Trans-Ancestry Analysis of Psychosis Biotypes: Shared Polygenic Risk and Unique Genomic Associations
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The Bipolar-Schizophrenia Network for Intermediate Phenotypes (B-SNIP) has categorized psychosis disorders (Schizophrenia, Schizoaffective Disorder and Bipolar Disorder) into three distinct Biotypes, based on neurobiological measurements in a multi-ancestry sample. Two recently developed post hoc ancestry adjustment methods of Polygenic Risk Scores (PRSs) generate Trans-Ancestry PRSs (TAPRSs), which allow for PRS analysis of multi-ancestry samples. Applied to schizophrenia PRS, we found the Khera TAPRS method to show superior portability and comparable prediction accuracy as compared with the Ge method. The three Biotypes of psychosis disorders had similar TAPRSs across ancestries. In genomic analysis of Biotypes, nine genes and isoforms showed significant genomic associations with Biotypes in Transcriptome-Wide Association Study (TWAS) of gene expression in adult brain and fetal brain, and of gene isoforms. TWAS inflation was successfully controlled by inclusion of genotype Principal Components in the association analyses. Biotypes and Biotype-related diagnosis distributions differ between African American and European ancestries.
