Genome-wide Association Study Identifies SORCS3 as a Novel Susceptibility Locus for Panic Disorder in the FinnGen Study

Panic disorder is an anxiety disorder with poorly understood etiology. Although twin studies suggest modest heritability ([~]40%), few genetic variants have been associated with it. We carried out a genome-wide association study in the Finnish longitudinal health register-based FinnGen study to identify genetic variants that predispose to panic disorder. FinnGen cases (N=3,549) were defined as individuals with an ICD-10 or ICD-9 lifetime diagnosis of panic disorder. Control subjects (N=159,869) were free of any psychiatric diagnoses. We identified a locus on chromosome 10q25.1 within SORCS3 that was significantly associated with panic disorder. The minor allele (T; frequency 21%) of the lead variant rs902306 increased the risk of panic disorder by 22% (OR=1.22, 95% CI=1.15-1.30, p-value=1.1x10-10). We also investigated serum SORCS3 protein levels in 107 panic disorder cases with or without agoraphobia and 95 controls free of axis I psychiatric disorders collected at the Anxiety Disorders Outpatient Unit of the Max Planck Institute of Psychiatry. Serum SORCS3 levels were 41% higher in panic disorder cases compared to controls ({beta}=0.694, SE=0.141, p-value=8.7x10-07). This finding replicated in 84 subjects from an independent German clinical panic disorder sample ({beta}=1.137, SE=0.532, p-value=0.04), but not in plasma samples of Finnish panic disorder patients from a biobank. Overall, SORCS3 is a novel panic disorder locus, which has previously been associated with other psychiatric and neurodevelopmental disorders. SORCS3 belongs to the sortilin family, with multiple functions related to brain plasticity. Characterization of its role in panic disorder will increase understanding of the neurobiological mechanisms involved in anxiety.