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

Abstract

We have previously described how the post-mortem 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 schizophrenia polygenic risk scores (PRS) in those two groups of schizophrenic patients and observe that PRS account for twice the variance in schizophrenia risk in the patients with a relatively normal DLPFC transcriptome (“Type 1”) compared to those with dramatically abnormal DLPFC transcriptomes (“Type 2”). That result supports the hypothesis that the DLPFC transcriptome-defined schizophrenia subtypes are biologically meaningful.As important as that result is, a serendipitous observation involving patient ancestry is potentially more important because it suggests an approach which future studies might use to investigate the pathogenic pathways leading to these two distinct forms of schizophrenia. Summary statistics from the Psychiatric Genetics Consortium (PGC) wave 3 core cohort GWAS data were used to calculate schizophrenia PRS. That cohort is composed primarily of Caucasians with about 13% Asians. It contains no Africans or African Americans. However, the cohort we studied here (the NIMH Human Brain Collection Core, or HBCC cohort) is composed of roughly 50% Caucasians and 50% African Americans. When the HBCC cohort is stratified based on ancestry it becomes obvious that in African Americans the polygenic risk scores based on summary statistics from the (Caucasian) PGC core cohort capture the genetic risk associated with Type 1, but not Type 2 schizophrenia. Future work comparing summary statistics from schizophrenia GWAS studies of Caucasian and African American populations should reveal the genes and genetic pathways which are specifically involved in the pathogenesis of the two types of schizophreniaDisclosuresThe 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.