Dataset Information

Cross-tissue eQTL enrichment of associations in schizophrenia.

ABSTRACT: 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 (? = 0.18, p = 8.8 × 10-06), epidermal (? = 0.12, p = 3.1 × 10-04), lymphoblastoid (? = 0.19, p = 6.2 × 10-08) and blood (? = 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.

SUBMITTER: Bettella F

PROVIDER: S-EPMC6126834 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Cross-tissue eQTL enrichment of associations in schizophrenia.

Bettella Francesco F Brown Andrew A AA Smeland Olav B OB Wang Yunpeng Y Witoelar Aree A Buil Demur Alfonso A AA Thompson Wesley K WK Zuber Verena V Dale Anders M AM Djurovic Srdjan S Andreassen Ole A OA

PloS one 20180906 9

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 schizo ...[more]

PMID: 30188921

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Project description:Multiple genetic approaches have identified microRNAs as key effectors in psychiatric disorders as they post-transcriptionally regulate expression of thousands of target genes. However, their role in specific psychiatric diseases remains poorly understood. In addition, epigenetic mechanisms such as DNA methylation, which affect the expression of both microRNAs and coding genes, are critical for our understanding of molecular mechanisms in schizophrenia. Using clinical, imaging, genetic, and epigenetic data of 103 patients with schizophrenia and 111 healthy controls of the Mind Clinical Imaging Consortium (MCIC) study of schizophrenia, we conducted gene set enrichment analysis to identify markers for schizophrenia-associated intermediate phenotypes. Genes were ranked based on the correlation between DNA methylation patterns and each phenotype, and then searched for enrichment in 221 predicted microRNA target gene sets. We found the predicted hsa-miR-219a-5p target gene set to be significantly enriched for genes (EPHA4, PKNOX1, ESR1, among others) whose methylation status is correlated with hippocampal volume independent of disease status. Our results were strengthened by significant associations between hsa-miR-219a-5p target gene methylation patterns and hippocampus-related neuropsychological variables. IPA pathway analysis of the respective predicted hsa-miR-219a-5p target genes revealed associated network functions in behavior and developmental disorders. Altered methylation patterns of predicted hsa-miR-219a-5p target genes are associated with a structural aberration of the brain that has been proposed as a possible biomarker for schizophrenia. The (dys)regulation of microRNA target genes by epigenetic mechanisms may confer additional risk for developing psychiatric symptoms. Further study is needed to understand possible interactions between microRNAs and epigenetic changes and their impact on risk for brain-based disorders such as schizophrenia.

Project description:BACKGROUND:One of the major challenges in current psychiatric epigenetic studies is the tissue specificity of epigenetic changes since access to brain samples is limited. Peripheral tissues have been studied as surrogates but the knowledge of cross-tissue genetic-epigenetic characteristics remains largely unknown. In this work, we conducted a comprehensive investigation of genetic influence on DNA methylation across brain and peripheral tissues with the aim to characterize cross-tissue genetic-epigenetic effects and their roles in the pathophysiology of psychiatric disorders. METHODS:Genome-wide methylation quantitative trait loci (meQTLs) from brain prefrontal cortex, whole blood, and saliva were identified separately and compared. Focusing on cis-acting effects, we tested the enrichment of cross-tissue meQTLs among cross-tissue expression QTLs and genetic risk loci of various diseases, including major psychiatric disorders. CpGs targeted by cross-tissue meQTLs were also tested for genomic distribution and functional enrichment as well as their contribution to methylation correlation across tissues. Finally, a consensus co-methylation network analysis on the cross-tissue meQTL targeted CpGs was performed on data of the three tissues collected from schizophrenia patients and controls. RESULTS:We found a significant overlap of cis meQTLs (45-73 %) and targeted CpG sites (31-68 %) among tissues. The majority of cross-tissue meQTLs showed consistent signs of cis-acting effects across tissues. They were significantly enriched in genetic risk loci of various diseases, especially schizophrenia, and also enriched in cross-tissue expression QTLs. Compared to CpG sites not targeted by any meQTLs, cross-tissue targeted CpGs were more distributed in CpG island shores and enhancer regions, and more likely had strong correlation with methylation levels across tissues. The targeted CpGs were also annotated to genes enriched in multiple psychiatric disorders and neurodevelopment-related pathways. Finally, we identified one co-methylation network shared between brain and blood showing significant schizophrenia association (p = 5.5 × 10-6). CONCLUSIONS:Our results demonstrate prevalent cross-tissue meQTL effects and their contribution to the correlation of CpG methylation across tissues, while at the same time a large portion of meQTLs show tissue-specific characteristics, especially in brain. Significant enrichment of cross-tissue meQTLs in expression QTLs and genetic risk loci of schizophrenia suggests the potential of these cross-tissue meQTLs for studying the genetic effect on schizophrenia. The study provides compelling motivation for a well-designed experiment to further validate the use of surrogate tissues in the study of psychiatric disorders.

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Cross-tissue eQTL enrichment of associations in schizophrenia.

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Cross-tissue eQTL enrichment of associations in schizophrenia.

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