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Association of Common Copy Number Variants at the Glutathione S Molecular Psychiatry (2010) 15, 1023–1033 & 2010 Macmillan Publishers Limited All rights reserved 1359-4184/10 www.nature.com/mp ORIGINAL ARTICLE Association of common copy number variants at the glutathione S-transferase genes and rare novel genomic changes with schizophrenia B Rodrı´guez-Santiago1, A Brunet2,3, B Sobrino4, C Serra-Juhe´ 1, R Flores1, Ll Armengol2, E Vilella5, E Gabau3, M Guitart3, R Guillamat3, L Martorell5, J Valero5, A Gutie´rrez-Zotes5, A Labad5, A Carracedo4, X Estivill2 and LA Pe´rez-Jurado1,6 1Unitat de Gene`tica, Universitat Pompeu Fabra, and Centro de Investigacio´n Biome´dica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain; 2Genes and Disease Program, Center for Genomic Regulation (CRG-UPF) and Centro de Investigacio´n Biome´dica en Red de Epidemiologı´a y Salud Pu´blica (CIBERESP), Barcelona, Spain; 3Corporacio´ Sanita`ria Parc Taulı´, Sabadell, Spain; 4Grupo de Medicina Xenomica, CEGEN-IML, and Centro de Investigacio´n Biome´dica en Red de Enfermedades Raras (CIBERER), Universidad de Santiago de Compostela, Santiago de Compostela, Spain; 5Hospital Psiquia`tric Universitari Institut Pere Mata, IISPV, Universitat Rovira i Virgili, Reus, Spain and 6Programa de Medicina Molecular i Gene`tica, Hospital Vall d’Hebron, Barcelona, Spain Copy number variants (CNVs) are a substantial source of human genetic diversity, influencing the variable susceptibility to multifactorial disorders. Schizophrenia is a complex illness thought to be caused by a number of genetic and environmental effects, few of which have been clearly defined. Recent reports have found several low prevalent CNVs associated with the disease. We have used a multiplex ligation-dependent probe amplification-based (MLPA) method to target 140 previously reported and putatively relevant gene-containing CNV regions in 654 schizophrenic patients and 604 controls for association studies. Most genotyped CNVs (95%) showed very low ( < 1%) population frequency. A few novel rare variants were only present in patients suggesting a possible pathogenic involvement, including 1.39 Mb overlapping duplications at 22q11.23 found in two unrelated patients, and duplications of the somatostatin receptor 5 gene (SSTR5) at 16p13.3 in three unrelated patients. Furthermore, among the few relatively common CNVs observed in patients and controls, the combined analysis of gene copy number genotypes at two glutathione S-transferase (GST) genes, GSTM1 (glutathione S-transferase mu 1) (1p13.3) and GSTT2 (glutathione S-transferase theta 2) (22q11.23), showed a statistically significant association of non-null genotypes at both loci with an additive effect for increased vulnerability to schizophrenia (odds ratio of 1.92; P = 0.0008). Our data provide complementary evidences for low prevalent, but highly penetrant chromosomal variants associated with schizophrenia, as well as for common CNVs that may act as susceptibility factors by disturbing glutathione metabolism. Molecular Psychiatry (2010) 15, 1023–1033; doi:10.1038/mp.2009.53; published online 16 June 2009 Keywords: structural variation; copy number variant; 22q11.23 duplication; genetic predisposition to disease; glutathione transferase/genetics Introduction differences also known as copy number variants (CNVs).1,4 CNVs are likely to contribute significantly Recent studies have highlighted structural variants as to human diversity and disease susceptibility, a a largely under-explored source of human genetic postulate further substantiated by the enriched CNV 1 variation that may be a common underlying factor in affecting genes involved in drug and hormone 2,3 human disease. Such variation includes insertions, metabolism, immune response, as well as in the deletions, inversions, duplications and translocations detoxification of environmental and dietary pro- of DNA sequences, and encompasses copy number carcinogens.5,6 Reported examples include low copy numbers of the CCL3L1, FCGR3B and DEFB4 genes, Correspondence: Professor LA Pe´rez-Jurado, Unitat de Gene`tica, which are associated with increased susceptibility to Universitat Pompeu Fabra, Parc de Recerca Biome`dica de AIDS, immunologically mediated glomerulonephritis Barcelona, Dr Aiguader 88, E-08003, Barcelona, Spain. 