological theories, extant epidemiological evidence, and established genetic risk structures to construct and test phenotypic models that examine shared versus disorder-specific genetic effects for comorbid, genetically-related anxiety spectrum disorders, are being applied. At the same time, statistically rigorous approaches that quantitatively assess, minimize, or account for various sources of heterogeneity before, within, and after association analyses are taken into account. With regard to the analyses, in this project GWAS, metaanalyses, gene-based tests, as well as polygenic association testing are performed.
The hereby identified variants conveying (statistically) a risk to the development of anxiety disorders are subsequently analysed with in-silico validation approaches to assess their potential functionality, followed by pathway-based analyses to investigate biological mechanisms of genetic liability that can inform new treatment targets.