Higher polygenic risk scores for anxiety disorders are associated with reduced area in the anterior cingulate gyrus

Anxiety disorders are heterogeneous, show a moderate genetic contribution and are associated with inconsistent cortical structure alterations. Here, we investigated whether genetic factors for anxiety disorders contribute to cortical alterations by conducting polygenic risk score (PRS) analyses. We calculated PRSs for anxiety disorders at several P value thresholds (from P_T ≤ 5.0 × 10^-8 to P_T ≤ 1.0) based on the latest large-scale genome-wide association study of anxiety disorders from the UK biobank (25,453 cases; 58,113 controls) in an independent sample of psychiatrically and physically healthy subjects (n = 174). Using regression after adjusting for confounding factors, we tested whether these PRSs were associated with the surface area and cortical thickness in 34 bilateral brain regions extracted using FreeSurfer. A higher PRS for anxiety disorders at P_T ≤ 1.0 was significantly associated with a reduced right caudal anterior cingulate area (beta = -0.25, p_uncorrected = 9.51 × 10^-4, p_corrected = 0.032). PRSs based on more common SNPs, especially from P_T ≤ 0.01 to P_T ≤ 1.0, were associated with the right caudal anterior cingulate area (a maximum at P_T ≤ 0.5: R² = 0.066, beta = -0.27, p_uncorr = 3.81 × 10^-4, p_corr = 0.013). Furthermore, individuals in the highest quartile for anxiety disorder PRS had lower surface area and volume in the right anterior cingulate gyrus than those in the lowest quartile. We suggest a shared genetic etiology between anxiety disorders and structural features of the anterior cingulate gyrus, possibly contributing to the pathogenesis of anxiety disorders via emotional dysregulations. Our findings suggest the potential usefulness of PRS to reduce pathological heterogeneity among anxiety disorders.