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

Full Abstract

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.

Author information

Author/s: Holliday, Elizabeth G (EG); McLean, Duncan E (DE); Nyholt, Dale R (DR); Mowry, Bryan J (BJ);

Affiliation: Queensland Centre for Mental Health Research, The Park, Wacol, Queensland 4076, Australia.

Grants: R01 MH59624 (Agency:NIMH NIH HHS)

Journal and publication information

Publication Type: Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Archives of general psychiatry (Arch Gen Psychiatry), published in United States. (Language: eng)

Reference: 2009-Oct; vol 66 (issue 10) : pp 1058-67

Dates: Created 2009/10/06; Completed 2009/10/13;

PMID: 19805696, status: MEDLINE (last retrieval date: 10/13/2009, IMS Date: )

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