Study Report

Reference	Lundorf, M. D.,2005 PMID: 15806582
Citation	Lundorf, M. D., H. N. Buttenschon, et al. (2005). Mutational screening and association study of glutamate decarboxylase 1 as a candidate susceptibility gene for bipolar affective disorder and schizophrenia. Am J Med Genet B Neuropsychiatr Genet 135B(1): 94-101.
Disease Type	Bipolar Disorder & Schizophrenia
Study Design	case-control
Study Type	Candidate-gene association study
Sample Size	in a Danish sample of 82 BPAD subjects and 120 controls and in a Scottish sample of 197 individuals with schizophrenia,200 BPAD subjects and 199 controls
SNP/Region/Marker Size	8 SNPs
Predominant Ethnicity	Caucasian
Population	Danish and Scottish

Sample Diagnosis	DSM
Sample Status	All cases fulfilled the DSM-IV [American Psychiatric Association, 1994] criteria for BPAD 1. Only patients with an age of onset before 35 years were included. The patients were all interviewed using the semi-structured interview SCAN version 2.1 [Wing et al.,1998]. Consensus best-estimate of lifetime diagnosis was made independently by two senior psychiatrists. Further details of the Danish sample have been reported previously [Borglum et al., 1999; Brunn and Ewald, 1999].Scottish subjects with schizophrenia or BPAD were inpatients or outpatients of the Royal Edinburgh Hospital or Hairmyres Hospital, Lanarkshire. Diagnoses were based on a direct interview of subjects by an experienced psychiatrist using the Schedule for Affective Disorders and Schizophrenia, SADS-L [Endicott and Spitzer, 1978], hospital case note review and interviews with relatives and carers. Final diagnoses were reached by consensus between two experienced psychiatrists. All cases met the DSMIII-Rcriteria for BPAD or schizophrenia. DNA from control subjects was obtained through the Edinburgh and SE Scotland Blood Transfusion Service. Controls were asked to complete a screening questionnaire and subjects taking regular medication or with a present or past history of serious physical or mental illness were excluded. All Danish and Scottish patients gave written consent to take part in these studies. All Danish and Scottish patients and controls were Caucasian in origin. Approvals of the local ethical committees were obtained prior to the study.
Technique	genotyping
Statistical Method	The statistical analyses were carried out using the statistical software package R (R Development Core Team, 2004) and a significance level of 0.05 was used.Deviation from Hardy-Weinberg equilibrium within each subject group and pairwise normalized linkage disequilibrium(LD) values D0 [Lewontin, 1964] between pairs of SNPs were evaluated using the R package genetics version 1.0.3. Association of polymorphisms with BPAD and schizophrenia was analyzed allele- and genotype-wise using Fisher's exact test.Association of statistically inferred haplotypes with disease was analyzed using the score method by Schaid et al. [2002].The haplotype analyses were also carried out using the haplo trend regression (HTR) method by Zaykin et al. [2002].
Result Summary	Strong pairwise LD was observed among all pairs of neighboring markers. In the Danish sample, we found weak association between BPAD and two promoter SNPs spaced 1 kb apart. Furthermore, one, two, and three loci haplotype analysis showed weak association with BPAD in the Danish sample. The results from the association studies indicate that promoter variants are of importance for the Danish BPAD cases and we cannot reject the hypothesis of GAD1 as a functional candidate gene for BPAD. No association was observed between BPAD or schizophrenia and any of the investigated SNPs in the Scottish sample set. Thus the results obtained from the Scottish sample suggest that the GAD1 gene variants do not play a major role in the predisposition to schizophrenia.