A family-based association study and gene expression analyses of netrin-G1 and -G2 genes in schizophrenia.
BACKGROUND
The netrin-G1 (NTNG1) and -G2 (NTNG2) genes, recently cloned from mouse, play a role in the formation and/or maintenance of glutamatergic neural circuitry. Accumulating evidence strongly suggests that disturbances of neuronal development and the N-methyl-d-aspartate receptor-mediated signaling system might represent a potential pathophysiology in schizophrenia. We therefore set out to examine the genetic contribution of human NTNG1 and NTNG2 to schizophrenia.


METHODS
Twenty-one single nucleotide polymorphisms (SNPs) from NTNG1 and 10 SNPs from NTNG2 were analyzed in 124 schizophrenic pedigrees. All genotypes were determined with the TaqMan assay. The expression levels of NTNG1 and NTNG2 were examined in the frontal (Brodmann's Area [BA]11 and BA46) and temporal (BA22) cortices from schizophrenic and control postmortem brains. The isoform-specific expression of NTNG1 splice variants was assessed in these samples.


RESULTS
Specific haplotypes encompassing alternatively spliced exons of NTNG1 were associated with schizophrenia, and concordantly, messenger ribonucleic acid isoform expression was significantly different between schizophrenic and control brains. An association between NTNG2 and schizophrenia was also observed with SNPs and haplotypes that clustered in the 5' region of the gene.


CONCLUSIONS
The NTNG1 and NTNG2 genes might be relevant to the pathophysiology of schizophrenia.
Aoki-Suzuki
Mika
M
Laboratories for Molecular Psychiatry, RIKEN Brain Science Institute, Wako, Japan.
Yamada
Kazuo
K
Meerabux
Joanne
J
Iwayama-Shigeno
Yoshimi
Y
Ohba
Hisako
H
Iwamoto
Kazuya
K
Takao
Hitomi
H
Toyota
Tomoko
T
Suto
Yumiko
Y
Nakatani
Noriaki
N
Dean
Brian
B
Nishimura
Sachiko
S
Seki
Kenjiro
K
Kato
Tadafumi
T
Itohara
Shigeyoshi
S
Nishikawa
Toru
T
Yoshikawa
Takeo
T
D000328:Adult; D000368:Aged; D000818:Animals; D016022:Case-Control Studies; D002540:Cerebral Cortex / Q000378:metabolism; D002874:Chromosome Mapping; D003001:Cloning, Molecular; D004252:DNA Mutational Analysis; D005091:Exons; D005192:Family Health; D005260:Female; D015870:Gene Expression / Q000502:physiology*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D023281:Genomics / Q000379:methods; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D008297:Male; D051379:Mice; D008875:Middle Aged; D009414:Nerve Growth Factors / Q000235:genetics*; D009419:Nerve Tissue Proteins / Q000235:genetics*; D000075385:Netrins; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012559:Schizophrenia / Q000235:genetics*
D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D000075385:Netrins; D020033:Protein Isoforms; D012333:RNA, Messenger; C413653:netrin-G1; C088894:netrin-2