Convergent evidence for 2',3'-cyclic nucleotide 3'-phosphodiesterase as a possible susceptibility gene for schizophrenia.

CONTEXT Convergent data make 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNP) a candidate gene for schizophrenia. Reduced expression has been reported in the schizophrenic brain. The CNP gene maps to a region to which we have reported linkage to schizophrenia. Mice in which the CNP gene has been knocked out display central nervous system pathological characteristics reminiscent of some features observed in schizophrenia. 2',3'-Cyclic nucleotide 3'-phosphodiesterase is used as a marker of myelin-forming cells and is detectable in cells of oligodendrocyte lineage throughout life. Because CNP is thought to be important for oligodendrocyte function, altered expression has been interpreted as supportive of the hypothesis that altered oligodendrocyte function may be an etiological factor in schizophrenia. However, it is unclear whether the observed changes in the schizophrenic brain are primary or secondary. OBJECTIVES To determine if CNP expression is influenced by DNA polymorphisms and to verify if these polymorphisms are associated with schizophrenia. DESIGN Allele-specific messenger RNA expression assay and genetic association studies. SETTING Unrelated subjects were ascertained from secondary psychiatric inpatient and outpatient services. PARTICIPANTS We used brain tissue from 60 anonymous individuals with no known psychiatric disorder; a case-control sample of 708 white individuals from the United Kingdom meeting DSM-IV criteria for schizophrenia matched for age, sex, and ethnicity to 711 blood donor controls; and a pedigree with DNA from 6 affected siblings and 1 parent, showing evidence for linkage to CNP. MAIN OUTCOME MEASURES Association between allele and gene expression. Association between allele and schizophrenia. RESULTS The exonic single nucleotide polymorphism rs2070106 was associated with CNP expression (P<.001). Compatible with underexpression of CNP messenger RNA in schizophrenia, the lower-expressing A allele was significantly associated with schizophrenia (P = .04) in the case-control sample. All affected individuals in the linked pedigree were homozygous for the lower-expression allele, providing independent support for the association (P = .03). CONCLUSIONS Our data support the hypothesis that reduced CNP expression in the schizophrenic brain is relevant to disease etiology and therefore provide support for the general hypothesis that altered oligodendrocyte function is an etiological factor in schizophrenia.

[1]  S. Antonarakis,et al.  Nomenclature for the description of human sequence variations , 2001, Human Genetics.

[2]  Philip D. Harvey,et al.  White matter changes in schizophrenia: evidence for myelin-related dysfunction. , 2003, Archives of general psychiatry.

[3]  J. Wolff,et al.  2′,3′-Cyclic nucleotide 3′-phosphodiesterase: A membrane-bound, microtubule-associated protein and membrane anchor for tubulin , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[4]  Jurg Ott,et al.  Handbook of Human Genetic Linkage , 1994 .

[5]  B. Devlin,et al.  Association and linkage analyses of RGS4 polymorphisms in schizophrenia. , 2002, Human molecular genetics.

[6]  Michael Owen,et al.  Cheap, accurate and rapid allele frequency estimation of single nucleotide polymorphisms by primer extension and DHPLC in DNA pools , 2000, Human Genetics.

[7]  J. Kelsoe,et al.  Identifying a series of candidate genes for mania and psychosis: a convergent functional genomics approach. , 2000, Physiological genomics.

[8]  M. Owen,et al.  A systematic genomewide linkage study in 353 sib pairs with schizophrenia. , 2003, American journal of human genetics.

[9]  L. Jones,et al.  Comparative sequencing of the proneurotensin gene and association studies in schizophrenia , 2000, Molecular Psychiatry.

[10]  P. Sham,et al.  Model-Free Analysis and Permutation Tests for Allelic Associations , 1999, Human Heredity.

[11]  Michael C O'Donovan,et al.  A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. , 2003, American journal of human genetics.

[12]  M. Owen,et al.  Cis-acting variation in the expression of a high proportion of genes in human brain , 2003, Human Genetics.

[13]  K. Nave,et al.  Disruption of Cnp1 uncouples oligodendroglial functions in axonal support and myelination , 2003, Nature Genetics.

[14]  M. Owen,et al.  Genome scans and microarrays: converging on genes for schizophrenia? , 2002, Genome Biology.

[15]  J. Kelsoe,et al.  Evidence that a single nucleotide polymorphism in the promoter of the G protein receptor kinase 3 gene is associated with bipolar disorder , 2003, Molecular Psychiatry.

[16]  W H Wong,et al.  Genome-wide expression analysis reveals dysregulation of myelination-related genes in chronic schizophrenia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  R. Ward,et al.  Haplotypic analysis of the TNF locus by association efficiency and entropy , 2003, Genome Biology.

[18]  D. Lewis,et al.  Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia , 2001, Molecular Psychiatry.

[19]  C. Aston,et al.  Microarray analysis of postmortem temporal cortex from patients with schizophrenia , 2004, Journal of neuroscience research.

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

[21]  W. Honer,et al.  Abnormalities of myelination in schizophrenia detected in vivo with MRI, and post-mortem with analysis of oligodendrocyte proteins , 2003, Molecular Psychiatry.

[22]  Peter B. Jones,et al.  Oligodendrocyte dysfunction in schizophrenia and bipolar disorder , 2003, The Lancet.

[23]  G. Kirov,et al.  Universal, robust, highly quantitative SNP allele frequency measurement in DNA pools , 2002, Human Genetics.

[24]  T. Brugha,et al.  SCAN. Schedules for Clinical Assessment in Neuropsychiatry. , 1990, Archives of general psychiatry.

[25]  M. O’Donovan,et al.  Optimal temperature selection for mutation detection by denaturing HPLC and comparison to single-stranded conformation polymorphism and heteroduplex analysis. , 1999, Clinical chemistry.