A schizophrenia associated CMYA5 allele displays differential binding with desmin.

CMYA5 is a candidate gene for schizophrenia because of the genetic association of variant rs10043986 (C > T) to this severe mental disorder. Studies of CMYA5 and its gene product, myospryn, in the brain and neuronal cells have not been previously reported. The SNP rs10043986 changes the 4,063rd amino acid from Pro to Leu, which is likely to alter protein function. To understand its potential role in the brain, we examined the neuronal expression of myospryn and its binding partner, desmin, an intermediate filament (IF) protein, and investigated how the two alleles of myospryn affect its binding to desmin. Myospryn and desmin are shown to be expressed in the brain and myospryn is shown to localize to the cytoplasm and nucleus of myoblast, neuroblastoma, and glioblastoma cell lines. Peripherin and vimentin, known brain IF proteins, have high protein similarity to desmin but were found not to interact with myospryn using yeast two-hybrid (Y2H). Using a quantitative Y2H assay and surface plasmon resonance, the T allele (Leu) of rs10043986 was found to have stronger binding to desmin than the C allele (Pro). Based on findings described in this report, we hypothesize that the interaction between myospryn to IF provides structural support and efficient rearrangement of the cytoskeleton network during early neuritogenesis.

Updated meta-analysis of CMYA5 rs3828611 and rs4704591 with schizophrenia in Asian populations.

AIM: Two single-nucleotide polymorphisms, rs3828611 and rs4704591, in the cardiomyopathy-associated protein 5 (CMYA5) gene have been extensively investigated for associations with schizophrenia in Asian populations, but with conflicting results. To assess the collective evidence across individual studies, we conducted an updated meta-analysis. METHODS: We performed a random-effect model meta-analysis of the associations of rs3828611 and rs4704591 with schizophrenia using seven case-control samples from Asian populations (8074 patients and 8139 controls). RESULTS: The meta-analysis indicated that rs3828611 and rs4704591 were not significantly associated with schizophrenia (odds ratios [OR] = 0.93, 95% confidence interval [CI] = 0.85-1.01 and OR = 0.99, 95% CI = 0.93-1.05, respectively). CONCLUSIONS: Our meta-analysis did not provide evidence supporting a contribution of CMYA5 rs3828611 and rs4704591 to schizophrenia susceptibility in Asian populations.

Association between CMYA5 gene polymorphisms and risk of schizophrenia in Uygur population and a meta-analysis.

AIM: Previous evidence has found that some single nucleotide polymorphisms (SNPs) in cardiomyopathy-associated 5 gene (CMYA5) were associated with schizophrenia in the Caucasian and Chinese Han populations. In this study, we aimed to investigate the relationship between CMYA5 gene polymorphisms and schizophrenia in Chinese Uygur population and perform a meta-analysis to synthetically analyse the association of CMYA5 gene polymorphisms with schizophrenia in Asian populations. METHOD: We retrospectively analysed 985 schizophrenia cases and 1123 healthy controls in Chinese Uygur population. Four SNPs (rs259127, rs3828611, rs4704591 and rs6883197) of CMYA5 were genotyped using TaqMan SNP genotyping assay. Meta-analysis was conducted across Asian studies by Review Manager 5.2. RESULTS: Results showed no significant difference in either allelic or genotypic frequency in four SNPs of the CMYA5 gene between cases and controls (P > 0.05). However, the age of onset and the PANSS positive-factor subscale score were significantly lower in schizophrenia patients with the A/A genotype of rs6883197 than those with A/G and G/G genotypes (P < 0.05). In addition, the meta-analysis showed the significant association of rs3828611 with risk of schizophrenia (P = 0.03, OR = 0.92, 95% CI: 0.91-0.99). CONCLUSIONS: Our results support the association between CMYA5 rs6883197 and schizophrenia in Chinese Uygur population. Meta-analysis demonstrated that rs3828611 was significantly associated with schizophrenia in Asian population. Genetic heterogeneity among populations may be the main reason of results conflict between studies. In conclusion, association between CMYA5 gene polymorphisms and schizophrenia was confirmed in Asian population.

A cross-species genetic analysis identifies candidate genes for mouse anxiety and human bipolar disorder.

Bipolar disorder (BD) is a significant neuropsychiatric disorder with a lifetime prevalence of ~1%. To identify genetic variants underlying BD genome-wide association studies (GWAS) have been carried out. While many variants of small effect associated with BD have been identified few have yet been confirmed, partly because of the low power of GWAS due to multiple comparisons being made. Complementary mapping studies using murine models have identified genetic variants for behavioral traits linked to BD, often with high power, but these identified regions often contain too many genes for clear identification of candidate genes. In the current study we have aligned human BD GWAS results and mouse linkage studies to help define and evaluate candidate genes linked to BD, seeking to use the power of the mouse mapping with the precision of GWAS. We use quantitative trait mapping for open field test and elevated zero maze data in the largest mammalian model system, the BXD recombinant inbred mouse population, to identify genomic regions associated with these BD-like phenotypes. We then investigate these regions in whole genome data from the Psychiatric Genomics Consortium's bipolar disorder GWAS to identify candidate genes associated with BD. Finally we establish the biological relevance and pathways of these genes in a comprehensive systems genetics analysis. We identify four genes associated with both mouse anxiety and human BD. While TNR is a novel candidate for BD, we can confirm previously suggested associations with CMYA5, MCTP1, and RXRG. A cross-species, systems genetics analysis shows that MCTP1, RXRG, and TNR coexpress with genes linked to psychiatric disorders and identify the striatum as a potential site of action. CMYA5, MCTP1, RXRG, and TNR are associated with mouse anxiety and human BD. We hypothesize that MCTP1, RXRG, and TNR influence intercellular signaling in the striatum.

