SU110 - ROLE OF 108 SCHIZOPHRENIA-ASSOCIATED LOCI IN MODULATING PSYCHOPATOLOGICAL DIMENSIONS IN SCHIZOPHRENIA AND BIPOLAR DISORDER

Abstract

Background Schizophrenia is a highly heritable disorder and the Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC) identified 108 loci with genome-wide association with broad schizophrenia diagnosis. Schizophrenia is a clinically complex entity and the role of these 108 loci in modulating specific clinical features of the disease is still unknown. This study investigated which symptom dimensions may be affected by these loci in schizophrenia and bipolar disorder. Methods Positive, negative and depressive symptoms, suicidal ideation, cognition, violent behaviors, quality of life and early onset were investigated in the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) and Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) samples. Only white subjects were included to avoid possible confounding from ancestry stratification. Imputation of genotypes was carried out after standard quality control using the Haplotype Reference Consortium panel as reference. Individual loci were investigated using linear or logistic regression, then genes within 50 Kbp from polymorphisms with p Results 89 polymorphisms among the 108 of interest were available in both samples, 479 and 810 white subjects were included from CATIE and STEP-BD, respectively. rs75059851 (IGSF9B gene) was associated with negative symptoms in CATIE (p=0.00048); no other variants survived after multiple-testing correction. rs1023500 (CENPM gene) showed a trend of association with early onset with consistent direction in both samples (p=0.033 in STEP-BD and p=0.073 in CATIE). GeneMania analysis showed that negative symptoms and suicidal ideation had a relevant enrichment of Gene Ontology (GO) terms related to acetylcholine neurotransmission, monoamines and ion channel activity while pyridoxal phosphate binding and fucose metabolism showed enrichment for cognition. GO terms referred to processes involved in extracellular matrix structure were found enriched for early onset. PRS showed nominal associations with violent behaviors (p=0.034, Nagelkerke's R2=0.014) and depressive symptoms (p=0.04, R2=0.009). Discussion This study provided preliminary evidence that a schizophrenia-associated variant in the IGSF9B (immunoglobulin superfamily member 9B) gene may modulate negative symptoms. IGSF9B is involved in GABAergic signaling and it may mediate negative symptoms by affecting depression and cognition. A polymorphism in the CENPM (centromere protein M) gene showed an interesting trend of association with early onset. CENPM encodes for an inner protein of the kinetochore, the multi-protein complex that binds spindle microtubules to regulate chromosome segregation during cell division. Multi-locus models may provide interesting insights about the biological mechanisms that medicate specific symptom domains and the genetic overlap between schizophrenia and bipolar disorder.