. Genome-wide association identifies a common variant in the reelin gene that increases the risk of schizophrenia only in women. PLoS Genet. 2008 Feb;4(2):e28. PubMed.

Recommends

Please login to recommend the paper.

Comments

  1. Shifman et al. have conducted a genome-wide association (GWA) study using schizophrenia patients and control cohorts, and found that a common variant (rs7341475) in the reelin gene increases the risk of this common psychiatric disorder in women. The investigators applied a DNA pooling approach to screen 500K SNPs in Affymetrix SNP arrays. Based on initial screening, they identified 194 SNPs to be used for individual genotyping in a case-control cohort originating from an Ashkenazi Jewish population. Several associated SNPs were identified. The SNP rs7341475, showing the lowest p value in the reelin gene, was prioritized for further analyses for the reason that this gene has been previously studied as a possible candidate gene for schizophrenia. Interestingly, rs7341475 showed a significant association, with an odds ratio of 2.1 in women. This finding, with a similar risk effect, was replicated in other case-control cohorts originating from different populations.

    Although this study introduces a genetic variant of the reelin gene that increases the risk of developing schizophrenia in women only, it also raises several important questions commonly related to GWA studies. For example: how to define true genetic association? In this study, multiple testing using the conservative Bonferroni correction indicated only a suggestive association. On the other hand, the fact that the initial finding was replicated in different populations supports the argument of genuine association.

    Another important question in this context is whether the associated variant is the functional alteration affecting the risk of schizophrenia in synergy with female gender, or whether it is just a genetic marker that is in linkage disequilibrium with the real functional alteration located in the vicinity of SNP rs7341475 in reelin gene. Although it is still unclear how this genetic variant predisposes only women to schizophrenia, this study provides a starting point for comprehensive functional assessments to establish the underlying biological role of reelin in schizophrenia.

    Reelin, an extracellular matrix protein, has an important role in the migration, correct positioning, and maturation of neurons during development. Though it is generally downregulated in the postnatal period, expression of this large glycoprotein continues in the adult brain in some cell populations. Reelin synthesized by Cajal-Retzius (CR) cells is an important component of a signaling pathway involved in embryonic development and modulation of synaptic circuitry. It is also implicated in the pathogenetic cascade in Alzheimer disease (AD). Although the majority of CR cells sequentially disappear from the postnatal cortical layer I, some of them persist in the normal adult brain. They continue to produce reelin, express a variety of other proteins, and are characterized by a typical morphology. CR cells have been reported to be altered in number and morphology in a variety of neurological and psychiatric diseases linked to maldevelopment.

    Riedel et al. (2003) showed that reelin-positive CR cells persist in the layer I of the entorhinal cortex in normal senescent brains and are also preserved in AD. However in AD, CR cells seem to be partially affected by the formation of paired helical filaments, indicating subtle changes that are suggested to be a result rather than a cause of the pathogenetic cascade of AD.

    Miettinen et al. (2005) examined the distribution of reelin-immunoreactivity (-ir) in the hippocampal formation of 9-month-old wild-type mice (WT). Then, reelin-ir in normal mice was compared to that of transgenic mice carrying mutated human APP and PS1 genes, which cause familial forms of AD. The APP/PS1 mice were additionally burdened with a second risk factor for AD, namely depletion of circulating gonadal hormones by ovariectomy (APP/PS1 + OVX). The analyses revealed that in adult WT, reelin-ir is expressed by Cajal-Retzius cells and a subgroup of interneurons throughout the hippocampal formation. In addition, layer II projection neurons in the lateral entorhinal subfields are reelin-ir. Interestingly, ovariectomy decreases the number of reelin-ir cells in the hilus in WT mice, whereas the AD-related genotype alone induces only a non-significant reduction. Unexpectedly, additional stress, e.g., depletion of gonadal hormones, does not aggravate the slight reduction in the reelin cell number in the APP/PS1 mice. The authors posited that the changes in normal reelin-ir are linked to disturbances in repair mechanisms in which APP/PS1 and gonadal hormones are involved, and which are perturbed in neurodegenerative conditions, namely AD.

    The paper by Shifman and colleagues thus brings up new ideas about the interconnection between reelin, sex hormones, and neurological and psychiatric diseases that show gender specificity.

    References:

    . Reelin-immunoreactive Cajal-Retzius cells: the entorhinal cortex in normal aging and Alzheimer's disease. Acta Neuropathol. 2003 Oct;106(4):291-302. PubMed.

    . Reelin-immunoreactivity in the hippocampal formation of 9-month-old wildtype mouse: effects of APP/PS1 genotype and ovariectomy. J Chem Neuroanat. 2005 Oct;30(2-3):105-18. PubMed.

Make a Comment

To make a comment you must login or register.