A family-based association study of DNA sequence variants in GRM7 with schizophrenia in an Indonesian population.

We previously reported genome-wide significant linkage to chromosome 3p in a sib-pair family sample from Indonesia. A promising candidate gene within the linked region is the metabotropic glutamate receptor subtype 7 (GRM7), involved in glutamatergic neurotransmission. We genotyped 18 single nucleotide polymorphisms in GRM7 in the sample of 124 Indonesian sib-pair families that had provided the significant linkage finding. Transmission disequilibrium analysis revealed nominally significant transmission distortion of rs17031835 in intron 1 of GRM7 (p=0.004, before correction for multiple testing), along with haplotypes containing rs17031835. No other single marker was found to be significantly associated with schizophrenia in our sample. The results from our study provide support for the idea that glutamatergic neurotransmission and specifically the GRM7 gene might be relevant to the development of schizophrenia. Further studies supporting this finding are warranted.

[1]  Irmansyah,et al.  Genome‐wide scan in 124 Indonesian sib‐pair families with schizophrenia reveals genome‐wide significant linkage to a locus on chromosome 3p26‐21 , 2008, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[2]  A. Singleton,et al.  Rare Structural Variants Disrupt Multiple Genes in Neurodevelopmental Pathways in Schizophrenia , 2008, Science.

[3]  M. Itokawa,et al.  A polymorphism of the metabotropic glutamate receptor mGluR7 (GRM7) gene is associated with schizophrenia , 2008, Schizophrenia Research.

[4]  O. Gureje,et al.  Questioning an Axiom: Better Prognosis for Schizophrenia in the Developing World? , 2007, Schizophrenia bulletin.

[5]  W. Maier,et al.  Evaluation of association of SNPs in the TNF alpha gene region with schizophrenia , 2007, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[6]  R. D'Hooge,et al.  Concomitant Deficits in Working Memory and Fear Extinction Are Functionally Dissociated from Reduced Anxiety in Metabotropic Glutamate Receptor 7-Deficient Mice , 2006, The Journal of Neuroscience.

[7]  Mark Daly,et al.  Haploview: analysis and visualization of LD and haplotype maps , 2005, Bioinform..

[8]  Michael Knapp,et al.  Maximum‐likelihood estimation of haplotype frequencies in nuclear families , 2004, Genetic epidemiology.

[9]  D. Nyholt.  A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. , 2004, American journal of human genetics.

[10]  T. Becker,et al.  Family-Based Association Analysis with Tightly Linked Markers , 2003, Human Heredity.

[11]  H. Stefánsson,et al.  Neuregulin 1 and susceptibility to schizophrenia. , 2002, American journal of human genetics.

[12]  S. Gabriel,et al.  The Structure of Haplotype Blocks in the Human Genome , 2002, Science.

[13]  R. Kerwin,et al.  Polymorphisms in the genes for mGluR types 7 and 8: association studies with schizophrenia , 2001, Schizophrenia Research.

[14]  M. Owen,et al.  No evidence for association between a non-synonymous polymorphism in the gene encoding human metabotropic glutamate receptor 7 and schizophrenia. , 2000, Psychiatric genetics.

[15]  D Castle,et al.  Psychotic Disorders in Urban Areas: An Overview of the Study on Low Prevalence Disorders , 2000, The Australian and New Zealand journal of psychiatry.

[16]  E. Laska,et al.  Long-term follow-up of schizophrenia in 16 countries , 1996, Social Psychiatry and Psychiatric Epidemiology.

[17]  N. Sartorius,et al.  Psychiatric assessment instruments developed by the World Health Organization , 1996, Social Psychiatry and Psychiatric Epidemiology.

[18]  J. Krystal,et al.  Subanesthetic effects of the noncompetitive NMDA antagonist, ketamine, in humans. Psychotomimetic, perceptual, cognitive, and neuroendocrine responses. , 1994, Archives of general psychiatry.

[19]  D. Javitt,et al.  Recent advances in the phencyclidine model of schizophrenia. , 1991, The American journal of psychiatry.

[20]  A. Farmer,et al.  A polydiagnostic application of operational criteria in studies of psychotic illness. Development and reliability of the OPCRIT system. , 1991, Archives of general psychiatry.

[21]  J. Clements,et al.  Presynaptic glutamate receptors depress excitatory monosynaptic transmission between mouse hippocampal neurones. , 1990, The Journal of physiology.

[22]  H. H. Kornhuber,et al.  Low cerebrospinal fluid glutamate in schizophrenic patients and a new hypothesis on schizophrenia , 1980, Neuroscience Letters.

[23]  Pak Chung Sham,et al.  Genetic Power Calculator: design of linkage and association genetic mapping studies of complex traits , 2003, Bioinform..

[24]  E. Laska,et al.  Long-term follow-up of schizophrenia in 16 countries. A description of the International Study of Schizophrenia conducted by the World Health Organization. , 1996, Social psychiatry and psychiatric epidemiology.