Support for "Disease-Only" Genotypes and Excess of Homozygosity at the CYTH4 Primate-Specific GTTT-Repeat in Schizophrenia.

OBJECTIVE: The role of short tandem repeats (STRs) in the control of gene expression among species is being increasingly understood following the identification of several instances in which certain STRs occur identically, or expand differentially, in primates versus nonprimates. These STRs may regulate genes that participate in characteristics that are associated with the divergence of primates from sibling orders (e.g., brain higher order functions). The CYTH4 gene contains the longest tetranucleotide STR in its core promoter, at 7-repeats, and links to the evolution of human and nonhuman primates. Allele and genotype distribution of this STR were studied in patients affected by schizophrenia (SCZ) and controls. METHODS: High-resolution data were obtained on the allele and genotype distribution of the CYTH4 STR and a novel C > T single-nucleotide polymorphism (SNP) at its immediate upstream sequence in 255 patients with SCZ and 249 controls. Each sample was sequenced twice using the fluorescent dye termination method. RESULTS: Novel alleles were detected at the long extreme of the GTTT-repeat, at 10- and 11-repeats, in the SCZ cases and controls. Excess of homozygosity was observed for the entire range of alleles across the GTTT-repeat and the C > T SNP in the SCZ patients in comparison with the controls (Yates corrected p < 0.011). Three genotypes consisting of the 11-repeat allele (i.e., 11/11, 10/11, and 7/11) were detected only in the SCZ patients (i.e., disease-only genotypes), and contributed to 2.3% of the SCZ genotypes (Mid p exact <0.007). The frequency of the 11-repeat allele was estimated at 0.02 and 0.006 in the SCZ patients and controls, respectively (Mid p exact <0.006). CONCLUSION: This indicates that STR genotypes that are absent in the control group may be risk factors for SCZ. Future studies are warranted to test the significance of our findings.

Association of ß-Secretase Functional Polymorphism with Risk of Schizophrenia.

AIM: The NRG1-ERBB4 neurotransmitter signaling pathway plays a key role in the pathogenesis of schizophrenia (SZ). The intronic single-nucleotide polymorphism rs707284 in ERBB4 links to PI3K-AKT suppression in SZ. Another protein indirectly affecting NRG1-ERBB4 signaling is ß-secretase, which is encoded by the BACE1 gene, and activates NRG1 by proteolytic cleavage. In this study, we aimed to investigate the association of ERBB4 rs707284 and BACE1 rs490460 with the risk of SZ in an Iranian population. SUBJECTS AND METHODS: A total of 973 subjects, including 480 SZ patients and 493 healthy controls, matched by ethnicity, age, and gender, were recruited in a case-control study. Genomic DNA was extracted from peripheral blood of all subjects and genotyping of rs707284 and rs490460 was performed using polymerase chain reaction (PCR)-restriction fragment length polymorphism and tetra-primer amplification refractory mutation system (tetra-ARMS) PCR genotyping assays, respectively. RESULTS: A significant association was observed between the rs490460 T allele and SZ (p = 0.0002, odds ratio 0.69, 95% confidence interval 0.57-0.84). There was no association between the risk of SZ and rs707284. CONCLUSION: Our data indicate that rs490460 is associated with the risk of SZ. In silico analysis indicates that rs490460 may be a potential splicing site, which affects protein structure. Replication studies are needed to confirm our data.