Association analysis of the rs10043986 polymorphism of cardiomyopathy-associated 5 gene with schizophrenia in Uygur Chinese population / 中华行为医学与脑科学杂志

Objective To evaluate the relationship between cardiomyopathy-associated 5 (CMYAS) gene rs10043986 polymorphism and schizophrenia in Uygur Chinese population.Methods The SNP rs10043986 in CMYA5 gene was genotyped in 325 patients with schizophrenia and 183 normal controls using TaqMan technology.The symptoms of schizophrenia were assessed by positive and negative syndrome scale (PANSS).The association of the loci with schizophrenia,age of onset,clinical symptom was analyzed.Results The allelic and genotypic distributions in rs10043986 between patients with schizophrenia (C,T allele:91.5％,8.5％ ; C/C,C/T,T/T genotypes:83.4％,16.3％,0.3％) and normal controls (C,T allele:96.4％,3.6％ ; C/C,C/T,T/T genotypes:92.9％,7.1％,0) had statistically significance after analysis (x2 =9.038,P=0.003 ; x2 =9.417,P=0.009).Via analysis of stratification by gender and age at onset.The results showed that both allele (x2=11.812,P=0.001) and genotype (x2=12.769,P=0.001) frequency in rs10043986 with patients were significantly different in females,but neither in males (all P＞0.05).Allelic or genotypic distributions between adult cases and controls had statistically significance (x2=8.219,P=0.004; x2=8.379,P=0.015),but there were not significant differences between adolescent cases and controls (all P＞ 0.05).Furthermore,we also notice that the PANSS scores of patients between Genotype C/C and C/T had no statistically significance (allP＞0.05).Conclusion The results reveal that T allele at CMYA5 rs10043986 may be confer risk for susceptibility of female and adult schizophrenia in Uygur Chinese population,and that rs 10043986 polymorphism may not significantly associate with symptoms severity of schizophrenia.

The CMYA5 gene confers risk for both schizophrenia and major depressive disorder in the Han Chinese population.

OBJECTIVES: A recent genome-wide association study (GWAS) of the European population implicated the CMYA5 gene in schizophrenia. Previous functional studies showed that the CMYA5 protein can interact with DTNBP1 and PKA, providing further support for a role of CMYA5 in the pathogenesis of schizophrenia. However, this association requires additional validation in independent populations. METHODS: To validate the association between CMYA5 and schizophrenia and major depressive disorder, we genotyped 16 SNPs within the CMYA5 gene and performed case-control studies in 1330 schizophrenia patients, 1045 patients with major depressive disorder, and 1235 normal controls. All patients were of Han Chinese origin. RESULTS: rs6883197 and rs259127 were significantly associated with schizophrenia, and rs12514461, rs259127, and rs7343 were associated with major depressive disorder. Additionally, one risk haplotype of rs16877109-rs3828611 (G-G) was associated with both schizophrenia (P = 0.0000784, after correction) and major depressive disorder (P = 0.00230, after correction). CONCLUSIONS: Our findings support the idea that specific alleles and haplotype in the CMYA5 confer genetic risk for both schizophrenia and major depressive disorder in the Han Chinese population.

The association between the Uygur patients with schizophrenia and CMYA5 polymorphism / 中国神经精神疾病杂志

Objective To investigate the association between Cardiomyopathy associated 5 (CMYA5) polymor?phisms and schizophrenia in the Uygur Chinese population. Methods Taq-man assay was used to detect CMYA5 gene rs3828611 in 684 schizophrenia patients and 678 healthy controls from Chinese population. The positive and negative symptoms scale (PANSS) was used to evaluate patients’symptoms. Results Neither the genotype nor the allele frequen?cies of rs3828611 was significantly different between the patients and the controls (P>0.05). The differences were not sig?nificant in either each gender subgroup or in each age (teenager and adult) subgroup (P>0.05). The total score and the sub scores of PANSS were not significantly different among patients with different genotype groups (P>0.05). Conclu?sions There is no association between CMYA5 rs3828611and schizophrenia in the Uygur Chinese population.

Genetic analysis of common variants in the CMYA5 (cardiomyopathy-associated 5) gene with schizophrenia.

Recently, CMYA5 was suggested as a susceptibility gene for schizophrenia based on two independent studies utilizing different ethnic samples. We designed a case-control study to examine whether 21 SNPs contained within CMYA5 were associated with the disorder in a western Han Chinese sample comprised of 488 schizophrenia patients and 516 healthy control subjects. The allele distribution of SNPs rs7714250, rs16877135 and rs13158477 showed significant association with schizophrenia (Puncorrected=0.008, Puncorrected=0.04, and Puncorrected=0.009, respectively) as well as the genotype distribution in the Cochran-Armitage trend test (Puncorrected=0.008, Puncorrected=0.037 and Puncorrected=0.011, respectively). After Bonferroni correction, rs7714250 showed a trend of association with schizophrenia both in allele distribution (Pcorrected=0.088) and genotype distribution (Pcorrected=0.088). Furthermore, significant associations were found in several two-, three-, four-, and five-SNP tests of haplotype analyses. Replications of the association of CMYA5 with schizophrenia across various studies suggest that it is very likely a potential common schizophrenia-related gene worldwide. Functional studies correlating CMYA5 with DTNBP1 and PKA warrant further investigation of the molecular basis of this gene in relationship to the signal transduction pathway(s) underlying the pathogenesis of schizophrenia.