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


OBJECTIVE
To determine if CNP expression is influenced by DNA polymorphisms and to verify if these polymorphisms are associated with schizophrenia.


METHODS
Allele-specific messenger RNA expression assay and genetic association studies.


METHODS
Unrelated subjects were ascertained from secondary psychiatric inpatient and outpatient services.


METHODS
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.


METHODS
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.
Peirce
Timothy R
TR
Department of Psychological Medicine, School of Medicine, Cardiff University, Cardiff, Wales.
Bray
Nicholas J
NJ
Williams
Nigel M
NM
Norton
Nadine
N
Moskvina
Valentina
V
Preece
Anna
A
Haroutunian
Vahram
V
Buxbaum
Joseph D
JD
Owen
Michael J
MJ
O'Donovan
Michael C
MC
D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases / Q000235:genetics* / Q000378:metabolism; D000483:Alleles; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000502:physiology; D016022:Case-Control Studies; D015870:Gene Expression / Q000235:genetics; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000502:physiology; D009836:Oligodendroglia / Q000378:metabolism* / Q000502:physiology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012559:Schizophrenia / Q000201:enzymology* / Q000453:epidemiology / Q000235:genetics*; D006113:United Kingdom / Q000453:epidemiology
D005819:Genetic Markers; D012333:RNA, Messenger; D015087:2',3'-Cyclic-Nucleotide Phosphodiesterases