Integration of Enhancer-Promoter Interactions with GWAS Summary Results Identifies Novel Schizophrenia-Associated Genes and Pathways

Wu, Chong; Pan, Wei

doi:10.1534/genetics.118.300805

Cited by 35 publications

(31 citation statements)

References 51 publications

(84 reference statements)

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“…Capture Hi-C (Mifsud et al, 2015) revealed a hotspot of long-range interactions between the region and many other loci, including the promoter region of MED19 . Notably, a recently developed burden test taking into account promoter-enhancer identified a significant association between MED19 expression and schizophrenia risk (Wu and Pan, 2018) supporting MED19 as a causal gene at this locus. .…”

Section: Gc-rich Estrs Are Predicted To Modulate Dna and Rna Secondarmentioning

confidence: 90%

“…MED19 is part of the mediator complex, which has previously been shown to play a role in schizophrenia and neurodevelopmental phenotypes (Snijders Blok et al, 2018;Spaeth et al, 2011) . Furthermore, a recently developed burden test taking into account promoter-enhancer identified a significant association between MED19 expression and schizophrenia risk (Wu and Pan, 2018) .…”

Section: Estrs Are Potential Drivers Of Complex Traitsmentioning

confidence: 99%

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Multi-tissue analysis reveals short tandem repeats as ubiquitous regulators of gene expression and complex traits

Fotsing¹,

Margoliash

Wang³

et al. 2018

Preprint

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Short tandem repeats (STRs) have been implicated in a variety of complex traits in humans. However, genome-wide studies of the effects of STRs on gene expression thus far have had limited power to detect associations and elucidate the underlying biological mechanisms. Here, we leverage whole genome sequencing and expression data for 17 tissues from GTEx to identify STRs whose repeat lengths are associated with expression of nearby genes (eSTRs). Our analysis reveals more than 3,000 high-confidence eSTRs, which are enriched in known or predicted regulatory regions. We show eSTRs may act through a variety of mechanisms. We further identify hundreds of eSTRs that potentially drive published GWAS signals and implicate specific eSTRs in height and schizophrenia. Overall, our results demonstrate that eSTRs potentially contribute to a range of human phenotypes. We expect that our comprehensive eSTR catalog will serve as a valuable resource for future studies of complex traits. link between an eSTR for RFT1 and height and use reporter assays to experimentally validate the effect of this STR on expression. Finally, the complete catalog of eSTRs is publicly available and will likely be a valuable resource for future studies of complex traits. Results Profiling expression STRs across 17 human tissuesWe performed a genome-wide analysis to identify associations between the number of repeats in each STR and expression of nearby genes (expression STRs, or "eSTRs", which we use to refer to a unique STR by gene association). We focused on 652 samples included in the Genotype Tissue Expression (GTEx) (GTEx Consortium, 2015) dataset for which both high coverage whole genome sequencing (WGS) and RNA-sequencing of multiple tissues were available. The WGS cohort consisted of 561 individuals with reported European ancestry, 75 of African ancestry, and 8, 3, and 5 of Asian, Amerindian, and Unknown ancestry, respectively. We used HipSTR (Willems et al., 2017) to genotype STRs in each sample. Resulting genotypes were subjected to stringent filtering to remove low quality calls ( Methods ). After filtering, 175,226 STRs remained for downstream analysis. To identify eSTRs, we performed a linear regression between average STR length and normalized gene expression for each individual at each STR within 100kb of a gene, controlling for sex, population structure, and technical covariates ( Methods , Figures S1, S2 ). Analysis was restricted to 17 tissues where we had data for at least 100 samples ( Figure 1A, Table S1, Methods ) and to genes with median RPKM greater than 0. As a control, for each STR-gene pair we performed a permutation analysis in which sample identifiers were shuffled. Altogether, we performed an average of 278,521 STR-gene tests across 16,065 genes per tissue.Using this approach, we identified 25,561 unique eSTRs associated with 11,810 genes in at least one tissue at a gene-level FDR of 10% ( Methods ). Of these, 8,417 (32.5%) were shared by two or more tissues and 469 were shared by 10 or more tissues ( Figure S3 ). P-value...

