The Genetics of Symptom-Based Phenotypes: Toward a Molecular Classification of Schizophrenia

Objective: Genetic linkage studies in schizophrenia (SZ) have primarily focused on the phenotype of disease susceptibility. A limited number of studies, however, have reported suggestive linkage to specific SZ symptom domains including regions on chromosomes 6, 8, and 20. We examined these chromosomal regions for association to positive, negative, and disorganized symptom clusters, using a dense set of single-nucleotide polymorphisms (SNPs).Methods: We ascertained 178 Caucasian patients with SZ for lifetime severity of clinical symptomatology using a structured diagnostic interview. The cohort was genotyped with the Affymetrix 500K microarray, from which we selected, a priori, 4833 intragenic SNPs located within chromosomal regions previously linked to specific SZ symptom clusters. Parametric tests, corrected for multiple testing, were used to compare the effects of allelic variation within these SNPs to the lifetime severity of the specific symptom domain that had been implicated by prior linkage studies.Results: We were able to extend previous reports of linkage between chromosome 6q and both positive and disorganized symptoms. Lifetime severity of positive symptoms was significantly (P = 2.50 x 10(-5)) associated with a SNP within the origin recognition complex subunit 3-like (ORC3L) gene, a gene implicated in synaptic plasticity. Level of disorganized symptoms was significantly (P < 6.00 x 10(-5)) associated 2 SNPs within the brain-specific angiogenesis inhibitor 3 (BAI3) gene, which is highly expressed in brain during development.Conclusions: These data point toward specific candidate genes located within previously implicated linkage peaks for clinical symptomatology. Identification of functional variants within these regions and a characterization of the effect of these risk genotypes on the treatment of specific clinical symptoms are needed.