Elsevier

Schizophrenia Research

Volume 152, Issue 1, January 2014, Pages 97-104
Schizophrenia Research

MIR137 gene and target gene CACNA1C of miR-137 contribute to schizophrenia susceptibility in Han Chinese

https://doi.org/10.1016/j.schres.2013.11.004Get rights and content

Abstract

Recently, evidence has accumulated indicating that the MIR137 gene and the target gene CACNA1C of miR-137 might be two of the most robustly implicated genes in schizophrenia. In this study, we examined 33 single nucleotide polymorphisms (SNPs) located in two genes by performing an association analysis in a cohort of 1430 schizophrenia patients and 1570 healthy Han Chinese control subjects. Single SNP association, sex-specific association and haplotype association analyses were performed. For the rs1625579 marker in MIR137 and the rs1006737 and rs4765905 markers in CACNA1C, significant differences in the allele frequencies were found between the patients and controls (p = 0.007949, p = 0.013658 and p = 0.013999, respectively), and the genotype association analysis for them suggested a similar pattern (p = 0.023167, p = 0.046623 and p = 0.047824, respectively). Further analysis of the haplotype rs1006737–rs4765905–rs882194 in CACNA1C showed significant associations with schizophrenia (corrected global p < 0.005), and two haplotypes (ACC and ACT) in the block were significantly increased in the patients. When the samples were analyzed separately by gender, we found no significant sex-specific associations in MIR137 and CACNA1C, which was similar to the results from the relevant haplotype association analysis in the female and male subgroups. We have provided new evidence supporting the association between MIR137 and CACNA1C and schizophrenia in the Han Chinese population.

Introduction

Schizophrenia (SCZ) is a devastating mental disorder that affects approximately 1% of the general population worldwide. Evidence from recent family, adoption, and twins studies supported high heritability in the development of SCZ of approximately 64% (Lichtenstein et al., 2009). The exact etiology and genetic mechanisms of SCZ are unknown. A possible reason might be that until now, the association studies have primarily focused on a small group of candidate genes that are predominantly involved in widespread alterations in neurodevelopment and neurotransmitter signaling from multiple causes. The etiology of this disorder might lie elsewhere. One plausible reason is that microRNAs (miRNAs) have the ability to coregulate multiple biological pathways that have been implicated in SCZ (Perkins et al., 2007, Beveridge et al., 2008). Many miRNAs were found to be differentially expressed in blood samples and postmortem tissue samples of patients with SCZ (Beveridge et al., 2010, Kim et al., 2010, Lai et al., 2011, Moreau et al., 2011, Santarelli et al., 2011, Gardiner et al., 2012, Miller et al., 2012) providing further evidence that miRNAs may affect the disorder.

MiRNAs are small noncoding RNAs that regulate the stability and translation of up to 60% of protein-coding mRNAs (Bartel, 2009). Dysregulation of a single miRNA can be sufficient to alter the gene-expression profile and developmental trajectory of cells (Lim et al., 2005, Friedman et al., 2009). MiRNAs contribute to the regulation of many mechanisms in the nervous system, including regulation of neuronal migration and differentiation, synaptic plasticity, and adult neurogenesis (Kosik, 2006, Cheng et al., 2009). One miRNA of particular interest is hsa-miR-137. The largest genome-wide association study (GWAS) for SCZ identified rs1625579, within an intron of MIR137 containing the primary transcript of miR-137, as the strongest new association with SCZ (Ripke et al., 2011). Despite evidence of a strongly significant association in Europeans, it is unknown whether the single nucleotide polymorphism (SNP) is associated with SCZ in Han Chinese, or whether significant association signals exist between other SNPs within MIR137 and SCZ in the Han population. Further research is required to confirm the associations of these variations in MIR137 with risk for SCZ in the Han Chinese population.

