Dissection of phenotype reveals possible association between schizophrenia and Glutamate Receptor Delta 1 (GRID1) gene promoter

Recent linkage and association data have implicated the Glutamate Receptor Delta 1 (GRID1) locus in the etiology of schizophrenia. In this study, we sought to test whether variants in the promoter region are associated with this disorder. The distribution of CpG islands, which are known to be relevant for transcriptional regulation, was computationally determined at the GRID1 locus, and the putative transcriptional regulatory region at the 51-terminus was systematically tagged using HapMap data. Genotype analyses were performed with 22 haplotype-tagging single nucleotide polymorphisms (htSNPs) in a German sample of 919 schizophrenia patients and 773 controls. The study also included two SNPs in intron 2 and one in intron 3 which have been found to be significantly associated with schizophrenia in previous studies. For the transcriptional regulatory region, association was obtained with rs3814614 (p = 0.0193), rs10749535 (p = 0.0245), and rs11201985 (p = .0222). For all further analyses, the patient samples were divided into more homogeneous subgroups according to sex, age at onset, positive family history of schizophrenia and lifetime history of major depression. The p-value of the schizophrenia association finding for the three markers decreased by approximately one order of magnitude, despite the reduction in the total sample size. Marker rs3814614 (unadjusted p=0.0005), located -2.0 kb from the transcriptional start point, also withstood a two-step correction for multiple testing (p=0.030). No support was obtained for previously reported associations with the intronic markers. Our results suggest that genetic variants in the GRID1 transcriptional regulatory region may play a role in the etiology of schizophrenia, and that future association studies of schizophrenia may require stratification to ensure more homogeneous patient subgroups. (C) 2009 Elsevier B.V. All rights reserved.