Polymorphisms in genes involved in neurodevelopment may be associated with altered brain morphology in schizophrenia: Preliminary evidence
Introduction
There is consistent evidence that schizophrenia (SZ) is a neurodevelopmental disorder. A number of twin and family studies point to a genetic basis for SZ, involving several genes and in many chromosomal regions (Kohn and Lerer, 2002, McGuffin et al., 2003), in conformity with complex-polygenic diseases. It has been suggested that nearly 30% of the human genes (many of which are developmentally regulated) are expressed in the brain (Kozlovsky et al., 2002). Many of these genes are located in chromosomal loci associated with SZ and are potential candidate genes due to their polymorphic status in the population and/or to events that alter their expression during embryonic stages, which might result in the putative neurodevelopmental abnormalities seen in this disease.
On the other hand, macroscopic abnormalities such as ventricular enlargement, volume reductions of prefrontal cortex and hippocampus and generalized brain reduction, among many other features, are well-documented and consistent findings (McCarley et al., 1999, Shenton et al., 2001), although of relatively small effect (Heinrichs, 2001). In addition, significant alterations in neuron size and morphology, as well as synaptic connectivity, have also been reported in SZ (Harrison, 1999).
The association of gene polymorphisms and brain structural or physiological abnormalities in SZ has been a field of intense activity in recent years (Egan et al., 2001, Rujescu et al., 2002, Szeszko et al., 2003, Callicott et al., 2005, Ho et al., 2005, Papiol et al., 2005, Prasad et al., 2005, Szeszko et al., 2005), but a vast population of genes still needs to be evaluated for a better understanding of how the genetic alterations can influence brain morphogenesis. All genes selected for our analyses, besides being polymorphic, encode proteins important in SZ-related processes such as neurogenesis, synaptogenesis, brain symmetry, neuronal differentiation and migration, and were preferentially mapped to genomic regions previously associated with the disease. Associations of these genes and brain-structure differences were investigated in a set of 25 schizophrenia patients. This is the first study of 27 of these 32 polymorphisms and the first time that 24 of these 30 genes were evaluated in SZ.
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Patients
Twenty-five schizophrenia patients were recruited at the Institute of Psychiatry, Hospital das Clínicas, FMUSP, São Paulo, Brazil. Diagnoses were made through structured interviews (SCIDP) based on DSM-IV criteria (First et al., 1996). Written informed consent was obtained from all participants after explanation of study protocols and purposes. The study was previously approved by the ethics committee of the institution. Detailed demographic data of the patients are described in Table 1.
Results
All SNPs selected for this analysis could be confirmed in this small group of individuals, suggesting their relatively high frequency. The consistency of the genotyping methods used here was investigated by replicates and cross-tests, and was shown to be 100%. After crossing the polymorphic status of 32 polymorphisms and their frequency according to the brain morphometry data, statistically significant associations were observed for two genes. The RELN polymorphism (C/G-Val997Leu) was
Discussion
The morphogenesis of the central nervous system is a complex phenomenon that involves sequential molecular events and a plethora of genes regulated in a highly coordinated process. The rational basis of this work was to evauate the morphological brain alterations found in SZ, in the light of the polymorphic status of neurogenesis-related genes preferentially mapped to genomic loci hypothetically associated with the disease. This is one of the largest sets of SNPs evaluated for the same group of
Acknowledgements
This work was supported by the Conselho Nacional de Pesquisas (CNPq), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) and Associação Beneficente Alzira Denise Hertzog da Silva (ABADHS). The authors thank Dr. Helio Elkis and Dr. Mario Louzã for their help in providing the infrastructure used for recruiting the patients studied here.
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