J Neural Transm (2008) 115: 513–519 DOI 10.1007/s00702-007-0844-z Printed in The Netherlands Comprehensive analysis of polymorphisms throughout GAD1 gene: a family-based association study in schizophrenia J. Du 1;2; , S. Duan 1;3; , H. Wang 1;3 , W. Chen 1;3 , X. Zhao 1;3 , A. Zhang 1;3 , L. Wang 1;3 , J. Xuan 1;3 , L. Yu 1;3 , S. Wu 1;3 , W. Tang 1;3 , X. Li 1;3 , H. Li 4 , G. Feng 4 , Q. Xing 1;3 , L. He 3;4;5 1 Bio-X Center, Shanghai JiaoTong University, Shanghai, P.R. China 2 Shanghai Institute of Planned Parenthood Research, Shanghai, P.R. China 3 Institute for Nutritional Sciences, Shanghai Institute of Biological Sciences, Chinese Academy of Sciences, Shanghai, P.R. China 4 Shanghai Institute of Mental Health, Shanghai, P.R. China 5 Bio-X Center, NHGG, Shanghai JiaoTong University, Shanghai, P.R. China Received 18 September 2007; Accepted 1 October 2007; Published online 12 March 2008 # Springer-Verlag 2008 Summary. Studies suggest that GAD1 gene is a functional candidate sus- ceptibility gene for schizophrenia. In order to investigate the contribution of GAD1 gene to the etiology of schizophrenia in Chinese, we carried out a family-based association study between GAD1 gene and schizophrenia in 235 Chinese Han family trios. The GAD1 gene is comprehensively analyzed using a systematic mutation scan and the following-up association studies between common SNPs and schizophrenia in both single-locus and haplo- type levels. Altogether, we have found 17 variants including 10 SNPs in 5 0 - flanking regions, 4 SNPs and one novel in-del in intronic regions and 2 SNPs (one novel SNP) in the 3 0 -untranslated region (UTR). Using the transmission disequilibrium test of the 9 common SNPs out of 17 variants, Significant evidence of SNP rs3791878-G allele in 5 0 -flanking region of GAD1 was preferentially transmitted to both the all offsprings of the trios (P ¼ 0.0063, respectively; odds ratio ¼ 1.83; 95% confidence interval: 1.26–2.65) and the male offsprings the trios (P ¼ 0.0045, respectively; odds ratio ¼ 2.21; 95% confidence interval: 1.37–3.56). Haplotype anal- ysis suggested that rs3762556(C)–rs3791878(G)–rs6755102(C) is the major risky haplotype preferentially transmitted in both all the trios and male-offspring trios (Global P ¼ 0.016 and 0.012, respectively). The gender-dependent of the risk of SNP rs3791878 suggest the com- plexity of GAD1 gene in schizophrenia. Given that the switch from G to T in SNP rs3791878 might cause the loss of ARNT and XBP1 transcrip- tional factor binding sites using a bioinformatics approach, our positive findings of this SNP support the hypothesis that the abruption of GAD1 gene is important to the risk of schizophrenia. Keywords: Glutamate decarboxylase 1; schizophrenia; single nucleotide polymorphism; family trios; association Introduction Schizophrenia is a complex and severe brain disorder that afflicts approximately 1% of the population throughout the world. The disorder is characterized by psychotic symp- toms and by cognitive, affective, and psychosocial im- pairment (Baron 2001). Understanding the etiology and pathogenesis of the disorder is one of the most important challenges facing psychiatry. Although evidence from fam- ily, twin, and adoption studies clearly demonstrates the high heritability of schizophrenia, the genetic mechanism underlying the disorder is still obscure (Baron 2001; O’Donovan et al. 2003). During the past two decades, link- age and association studies have been the main approaches in searching for complex disease genes (Cloninger 2002). Positive linkage findings increasingly point to the chromo- somes 1q, 3p, 6p, 8p, 13q, and 22q (Straub et al. 1995; Karayiorgou and Gogos 1997; Blaveri et al. 2001; Brzustowicz et al. 2002; Lohmueller et al. 2003; Chen et al. 2004). From the large number of candidate genes, COMT , DTNBP1, NRG1, and G72 are the most promising. Other genes, like GAD1, DAO, GRM3, PPP3CC, CHRNA7, PRODH2, AKT1 ZDHHC8, and SYN-II, etc., still require further independent studies to consolidate previous positive findings (Harrison and Weinberger 2005). Dysfunction of the dorsolateral prefrontal cortex repre- sents one of the central features of the pathophysiology of schizophrenia and appears to contribute to at least some of  These authors have contributed equally to this work. Correspondence: Lin He or Qinghe Xing, Bio-X Center, Shanghai Jiao Tong University, Haoran Building, 1954 Huashan Road, Shanghai 200030, P.R. China e-mail: helin@bio-x.cn or xingqinghe@sjtu.edu.cn