7–9 E-mail: [email protected] and Crohn’s disease, respectively. In addition, Received 19 December 2008; revised 24 April 2009; accepted 4 evidence is accumulating that multiple rare CNVs May 2009; published online 16 June 2009 contribute to the genetic component of vulnerability Rare and common CNVs associated with schizophrenia B Rodrı´guez-Santiago et al 1024 to neuropsychiatric conditions, such as autism or 22q11.23 and duplications of the somatostatin recep- schizophrenia.10 Some karyotypic and submicro- tor 5 gene (SSTR5) at 16p13.3), which were further scopic CNV abnormalities associated with schizo- characterized by array technology. Among the few phrenia have been described, such as the 3 Mb CNVs with relatively high population prevalence, hemizygous microdeletion at 22q11 causing variation at the GSTM1 (glutathione S-transferase mu velo-cardio-facial syndrome (VCFS).11–13 Other chro- 1) and GSTT2 (glutathione S-transferase theta 2), mosomal aberrations have been detected in affected encoding two members of a superfamily of proteins individuals with schizophrenia and other psychiatric that catalyse the conjugation of reduced glutathione disorders,14 leading to the discovery of potential (GSH) to a variety of electrophilic and hydrophobic disease-causing mutations in DISC1, PDE4B15 and compounds, were found associated to the disease. NPAS3.16 Genotypes containing GSTM1 and the GSTT2-specific The increasing use of genome-scan array technolo- copy were found significantly associated with an gies has revealed several new CNVs at different loci in increased vulnerability to schizophrenia with addi- schizophrenic patients. In an initial report, four tive effect. Our results indicate that rare but highly aberrant regions containing genes involved in neuro- penetrant CNVs can be responsible for a reduced nal function were observed in 12 schizophrenic number of schizophrenia cases, whereas common patients,17 although these results were not reproduced CNVs, such as those affecting the glutathione S- later by using an independent method.18 Variation of transferase (GST) genes, may influence a risk of multiple loci were reported in the study of a small developing the disease. sample of 30 patients without enough control data.19 The lack of reproducibility emphasizes the impor- Materials and methods tance of reliable methods for CNVs validation before full-scale association studies are carried out.18 Despite Subjects this controversy, there is a rapidly growing number of Unrelated patients (n = 654; 451 male patients and well-defined CNVs associated with schizophrenia 204 female patients, mean age = 46.52±17.08 years) with low prevalence, but high penetrance. Hemizy- were recruited from in-patient and out-patient ser- gous deletions of varying sizes affecting the vices in two different psychiatric hospitals (Consorci CNTNAP2 gene at 7q34–36.1 were found in three Hospitalari Parc Taulı´, Sabadell, Spain and Institut unrelated individuals with a complex phenotype of Universitari de Psiquiatria Pere Mata, Reus, Spain). schizophrenia, epilepsy and cognitive impairment.20 All patients had a consensus diagnosis from two Overall, thirteen aberrations with two of them likely senior psychiatrists according to several semi-struc- pathogenic, a 2p16.3 deletion disrupting the NRXN1 tured interviews for Diagnostic and Statistical Manual gene in affected siblings and a de novo 15q13.1 of Mental Disorders (DSM-IV) criteria. Concordant duplication spanning the APBA2 gene, were found values between psychiatrists varied between 0.6 among 93 schizophrenic patients.21 Furthermore, and 0.95. Unrelated subjects (n = 604; 339 male three recent studies have established that rare de individuals and 265 female individuals, mean novo germline mutations contribute to schizophrenia age = 41.42±12.83 years) from the same geographical vulnerability in sporadic cases and that rare genomic region (Catalonia, Spain) and free of signs of neurop- lesions at many different loci can account, at least in sychiatric illness were used as controls. Additional part, for the genetic heterogeneity of this disease, details of the selection and recruitment of patients including recurrent deletions at 1q21.1, 15q13.3 and and controls have already been reported.26 Family 15q11.2.22–24 It is interesting to note that genes relatives of several probands with CNVs were also involved in pathways important for brain develop- recruited for this study. Isolation of DNA was carried ment are over-represented among those disrupted by out from peripheral blood following standard proce- structural variants in patients, suggesting that rare dures. All samples were obtained under institutional mutations affecting those genes contribute to schizo- review board-approved informed consent. phrenia.25 Therefore, the role of structural genomic variation in the development of schizophrenia, either Selection of gene containing CNVs directly causing the disease or acting as susceptibility The database of genomic variants (DGVs, http:// factor, is a topic of considerable interest. projects.tcag.ca/variation)27 was used to select gene- To further understand the contribution of this type containing CNV regions reported in more than one of genomic variation to human diversity and complex individual or by more
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