Subtyping schizophrenia: implications for genetic research

A Jablensky

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Figure 1.

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Profiles of the two cognitive subtypes (CD and CS), identified in the Western Australian Family Study of Schizophrenia.²⁴³

To test the hypothesis that the two subtypes are genetically distinct, a 10 cM whole genome scan was performed using 380 microsatellite markers in 93 schizophrenia families (34 of which had been assigned the CD subtype). Linkage analysis revealed evidence for linkage on several chromosomes, with the most significant finding at 6p25–24.²⁴³ The data were then assessed by ordered subsets analyses (OSA), where the families were rank-ordered by their CD and CS quantitative trait scores (highest to lowest) and compared for changes in the logarithm of odds (LOD) scores between the subset and the overall sample. The greatest increase in the LOD score, at 6p24, was accounted for by the families ranked from 1st to 47th by the proband's CD score. Fifteen additional microsatellite markers genotyped in this region (6p25–22) increased the maximal LOD score in the CD families to 3.32. Linkage was excluded in the non-CD families for the entire chromosome 6. The 6p25–24 locus coincides almost exactly with the linkage findings in 270 Irish schizophrenia families, previously reported by Straub et al.³⁰³ The coincident linkage region and the common ancestry (Anglo-Irish) of our families lead us to believe that they share the same susceptibility allele(s). Important independent support for these findings was recently provided by a study of general cognitive abilities in 634 healthy sib pairs,³⁰⁴ which reported quantitative trait loci evidence of linkage of full-scale IQ and verbal IQ to the same 6p region. A notable aspect of the linkage results is that they were predicted with considerable accuracy by the composite endophenotypes defined prior to genetic analysis (Figure 2), and that the distributions of several of the cognitive measures differentiating the two subtypes suggest bimodality, supporting their relative independence.

Figure 2.

Genetic findings (linkage to chromosome 6p25–22) in the Western Australian Family Study of Schizophrenia²⁴³ for 93 fully characterized families phenotypically classified into a CD and a CS subtype, based on the probands' GoM (g_ik) scores on composite quantitative traits CD and CS. =linked family; =nonlinked family. (a) Distribution of the families on trait CD. (b) Distribution of the families on trait CS.

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FIGURE 2

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Date: 2016-04-22; view: 848