Genetic and functional analysis of the gene encoding neurogranin in schizophrenia.
OBJECTIVE
Schizophrenia is a highly heritable disorder, but many aspects of its etiology and pathophysiology remain poorly understood. Recently, a SNP rs12807809 located upstream of the neurogranin (NRGN) gene achieved genome-wide significance in this disorder.


METHODS
In order to find the causal variants of NRGN gene in schizophrenia, we searched for genetic variants in the promoter region and all the exons (including both UTR ends and rs12807809) using direct sequencing in a sample of patients with schizophrenia (n=346) and non-psychotic controls (n=345), both being Han Chinese from Taiwan, and conducted an association and functional study.


RESULTS
We identified 7 common polymorphisms in the NRGN gene. SNP and haplotype-based analyses displayed no associations with schizophrenia. Additionally, we identified 5 rare variants in 6 out of 346 patients, including 3 rare variants located at the promoter region (g.-620A>G, g.-578C>G, and g.-344G>A) and 2 rare variants located at 5' UTR (c.-74C>G, and c.-41G>A). No rare variants were found in the control subjects. The results of the reporter gene assay demonstrated that the regulatory activity of construct containing g.-620G, g.-578G, g.-344A, c.-74G, and c.-41A was significantly lower as compared to the wild type construct (P<0.01 for g.-578G; P<0.001 for the other constructs). In silico analysis also demonstrated their influences on the regulatory function of NRGN gene.


CONCLUSIONS
Our study lends support to the hypothesis of multiple rare mutations in schizophrenia, and provides genetic clues that indicate the involvement of NRGN in this disorder.
Department of Psychiatry, Tzu Chi General Hospital, Hualien, Taiwan.
Yu-Chih
YC
Shen
Ho-Min
HM
Tsai
Min-Chih
MC
Cheng
Shih-Hsin
SH
Hsu
Shih-Fen
SF
Chen
Chia-Hsiang
CH
Chen
D000328:Adult; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D051579:Neurogranin / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D013624:Taiwan / Q000453:epidemiology / Q000208:ethnology
D051579:Neurogranin