PSYCHIATRIC GENOMICS CONSORTIA ANXIETY PHASE 2: DISAGGREGATING GENOMIC EFFECTS ON INDIVIDUAL ANXIETY DISORDERS AND DELVING INTO BIOLOGICAL MECHANISMS

Overall Abstract The recent PGC-ANX flagship publications of their case-control and dimensional anxiety genome-wide association studies (GWAS) have established a robust foundation for investigating the genomic and biological underpinnings of anxiety-related distress and impairment. However, key questions remain regarding 1) the extent to which genetic risk is shared across anxiety disorders versus specific to individual diagnostic categories; 2) how these genetic signals translate across ancestries; 3) the influence of rare genetic variants; and 4) how the polygenic scores can illuminate temporal trends in indirect and direct genetic effects for anxiety. Phase 2 of the PGC-Anxiety working group, highlighted by the current symposium, directly addresses these gaps. Dr. Nora Strom from Humboldt-Universität will present results from a large-scale GWAS meta-analysis of panic disorder, highlighting novel loci and distinct and overlapping genetic signals. Dr. Daniel Levey from Yale University will discuss findings from multi-ancestry GWAS of generalized anxiety disorder, emphasizing the importance of increasing ancestral diversity for gene discovery and generalizability. Ms. Sydney Kramer will delve into the impact of rare single nucleotide and copy number variants on anxiety disorders and post-traumatic stress disorder. Dr. Johanne Hagen Pettersen from Lovisenberg Diaconal Hospital will leverage polygenic scores constructed from the recent PGC-ANX analyses to estimate direct and indirect genetic effects on anxiety outcomes in adolescence and across birth cohorts in the world’s largest sample of genotyped nuclear families. These presentations illustrate how integrating diverse genomic approaches can move the field beyond locus discovery toward mechanistic insights. By disaggregating genetic effects and linking them to developmental and biological processes, Phase 2 of PGC Anxiety aims to bridge the gap between gene discovery and clinical translation. Dr. John Hettema from Texas A and M University will serve as discussant, synthesizing findings and outlining future directions for the field.