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

Abstract

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.

Psychiatric disorders in China: strengths and challenges of contemporary research and clinical services

“…Some recent studies showed that different functional dysconnectivity patterns exist in first-episode and chronic patients (Li et al, 2017 a ; Wang et al, 2019 b ). Dysconnectivity in the early stage of illness mainly involves the inferior frontal gyrus, which correlates with the polygenic risk score of language-related FOXP2 genes, supporting the notion that the genesis of schizophrenia is related to language-related anomalies (Crow, 1997; Du et al, 2021) (Fig. 3 c ).…”

“…For autism spectrum disorders, a (Li et al, 2017a(Li et al, , 2017b. (c) Implications to disease neuropathology and clinical application from neuroimaging studies of major depressive disorder (Cheng et al, 2016), schizophrenia (Du et al, 2021) and autism (Dai et al, 2021 (Wang et al, 2016a, b). In a follow-up study, the authors found that transmission of deleterious mutations is primarily associated with DN mutations (Guo et al, 2018).…”

“…( b ) Genome-wide associations in the Chinese schizophrenia cases (lower) and in the combined sample (upper) of the Psychiatry Genomics Consortium (PGC2) and Chinese populations (43 175 cases; 65 166 controls) (Li et al, 2017a, 2017b). ( c ) Implications to disease neuropathology and clinical application from neuroimaging studies of major depressive disorder (Cheng et al, 2016), schizophrenia (Du et al, 2021) and autism (Dai et al, 2021). Figures reproduced with permission.…”

Reply to: “Historical pursuits of the language pathway hypothesis of schizophrenia”

“…We appreciate the comments by Dr. DeLisi 1 regarding our study investigating the genetic determinants of language-network dysconnectivity in early-stage schizophrenia 2 . In her comments, Dr. DeLisi highlights the missing historical context of the focus of our study and the lack of evidence linking our choice of language-related genes to the elevated genetic risk for schizophrenia.…”

Historical pursuits of the language pathway hypothesis of schizophrenia

“…I read with great interest the publication recently in this journal by Du et al 1 , examining language dysconnectivity early in the illness course of schizophrenia and relating its occurrence to genetic determinants of language. These authors found elevated functional connectivity between Broca’s area for speech production, the thalamus and temporal lobe in first-episode schizophrenia, but dysconnectivity between Broca’s area and the anterior cingulate early in the illness onset that was associated with high polygenic risk scores for schizophrenia calculated specifically from FOXP2 language-related genes.…”