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Timothy R. Peirce, PhD; Nicholas J. Bray, PhD; Nigel M. Williams, PhD; Nadine Norton, PhD; Valentina Moskvina, PhD; Anna Preece, Bsc; Vahram Haroutunian, PhD; Joseph D. Buxbaum, PhD; Michael J. Owen, PhD, FRCPsych; Michael C. O’Donovan, PhD, FRCPsych

Arch Gen Psychiatry. 2006;63:18-24.

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.

Author Affiliations: Department of Psychological Medicine (Drs Peirce, Bray, Williams, Norton, Owen, and O’Donovan and Ms Preece) and Biostatistics and Bioinformatics Unit (Dr Moskvina), School of Medicine, Cardiff University, Cardiff, Wales; Department of Psychiatry, Mount Sinai School of Medicine, New York, NY (Drs Haroutunian and Buxbaum); Mental Illness Research, Education and Clinical Centers, Bronx Veterans Affairs Medical Center, New York (Dr Haroutunian).

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