Genetic and neural mechanisms shared by schizophrenia and depression

Schizophrenia (SCZ) and depression are two prevalent mental disorders characterized by comorbidity and overlapping symptoms, yet the underlying genetic and neural mechanisms remain largely elusive. Here, we investigated the genetic variants and neuroimaging changes shared by SCZ and depression in Europeans and then extended our investigation to cross-ancestry (Europeans and East Asians) populations. Using conditional and conjunctional analyses, we found 213 genetic variants shared by SCZ and depression in Europeans, of which 82.6% were replicated in the cross-ancestry population. The shared risk variants exhibited a higher degree of deleteriousness than random and were enriched for synapse-related functions, among which fewer than 3% of shared variants showed horizontal pleiotropy between the two disorders. Mendelian randomization analyses indicated reciprocal causal effects between SCZ and depression. Using multiple trait genetic colocalization analyses, we pinpointed 13 volume phenotypes shared by SCZ and depression. Particularly noteworthy were the shared volume reductions in the left insula and planum polare, which were validated through large-scale meta-analyses of previous studies and independent neuroimaging datasets of first-episode drug-naïve patients. These findings suggest that the shared genetic risk variants, synapse dysfunction, and brain structural changes may underlie the comorbidity and symptom overlap between SCZ and depression.