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Implications of Newly Identified Brain eQTL Genes and Their Interactors in Schizophrenia.

ABSTRACT: Schizophrenia (SCZ) is a devastating genetic mental disorder. Identification of the SCZ risk genes in brains is helpful to understand this disease. Thus, we first used the minimum Redundancy-Maximum Relevance (mRMR) approach to integrate the genome-wide sequence analysis results on SCZ and the expression quantitative trait locus (eQTL) data from ten brain tissues to identify the genes related to SCZ. Second, we adopted the variance inflation factor regression algorithm to identify their interacting genes in brains. Third, using multiple analysis methods, we explored and validated their roles. By means of the aforementioned procedures, we have found that (1) the cerebellum may play a crucial role in the pathogenesis of SCZ and (2) ITIH4 may be utilized as a clinical biomarker for the diagnosis of SCZ. These interesting findings may stimulate novel strategy for developing new drugs against SCZ. It has not escaped our notice that the approach reported here is of use for studying many other genome diseases as well.

SUBMITTER: Cai L

PROVIDER: S-EPMC6041437 | biostudies-literature | 2018 Sep

REPOSITORIES: biostudies-literature

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Implications of Newly Identified Brain eQTL Genes and Their Interactors in Schizophrenia.

Cai Lei L Huang Tao T Su Jingjing J Zhang Xinxin X Chen Wenzhong W Zhang Fuquan F He Lin L Chou Kuo-Chen KC

Molecular therapy. Nucleic acids 20180711

Schizophrenia (SCZ) is a devastating genetic mental disorder. Identification of the SCZ risk genes in brains is helpful to understand this disease. Thus, we first used the minimum Redundancy-Maximum Relevance (mRMR) approach to integrate the genome-wide sequence analysis results on SCZ and the expression quantitative trait locus (eQTL) data from ten brain tissues to identify the genes related to SCZ. Second, we adopted the variance inflation factor regression algorithm to identify their interact ...[more]

PMID: 30195780

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Project description:The genome-wide association study of the Psychiatric Genomics Consortium identified over one hundred schizophrenia susceptibility loci. The number of non-coding variants discovered suggests that gene regulation could mediate the effect of these variants on disease. Expression quantitative trait loci (eQTLs) contribute to variation in levels of mRNA. Given the co-occurrence of schizophrenia and several traits not involving the central nervous system (CNS), we investigated the enrichment of schizophrenia associations among eQTLs for four non-CNS tissues: adipose tissue, epidermal tissue, lymphoblastoid cells and blood. Significant enrichment was seen in eQTLs of all tissues: adipose (β = 0.18, p = 8.8 × 10-06), epidermal (β = 0.12, p = 3.1 × 10-04), lymphoblastoid (β = 0.19, p = 6.2 × 10-08) and blood (β = 0.19, p = 6.4 × 10-06). For comparison, we looked for enrichment of association with traits of known relevance to one or more of these tissues (body mass index, height, rheumatoid arthritis, systolic blood pressure and type-II diabetes) and found that schizophrenia enrichment was of similar scale to that observed when studying diseases in the context of a more likely causal tissue. To further investigate tissue specificity, we looked for differential enrichment of eQTLs with relevant Roadmap affiliation (enhancers and promoters) and varying distance from the transcription start site. Neither factor significantly contributed to the enrichment, suggesting that this is equally distributed in tissue-specific and cross-tissue regulatory elements. Our analyses suggest that functional correlates of schizophrenia risk are prevalent in non-CNS tissues. This could be because of pleiotropy or the effectiveness of variants affecting expression in different contexts. This suggests the utility of large, single-tissue eQTL experiments to increase eQTL discovery power in the study of schizophrenia, in addition to smaller, multiple-tissue approaches. Our results conform to the notion that schizophrenia is a systemic disorder involving many tissues.

Project description:PURPOSE:Osteoporosis is a common global health problem characterized by low bone mineral density (BMD) and increased risk of fracture. Genome-wide association studies (GWAS) have identified >100 genetic loci associated with BMD. However, the functional genes responsible for most associations remain largely unknown. We conducted an innovative summary statistic data-based Mendelian randomization (SMR) analysis to identify novel causal genes associated with BMD and explored their potential functional significance. METHODS:After quality control of the largest GWAS meta-analysis data of BMD and the largest expression quantitative trait loci (eQTL) meta-analysis data from peripheral blood samples, 5967 genes were tested using the SMR method. Another eQTL data was used to verify the results. Next we performed a fine-mapping association analysis to investigate the functional SNP in the identified loci. Weighted gene co-expression network analysis (WGCNA) was used to explore functional relationships for the identified novel genes with known putative osteoporosis genes. Further, we assessed functions of the identified genes through in vitro cellular study or previous functional studies. RESULTS:We identified two potentially causal genes (ASB16-AS1 and SYN2) associated with BMD. SYN2 was a novel osteoporosis candidate gene and ASB16-AS1 locus was known to be associated with BMD but was not the nearest gene to the top GWAS SNP. Fine-mapping association analysis showed that rs184478 and rs795000 was predicted to be possible causal SNPs in ASB16-AS1 and SYN2, respectively. ASB16-AS1 co-expressed with several known putative osteoporosis risk genes. In vitro cellular study showed that over-expressed ASB16-AS1 increased the expression of osteoblastogenesis related genes (BMP2 and ALPL), indicating its functional significance. CONCLUSION:Our findings support that ASB16-AS1 and SYN2 may represent two novel functional genes underlying BMD variation. The findings provide a basis for further functional mechanistic studies.

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Implications of Newly Identified Brain eQTL Genes and Their Interactors in Schizophrenia.

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Implications of Newly Identified Brain eQTL Genes and Their Interactors in Schizophrenia.

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