Association of missense variants of the PRKC, apoptosis, WT1, regulator (PAWR) gene with schizophrenia.
Abnormal dopamine signal transduction is implicated in the pathophysiology of schizophrenia. A recent study showed that prostate apoptosis response 4 protein (Par-4) interacts with dopamine D2 receptor and plays an important role in dopamine signaling. Par-4 knockout mice showed depression-like behavior, suggesting that Par-4 gene may be associated with mental disorders in human. The study was aimed to determine whether the PRKC, apoptosis, WT1, regulator gene (PAWR) that encodes the human homolog of Par-4 protein is a susceptibility gene for schizophrenia. We systematically screened for mutations at the 5' untranslated region (5'UTR) and all the exonic regions of the PAWR gene in a sample of Han Chinese schizophrenic patients from Taiwan. We identified two missense single nucleotide polymorphisms (SNPs) that are in strong linkage in our sample (D'=0.98), i.e. P78R at exon 2 and I199M at exon 3, respectively. SNP- and haplotype-based analysis showed that these two variants are associated with schizophrenia; there is an overrepresentation of RR homozygotes of P78R (OR=2.00, 95% CI=1.05-3.83) and MM homozygotes of I199M (OR=1.81, 95% CI=0.95-3.54) in schizophrenic patients as compared to control subjects. When subjects were divided by gender, the association is specifically with female patients (OR=2.94 for RR and OR=2.7 for MM), but not with male patients. Our results indicate that the PAWR gene is associated with schizophrenia in our population, and this study provides genetic evidence to support the dopamine hypothesis of schizophrenia.
Wang
Ling-Hsuan
LH
Institute of Human Genetics, Tzu-Chi University, Hualien 970, Taiwan.
Chen
Jen-Yeu
JY
Liou
Ying-Jay
YJ
Wang
Ying-Chieh
YC
Lai
I-Ching
IC
Liao
Ding-Lieh
DL
Chen
Chia-Hsiang
CH
D020121:5' Untranslated Regions / Q000378:metabolism; D000328:Adult; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001120:Arginine / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007532:Isoleucine / Q000235:genetics; D008297:Male; D008715:Methionine / Q000235:genetics; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D011110:Polymorphism, Genetic; D011392:Proline / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics*; D012737:Sex Factors; D013624:Taiwan
D020121:5' Untranslated Regions; D051017:Apoptosis Regulatory Proteins; C101296:prostate apoptosis response-4 protein; D007532:Isoleucine; D001120:Arginine; D011392:Proline; D008715:Methionine