Dataset Information

Integration of methylation QTL and enhancer-target gene maps with schizophrenia GWAS summary results identifies novel genes.

ABSTRACT: MOTIVATION:Most trait-associated genetic variants identified in genome-wide association studies (GWASs) are located in non-coding regions of the genome and thought to act through their regulatory roles. RESULTS:To account for enriched association signals in DNA regulatory elements, we propose a novel and general gene-based association testing strategy that integrates enhancer-target gene pairs and methylation quantitative trait locus data with GWAS summary results; it aims to both boost statistical power for new discoveries and enhance mechanistic interpretability of any new discovery. By reanalyzing two large-scale schizophrenia GWAS summary datasets, we demonstrate that the proposed method could identify some significant and novel genes (containing no genome-wide significant SNPs nearby) that would have been missed by other competing approaches, including the standard and some integrative gene-based association methods, such as one incorporating enhancer-target gene pairs and one integrating expression quantitative trait loci. AVAILABILITY AND IMPLEMENTATION:Software: wuchong.org/egmethyl.html. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.

SUBMITTER: Wu C

PROVIDER: S-EPMC6761938 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Integration of methylation QTL and enhancer-target gene maps with schizophrenia GWAS summary results identifies novel genes.

Wu Chong C Pan Wei W

Bioinformatics (Oxford, England) 20191001 19

<h4>Motivation</h4>Most trait-associated genetic variants identified in genome-wide association studies (GWASs) are located in non-coding regions of the genome and thought to act through their regulatory roles.<h4>Results</h4>To account for enriched association signals in DNA regulatory elements, we propose a novel and general gene-based association testing strategy that integrates enhancer-target gene pairs and methylation quantitative trait locus data with GWAS summary results; it aims to both ...[more]

PMID: 30850848

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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.

Dataset Information

Integration of methylation QTL and enhancer-target gene maps with schizophrenia GWAS summary results identifies novel genes.

Publications

Integration of methylation QTL and enhancer-target gene maps with schizophrenia GWAS summary results identifies novel genes.

Similar Datasets

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