Identification of a single nucleotide polymorphism at the 5′ promoter region of human reelin gene and association study with schizophrenia

Abstract

MIT, the haplotype frequencies of the five SNPs in the COMT region were estimated. 8 No significant transmission distortion of the seven common haplotypes has been found. (The global P value for the haplotype of all five markers was 0.19, data not shown.)COMT is a promising candidate gene for a number of neurologic disorders that involve noradrenergic or dopaminergic systems. As reviewed in the introduction there have been conflicting reports in the literature regarding COMT's association with schizophrenia susceptibility, however it is possible that many of these can be attributed to small and/or heterogeneous case/control samples. To further test the possible implication of COMT in the aetiology of schizophrenia, we used transmission distortion analysis in family trios (implemented by the ETDT and TRANSMIT programs), to fine-map the COMT locus and to attempt to replicate the findings of Li et al 1 and Egan et al. 2 Five SNP markers were genotyped and analysed both individually and as haplotype in 166 family trios from the Han Chinese population. Significant linkage disequilibrium (P Ͻ 0.000001) was found between the majority of SNP markers (8/10 pairwise combinations). The linkage disequilibrium relationship between the polymorphisms was consistent with earlier observations in the Han Chinese. 1 No preferential transmission of any allele or haplotype was detected for all of the polymorphisms studied. Thus, our analysis did not suggest an association between the COMT gene and susceptibility to schizophrenia, consistent with other recent findings. 9 Therefore, it appears unlikely that the COMT plays a major role in the aetiology of schizophrenia. However, we cannot exclude COMT from playing a small or minor role in the aetiology of the disorder and further studies using larger numbers of samples will be necessary to clarify this question.

Molecular abnormalities of the hippocampus in severe psychiatric illness: postmortem findings from the Stanley Neuropathology Consortium

“…An association of a single-nucleotide polymorphism at the 5' promoter region of the reelin gene with the schizophrenia phenotype has been reported, 27 but was not confirmed in a larger case-control association study. 28 The fact that reelin was most abnormal in the dentate gyrus granule cells is notable in light of other findings.…”

Reelin glycoprotein: structure, biology and roles in health and disease

“…68 By the same token, Chen et al studied a single nucleotide polymorphism at the 5 0 promoter region of the human Reln gene in 279 Han Chinese schizophrenic patients and 255 controls and could not demonstrate any significant associations in the Reln gene polymorphisms and schizophrenia. 69 In a series of postmortem studies, Fatemi et al 70 also showed reductions in Reelin protein in several brain sites in autism. Brain levels of Reelin 410 kDa was reduced significantly in frontal (Area 9) and cerebellar areas and nonsignificantly in parietal (Area 40) cortex of autistic subjects vs. controls.…”

“…Despite these biochemical findings, two recent reports fail to report any association between Reln gene polymorphisms and schizophrenia. 68,69 Akahane et al examined the polymorphic CGG repeat in the 5 0 untranslated region of the Reln gene in 150 schizophrenic and 150 controls matched for age, sex and ethnicity and found no evidence for any significant association of schizophrenia with polymorphisms for Reln or VLDLR genes. 68 By the same token, Chen et al studied a single nucleotide polymorphism at the 5 0 promoter region of the human Reln gene in 279 Han Chinese schizophrenic patients and 255 controls and could not demonstrate any significant associations in the Reln gene polymorphisms and schizophrenia.…”

Reelin-mediated signaling in neuropsychiatric and neurodegenerative diseases

“…The gene product of disc1 is part of a microtubule motor complex, which is controlled by the Reelin and LIS1 signaling pathway (Assadi et al, 2003) and mutations in this gene result in abnormal development of the cortex (Kamiya et al, 2005). However, other genetic association screenings have yielded inconclusive results, including the searches for associations between reelin polymorphisms and schizophrenia (Akahane et al, 2002;Chen et al, 2002;Goldberger et al, 2005;Huang and Chen, 2006;Persico et al, 2006;Shifman et al, 2008;Gregorio et al, 2009). In contrast, a strong correlation between S-adenosyl-methionine (SAM), DNMT1, hypermethylation of the reelin promoter, and decreased Reelin expression in postmortem brains of subjects with schizophrenia has been reported Veldic et al, 2004;Abdolmaleky et al, 2005;Grayson et al, 2005;Guidotti et al, 2007;Ruzicka et al, 2007;Tochigi et al, 2008).…”