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Endophenotypes can help to bridge the gap between psychosis and its genetic predispositions, but their underlying mechanisms remain largely unknown. This study aims to identify biological mechanisms that are relevant to the endophenotypes for psychosis, by partitioning polygenic risk scores into specific gene sets and testing their associations with endophenotypes.

We computed polygenic risk scores for schizophrenia and bipolar disorder restricted to brain-related gene sets retrieved from public databases and previous publications.

Three hundred and seventy-eight gene-set-specific polygenic risk scores were generated for participants. Seven endophenotypes were also measured in the sample. Linear mixed-effects models were fitted to test associations between each endophenotype and each gene-set-specific polygenic risk score. Our finding on reduced P amplitudes suggests that certain genetic variants alter early brain development thereby increasing schizophrenia risk years later.

Gene-set-specific polygenic risk scores are a useful tool to elucidate biological mechanisms of psychosis and endophenotypes, offering leads for experimental validation in cellular and animal models. Partitioning the effects of risk loci into distinct brain functional domains can provide important biological insights into the mechanisms of psychosis. One such approach uses endophenotypes, ie, heritable phenotypes associated with a, putatively more complex, illness. Polygenic risk scores, the sum of the number of risk alleles weighted by their effect sizes, provide a method to test the genetic overlap between psychosis and its endophenotypes.