Genetic Analysis of Psychosis Biotypes: Shared Ancestry-Adjusted Polygenic Risk and Unique Genomic Associations.

The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) created psychosis Biotypes based on neurobiological measurements in a multi-ancestry sample. These Biotypes cut across DSM diagnoses of schizophrenia, schizoaffective disorder and bipolar disorder with psychosis. Two recently developed ancestry adjustment methods of Polygenic Risk Scores (PRSs) generate Ancestry-Adjusted PRSs (AAPRSs), which allow for PRS analysis of multi-ancestry samples. Applied to schizophrenia PRS, we found the Khera AAPRS method to show superior portability and comparable prediction accuracy as compared with the Ge method. The three Biotypes of psychosis disorders had similar AAPRSs across ancestries. In genomic analysis of Biotypes, 12 genes and isoforms showed significant genomic associations with specific Biotypes in Transcriptome-Wide Association Study (TWAS) of genetically regulated expression (GReX) in adult brain and fetal brain. TWAS inflation was addressed by inclusion of genotype principal components in the association analyses. Seven of these 12 genes/isoforms satisfied Mendelian Randomization (MR) criteria for putative causality, including four genes , , , , and three transcripts ENSG00000272941, ENSG00000257176, ENSG00000287733. These genes are enriched in the biological pathways of Rearranged during Transfection (RET) signaling, Neural Cell Adhesion Molecule 1 (NCAM1) interactions, and NCAM signaling for neurite out-growth. The specific associations with Biotypes suggest that pharmacological clinical trials and biological investigations might benefit from analyzing Biotypes separately.