Intelligence as proxy phenotype providing insight into the heterogeneity of schizophrenia

Schizophrenia is a mental disorder constituting different symptom clusters. Its high heterogeneity in both pathophysiology and clinical manifestations hampered effective prevention and treatment. It has long been recognized that one of the core features of schizophrenia is its intellectual decline. Using the proxy-phenotype method (PPM), we tried to identify core genes, the expression of which in the dorsal lateral prefrontal cortex (DLPFC) showed a genetic dependence between intelligence (IT) and schizophrenia (SCZ). The result revealed ten genes of genetic dependence in their genetic expression in DLPFC between IT and schizophrenia. Further, a clustering analysis using the expression matrix of these ten genes identified four biotypes in our patient group. Subsequent phenotypic profiling of these four biotypes indicated a significant difference in working memory capacity, the gray matter volume (GMV) of five brain regions (lLimbicA\_TempPole\_2, rLimbicA\_TempPole\_2 rLimbicB\_OFC\_1, rContA\_IPS\_1 and rContB\_PFClv\_1), structural network and psychopathology. An in-vitro investigation of the biological functions of these core genes indicated their potentially critical role in neuronal growth, especially in dendritic spines. Our current study employed a novel statistical approach to identify the core genes associated with IT and explore the possibility of using the expression knowledge of these core genes to reduce the heterogeneity of schizophrenia. The results pinpointed one biotype that exhibited significant deficits in working memory, GMV in limbic and prefrontal areas, and also showed psychopathology of core negative symptom and worse outcomes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement the National Natural Science Foundationof China (grant number 81920108018), the Key R & D Program of Zhejiang (grant number 2022C03096), Project for Hangzhou Medical Disciplines of Excellence. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors