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Background: Evidence from meta-analyses of MRI-based brain morphometry suggested a common neurobiological substrate (CS) for psychiatric disorders in the dorsal anterior cingulate (dACC) and the anterior insular cortices (AIC). Methods: We analyzed the first principal component of voxel-based morphometric volumes forming the CS (hereafter abbreviated as CCS). We conducted genome-wide association studies (GWAS) of the CCS in four cohorts (discovery, n=2,271), followed by meta-analysis, and replication in a fifth cohort (n=865). Secondary genetic and clinical imaging analyses were performed in two major depressive disorder case/control cohorts (n=967 cases and n=508 controls). Results: The single-nucleotide polymorphism (SNP) rs17076061 on chromosome 5q35.2 was associated with the CCS at genome-wide significance and replicated. Psychiatric cross-disorder polygenic risk scores were associated with the CCS at nominal significance. However, no significant genome-wide overlap between genetic variants influencing the CCS and genetic risk for different disorders was found after correction for multiple testing. Further secondary analyses revealed a dependence of the association of the identified variant on interactions with age. Conclusions: We identified a significant association between a genetic variant and a transdiagnostic psychiatric marker. The SNP maps to a locus harboring genes involved in neuronal development and regeneration. Dependence of this association on age and the absence of direct associations with major psychiatric disorders suggest an indirect relationship between the CCS and disease risk, contingent on environmental and additional, unknown genetic factors. Overall, our study indicates a complex interplay between common genetic variation and the function of brain regions affected in psychiatric patients.

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