The genetic determinants of language network dysconnectivity in drug-naïve early stage schizophrenia

Schizophrenia is a neurocognitive illness of synaptic and brain network-level dysconnectivity that often reaches a persistent chronic stage in many patients. Subtle language deficits are a core feature even in the early stages of schizophrenia. However, the primacy of language network dysconnectivity and language-related genetic variants in the observed phenotype in early stages of illness remains unclear. This study used two independent schizophrenia dataset consisting of 138 and 53 drug-naïve first-episode schizophrenia (FES) patients, and 112 and 56 healthy controls, respectively. A brain-wide voxel-level functional connectivity analysis was conducted to investigate functional dysconnectivity and its relationship with illness duration. We also explored the association between critical language-related genetic (such as FOXP2) mutations and the altered functional connectivity in patients. We found elevated functional connectivity involving Broca’s area, thalamus and temporal cortex that were replicated in two FES datasets. In particular, Broca’s area - anterior cingulate cortex dysconnectivity was more pronounced for patients with shorter illness duration, while thalamic dysconnectivity was predominant in those with longer illness duration. Polygenic risk scores obtained from FOXP2-related genes were strongly associated with functional dysconnectivity identified in patients with shorter illness duration. Our results highlight the criticality of language network dysconnectivity, involving the Broca’s area in early stages of schizophrenia, and the role of language-related genes in this aberration, providing both imaging and genetic evidence for the association between schizophrenia and the determinants of language.