Association of common copy number variants at the glutathione S-transferase genes and rare novel genomic changes with schizophrenia

作者：Rodriguez Santiago B; Brunet A; Sobrino B; Serra Juhe C; Flores R; Armengol L I; Vilella E; Gabau E; Guitart M; Guillamat R; Martorell L; Valero J; Gutierrez Zotes A; Labad A; Carracedo A; Estivill X; Perez Jurado L A^*

来源：Molecular Psychiatry, 2010, 15(10): 1023-1033.

DOI：10.1038/mp.2009.53

• structural variation
• copy number variant
• 22q11.23 duplication
• genetic predisposition to disease
• glutathione transferase/genetics

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

• 出版日期2010-10