Polygenic Risk Scores Provide Strong Evidence for the Biologic Relevance of Molecular Subtypes of Schizophrenia

We have previously described how the DLPFC transcriptomes of schizophrenia patients can be used to define two patient groups: "Type 1" patients with a relatively normal DLPFC transcriptome and "Type 2" patients with hundreds of genes differentially expressed in the DLPFC at a statistical significance which survives Bonferroni correction. The biological significance of the distinction between Type 1 and Type 2 patients remains an open question. In the present report we examine the polygenic risk scores (PRS) in those two groups of schizophrenic patients and observe Type1 and Type 2 schizophrenia have dramatically different genetic architectures. That result supports the hypothesis that the DLPFC transcriptome-defined schizophrenia subtypes are biologically meaningful. There were three unexpected findings in this study. The first unexpected finding was that PRS based on summary statistics from GWAS for schizophrenia captures very little of genetic contribution to the risk of Type 2 schizophrenia in the African-Americans in this study. Our working hypothesis is that in this Medical Examiner-derived cohort African-American ancestry may be a surrogate marker for socio-economic disadvantage and/or poor perinatal or obstetric care and that when present this environmental factor may overwhelm much of the genetic component for risk of type 2 schizophrenia. If in this particular cohort African-American ancestry is in fact a surrogate marker for socio-economic disadvantage, that makes this an especially valuable cohort for further study. Of course, the fact that PRS based on any particular GWAS study does not capture the genetic risk for Type 2 schizophrenia in the African-Americans in this cohort does not imply that there is no genetic component to that risk. The second unexpected finding was that PRS for Cannabis Use Disorder captures genetic risk for Type 2, but not for Type 1 schizophrenia in the African-Americans in this cohort. The scientific and epidemiologic implications of this finding are unclear, but the finding rules out many of the technical artifacts that might have accounted for the failure of PRS based on the available GWAS studies of schizophrenia to capture that risk. The third unexpected finding was that PRS based on summary statistics from GWAS for treatment-resistant schizophrenia captures genetic risk for Type 2, but not the Type 1 schizophrenia in the Caucasians in this cohort. This is, perhaps, the most important finding in this study because it suggests that the distinction between Type 1 and Type 2 schizophenia is clinically as well as biologically meaningful. Disclosures: The opinions expressed herein are those of the authors and not necessarily representative of those of the Uniformed Services University of the Health Sciences (USU), the Department of Defense (DOD), the United States Army, Navy, Air Force, VA, NIH or any other US federal agency.