Genome-Wide Association Study of Clinical Characterized Schizophrenic Patients Reveals Locus for Cognitive Phenotype Cataphasia - Abstract
Introduction: Schizophrenic psychoses are highly heterogeneous in their clinical manifestation including their outcome and their dynamics. While psychoses show a high heritability, details of genetic contribution on the phenotype level are still unknown. We wanted to examine if differentiated phenotyping according to clinical homogenous subgroups enhances the search for new disease-associated loci. Methods: We applied the classification of endogenous psychoses according to Karl Leonhard to take account of clinical details within schizophrenic spectrum. Patients diagnosed with schizophrenia were, depending on their clinical symptoms, assigned to one of nine phenotypes, which in turn represent three forms of progression. Patients (n = 1255) and controls (n = 1555) were genotyped as part of the PGC initiative. We conducted Genome wide association studies (GWAS) for each phenotype and each course of illness. We also calculated polygenic risk scores (PRS) for each form of progression based on the PGC samples of schizophrenia and bipolar disorder. Results: GWAS revealed a genome wide significant (p < 5x10-8) locus on chromosome 11 within the CTSD gene for phenotype Cataphasia with distinctive cognitive manifestations. PRS for schizophrenia were highest in patients with a poorer outcome whereas PRS for bipolar disorder were highest in phasic remitting as compared to chronic progressive forms. Conclusion: Our study shows possible advantages of a differentiated approach in the genetic research of schizophrenic psychoses and may contribute to phenotype-genotype correlations. Bipolar and schizophrenia PRS scores reflected outcome and treatment response thus strengthening the idea of different biological underpinnings for phasic and treatment resistant schizophrenic psychoses.