Susceptibility locus on chromosome 1q23-25 for a schizophrenia subtype resembling deficit schizophrenia identified by latent class analysis.

CONTEXT Identifying susceptibility genes for schizophrenia may be complicated by phenotypic heterogeneity, with some evidence suggesting that phenotypic heterogeneity reflects genetic heterogeneity. OBJECTIVE To evaluate the heritability and conduct genetic linkage analyses of empirically derived, clinically homogeneous schizophrenia subtypes. DESIGN Latent class and linkage analysis. SETTING Taiwanese field research centers. PARTICIPANTS The latent class analysis included 1236 Han Chinese individuals with DSM-IV schizophrenia. These individuals were members of a large affected-sibling-pair sample of schizophrenia (606 ascertained families), original linkage analyses of which detected a maximum logarithm of odds (LOD) of 1.8 (z = 2.88) on chromosome 10q22.3. MAIN OUTCOME MEASURES Multipoint exponential LOD scores by latent class assignment and parametric heterogeneity LOD scores. RESULTS Latent class analyses identified 4 classes, with 2 demonstrating familial aggregation. The first (LC2) described a group with severe negative symptoms, disorganization, and pronounced functional impairment, resembling "deficit schizophrenia." The second (LC3) described a group with minimal functional impairment, mild or absent negative symptoms, and low disorganization. Using the negative/deficit subtype, we detected genome-wide significant linkage to 1q23-25 (LOD = 3.78, empiric genome-wide P = .01). This region was not detected using the DSM-IV schizophrenia diagnosis, but has been strongly implicated in schizophrenia pathogenesis by previous linkage and association studies.Variants in the 1q region may specifically increase risk for a negative/deficit schizophrenia subtype. Alternatively, these results may reflect increased familiality/heritability of the negative class, the presence of multiple 1q schizophrenia risk genes, or a pleiotropic 1q risk locus or loci, with stronger genotype-phenotype correlation with negative/deficit symptoms. Using the second familial latent class, we identified nominally significant linkage to the original 10q peak region. CONCLUSION Genetic analyses of heritable, homogeneous phenotypes may improve the power of linkage and association studies of schizophrenia and thus have relevance to the design and analysis of genome-wide association studies.