Schizophrenia and Genome

Integrating genome-wide association study and methylation functional annotation data identified candidate genes and pathways for schizophrenia

By Qi, Xin, Guan, Fanglin, Wen, Yan, Li, Ping, Ma, Mei, Cheng, Shiqiang, Zhang, Lu, Liang, Chujun, Cheng, Bolun, Zhang, Feng

Abstract Background: Schizophrenia (SCZ) is a severe mental disorder. Both environmental and genetic factors contribute to the development of SCZ. The estimated heritability of SCZ is about 80%. Previous genetic studies of SCZ mainly focused on the genetic variations associated the risk of SCZ. Limited efforts are paid to explore the roles and biological mechanism of nuclear acid methylation implicated in the pathogenesis of SCZ. Methods: A two-stage integrative analysis of SCZ GWAS and nuclear acid methylation functional annotation data (including meQTLs and m6A) was performed in this study. First, the discovery GWAS of SCZ was aligned with genomic meQTLs and m6A annotation data to identify the candidate genes associated with SCZ. Second, another independent replication GWAS dataset of SCZ was applied to validate the discovery results. Furthermore, the functional relevance of identified candidate genes with SCZ were validated by the mRNA expression profiling of SCZ brain tissues. Gene ontology (GO) and pathway enrichment analysis of identified candidate genes was performed by the DAVID tool. Results: The two-stage integrative analysis detected 106 meQTLs related candidate genes for SCZ. After comparing with the differentially expressed genes in SCZ brain tissues, 49 overlapped genes were identified for meQTLs, such as ZSCAN12, BTN3A2 and HLA-DQA1. Besides, for meQTLs, 29 SCZ associated pathways and 56 SCZ associated GO terms were detected, such as cell adhesion molecules and asthma. For m6A, 25 candidate genes were detected by the two-stage integrative analysis for SCZ, such as ZSCAN12, HLA-DQA1 and SNX19. Furthermore, 17 of the 25 genes were detected in the mRNA expression profiling of SCZ brain tissues. Conclusion: This study identified multiple SCZ associated genes and pathways, supporting the implication of nuclear acid methylation in the pathogenesis of SCZ.

Keywords: schizophrenia; N6-methyladenosine; methylation quantitative trait loci; pathway

1. Introduction Schizophrenia (SCZ) is a severe mental disorder, which typically first occurs in late adolescence and early adulthood [1]. The global prevalence of SCZ is around 1% [2]. Neuropsychological deficits are the significant features of SCZ, especially cognitive and psychosocial dysfunctions [3]. SCZ brings heavy financial and medical burden to society and patients, due to the loss of ability to work and long-term treatments [4]. Besides, co-existing depression, caregiver burden and cognitive impairment are also considered as humanistic burden [5]. Recently, dysregulation of immune system has been considered as an important pathogenesis of SCZ [6, 7]. However, the biological mechanism of SCZ is complex and remains largely unknown. Nucleic acid methylation is an important epigenetic modification, mainly including DNA methylation and RNA methylation. DNA methylation involves addition of methyl groups to DNA bases, typically the cytosine of CpG dinucleotides, 

and plays an important role in gene expression regulation [8]. Recent studies demonstrated that DNA methylation was implicated in the development of multiple human complex diseases, such as SCZ [9]. N6-methyladenosine (m6A) is the methylation modification on the nitrogen at the 6th position of the adenosine base, which is considered to be the most abundant and enigmatic post-transcriptional RNA modification in messenger RNA (mRNA) and long noncoding RNA (lncRNA) across eukaryotes [10]. Through m6A-specific binding proteins, m6A modification has an effect on the process of mRNA splicing, nuclear export, translation, and degradation [11]. Recent studies suggested that m6A modification was involved in the regulation of multiple key biological processes, such as synaptic signaling, sperm development, stem cell differentiation and circadian periods [12]. However, limited efforts were paid to explore the potential roles of m6A in the pathogenesis of SCZ. Both environmental and genetic factors play important roles in the etiology of SCZ. Multiple environmental factors, such as tobacco smoking, obesity and early parental loss, have been suggested to be associated with SCZ [13]. Genetic factors also contributed greatly to the development of SCZ with the estimated heritability of around 80% [14]. More than 100 risk loci associated with SCZ have been identified by now [15]. However, the risk of SCZ explained by the identified genetic loci is limited, suggesting the existence of undiscovered genetic factors for SCZ. Recent studies observed that the genetic loci identified by genome-wide association study (GWAS) were enriched in regulatory genetic variants, such as expression quantitative trait loci and methylation quantitative trait loci (meQTLs) [16, 17]. Integrating the GWAS results of complex diseases and the annotation data of regulatory genetic variants is capable of providing new insight into the pathogenesis of target diseases [18]. For instance, Zhu et al. identified candidate genes (SNX19 and NMRAL1) for SCZ using GWAS data and eQTL data [19]. To the best of our knowledge, limited efforts have been paid to investigate the functional relevance of methylation related regulatory genetic variants with SCZ. 

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