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

Holliday, Elizabeth G., McLean, Duncan E., Nyholt, Dale R., & Mowry, Bryan J. (2009) Susceptibility locus on chromosome 1q23-25 for a schizophrenia subtype resembling deficit schizophrenia identified by latent class analysis. Archives of General Psychiatry, 66(10), pp. 1058-1067.

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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.

Impact and interest:

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ID Code: 92004
Item Type: Journal Article
Refereed: Yes
Keywords: Adult, *Chromosome Mapping, Chromosomes, Human, Pair 1/*genetics, Diagnostic and Statistical Manual of Mental Disorders, Female, Genetic Heterogeneity, Genetic Linkage/genetics, Genetic Predisposition to Disease/*genetics, Genome, Human, Genome-Wide Association Study, Genotype, Humans, Male, Models, Statistical, Multivariate Analysis, Phenotype, Psychiatric Status Rating Scales/statistics & numerical data, Schizophrenia/classification/*diagnosis/*genetics, Taiwan
DOI: 10.1001/archgenpsychiatry.2009.136
ISSN: 1538-3636
Divisions: Current > Schools > School of Biomedical Sciences
Current > QUT Faculties and Divisions > Faculty of Health
Current > Institutes > Institute of Health and Biomedical Innovation
Copyright Owner: Copyright 2009 American Medical Association
Deposited On: 19 Jan 2016 00:28
Last Modified: 20 Jan 2016 04:14

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