Putative miR-137 target genes are significantly enriched for association with SCZ in the Psychiatric Genomics Consortium (PGC) study (Ripke et al., 2011), and three of these associated genes (ZNF804A, TCF4 and CACNA1C) have been validated as miR-137 targets by in-vitro methods (Kim et al., 2012, Kwon et al., 2013). Previous studies have confirmed that ZNF804A and TCF4 are significantly associated with SCZ in the Han population (Li et al., 2010), and GWASs have previously detected CACNA1C as a risk factor for bipolar disorder (BPD) (Ferreira et al., 2008, Sklar et al., 2008). Subsequent studies have identified robust and replicable statistical association between CACNA1C and major depressive disorder (Casamassima et al., 2010, Green et al., 2010, Shi et al., 2011) and SCZ (Bigos et al., 2010, Green et al., 2010, Nyegaard et al., 2010, Hamshere et al., 2013, Smoller et al., 2013). Up to now, a number of recently published studies in multiple populations have repeatedly linked the SNPs in CACNA1C to multiple psychiatric disease diagnoses and indicated that the associations between CACNA1C polymorphisms are not unique to one psychiatric disorder (Table 1). The evidence shown in Table 1 implicates CACNA1C as the most statistically robust finding when combining multiple psychiatric diseases, including BPD, SCZ and depression, and growing evidence suggests overlapping genetic risk and expression profiles among them (Craddock et al., 2006, Shao and Vawter, 2008, Lichtenstein et al., 2009, Purcell et al., 2009, Potkin et al., 2010, Ripke et al., 2011). It is also unknown whether CACNA1C might confer a risk for SCZ in the Han Chinese population.

In this study, we conducted the first large genetic association study to investigate the associations of the MIR137 rs1625579 polymorphism and other SNPs with SCZ, using SCZ patients and healthy control subjects from the Han Chinese population. Our secondary purpose was to examine whether the miR-137 target gene, CACNA1C, would be associated with SCZ in the Han population. There is evidence of a sex-specific association of certain genes with many complex diseases including schizophrenia (Patsopoulos et al., 2007), where sex differences have been described for genes such as COMT (Shifman et al., 2002), PDE4B (Pickard et al., 2007), RELN (Shifman et al., 2008), XBP1 (Chen et al., 2004), Nogo (Tan et al., 2005) and IL-10 (Paul-Samojedny et al., 2010). The third aim of the study was to explore whether the sex-specific genetic associations of these polymorphisms exist in the Han population.

Section snippets

Subjects

Our study sample, which includes subjects of Han descent, includes 1430 patients (666 women, the mean age = 35.1, the standard deviation (SD) = 10.6; and 764 men, the mean age = 37.6, the SD = 11.2) from the inpatient and outpatient clinical services of a psychiatric unit at the First Affiliated Hospital of Xi'an Jiaotong University and Xi'an Mental Health Center, and 1570 unrelated healthy controls (710 women, the mean age = 34.2, the SD = 11.7; and 860 men, the mean age = 32.9, the SD = 10.9) from local

Results

Twelve SNPs in MIR137 and 21 SNPs in CACNA1C were genotyped in 1430 SCZ patients and 1570 controls. All the frequencies of the 33 SNPs in the patients and controls, including the results of the Hardy–Weinberg equilibrium (HWE) test, are shown in Table 2 and Table S1. The genotype distributions of these SNPs were all in HWE (p > 0.05).

We first conducted a single SNP association analysis. For marker rs1625579 (T-allele) in MIR137, a significant difference was found between the patient and control

Discussion

The recent predominant hypothesis has been that the genetic architecture of SCZ involves common variants of small effects and possibly rare variants with much larger effects. With the rapid development and extensive use of GWAS, additional SCZ susceptibility loci will be reported; however, the observation will require further evidence from different populations. We conducted the first large genetic association study of MIR137 and its target gene of the primary transcript miR-137, CACNA1C, with

Role of the funding source

This research was totally supported by China Postdoctoral Science Foundation Funded Project (M532029), Fundamental Research Funds for the Central Universities (08142024 and 08143003) and National Natural Science Foundation of China (Grant No. 81273351). The funding sources had no role in the design of this study, the collection, analysis and interpretation of data, the writing of the report, or the decision to submit the paper for publication.

Contributors

Authors Guan FL and Liu XS conceived and designed the study. Zhang Bo and Zhang Ba carried out the computational analyses and candidate SNPs selection. Yan TL and Li L conducted subject screening. Guan FL performed the statistical analysis of the genotype and haplotype data. Li SB provided the guidance and additional support on this project. Guan FL wrote the first draft of the paper, and all authors revised the current paper. Liu F and Li T recruited, diagnosed, and gathered patients. Guan FL,

Conflict of interest

All authors have no conflicts of interest to declare.

Acknowledgments

We thank all the donors for their assistance in accessing collections and their advice and comments during the preparation of this paper.

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