Role of 108 schizophrenia-associated loci in modulating psychopathological dimensions in schizophrenia and bipolar disorder.

The Schizophrenia Working Group of the Psychiatric Genomics Consortium (PGC) identified 108 loci associated with schizophrenia, but their role in modulating specific psychopathological dimensions of the disease is unknown. This study investigated which symptom dimensions may be affected by these loci in schizophrenia, and bipolar disorder. Positive, negative and depressive symptoms, suicidal ideation, cognition, violent behaviors, quality of life, and early onset were investigated in schizophrenia and bipolar disorder using the clinical antipsychotic trials of intervention effectiveness (CATIE) and systematic treatment enhancement program for bipolar disorder (STEP-BD) studies. Individual loci were investigated, then genes within 50 Kbp from polymorphisms with p < 0.10 were included in an enrichment analysis (Cytoscape GeneMania plugin) and used to estimate polygenic risk scores (PRS). Covariates were center, age, gender, ancestry-informative population, principal components, and for cognition, also years of education were considered. Eighty-nine polymorphisms were available, 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). Genes within 50 Kbp from variants contributing to negative symptoms and suicide were enriched with GO terms involved in acetylcholine neurotransmission, cognition showed enrichment with GO terms involved in vitamin B6 and fucose metabolism while early onset with GO terms related to extracellular matrix structure. PRS showed nominal associations with violent behaviors and depressive symptoms. This study provided preliminary evidence that a schizophrenia-associated variant (rs75059851) may modulate negative symptoms. Multi-locus models may provide interesting insights about the biological mechanisms that mediate psychopathological dimensions.