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Section: Gc-rich Estrs Are Predicted To Modulate Dna and Rna Secondarmentioning

confidence: 90%

Section: Estrs Are Potential Drivers Of Complex Traitsmentioning

confidence: 99%

Multi-tissue analysis reveals short tandem repeats as ubiquitous regulators of gene expression and complex traits

Fotsing¹,

Margoliash

Wang³

et al. 2018

Preprint

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“…These efforts were spearheaded by the Encyclopedia of DNA Elements (ENCODE) Consortium (Dunham et al, ), and led to the identification of chromatin signatures that are strongly associated with active enhancers. Furthermore, these data demonstrated that single nucleotide polymorphisms associated with disease reside disproportionately within candidate enhancers (Corradin & Scacheri, ; Ernst et al, ; Wu & Pan, ), highlighting the importance of elucidating how enhancer sequences contribute to development, homeostasis, and disease.…”

Section: Genome‐wide Methodologies To Identify Putative Enhancersmentioning

confidence: 98%

Functional genomic approaches to elucidate the role of enhancers during development

Ryan

Farley

2019

WIREs Mechanisms of Disease

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Successful development depends on the precise tissue-specific regulation of genes by enhancers, genetic elements that act as switches to control when and where genes are expressed. Because enhancers are critical for development, and the majority of disease-associated mutations reside within enhancers, it is essential to understand which sequences within enhancers are important for function. Advances in sequencing technology have enabled the rapid generation of genomic data that predict putative active enhancers, but functionally validating these sequences at scale remains a fundamental challenge. Herein, we discuss the power of genome-wide strategies used to identify candidate enhancers, and also highlight limitations and misconceptions that have arisen from these data. We discuss the use of massively parallel reporter assays to test enhancers for function at scale. We also review recent advances in our ability to study gene regulation during development, including CRISPR-based tools to manipulate genomes and single-cell transcriptomics to finely map gene expression. Finally, we look ahead to a synthesis of complementary genomic approaches that will advance our understanding of enhancer function during development.

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“…However, existing methods are largely focused on individual CpG by testing each CpG separately. Additionally, we and others have shown that integrating enhancer-promoter interactions will lead to improved statistical power for gene-level association tests [22] as enhancers are key gene-regulatory DNA sequences that control gene expression by engaging in physical contacts with their cognate genes [23]. However, it is still unclear how to effectively integrate genetically regulated DNAm and promoter-enhancer interactions with GWAS results.…”

Section: Introductionmentioning

confidence: 99%

A gene-level methylome-wide association analysis identifies novel Alzheimer’s disease genes

Bradley

Liu

et al. 2020

Preprint

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Motivation: Transcriptome-wide association studies (TWAS) have successfully facilitated the discovery of novel genetic risk loci for many complex traits, including late-onset Alzheimer's disease (AD). However, most existing TWAS methods rely only on gene expression and ignore epigenetic modification (i.e., DNA methylation) and functional regulatory information (i.e., enhancer-promoter interactions), both of which contribute significantly to the genetic basis of AD. Results: This motivates us to develop a novel gene-level association testing method that integrates genetically regulated DNA methylation and enhancer-target gene pairs with genome-wide association study (GWAS) summary results. Through simulations, we show that our approach, referred to as the CMO (cross methylome omnibus) test, yielded well controlled type I error rates and achieved much higher statistical power than competing methods under a wide range of scenarios. Furthermore, compared with TWAS, CMO identified an average of 124% more associations when analyzing several brain imaging-related GWAS results. By analyzing to date the largest AD GWAS of 71,880 cases and 383,378 controls, CMO identified six novel loci for AD, which have been ignored by competing methods. Availability and implementation: Software: https://github.com/ChongWuLab/CMO

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Integration of Enhancer-Promoter Interactions with GWAS Summary Results Identifies Novel Schizophrenia-Associated Genes and Pathways

Cited by 35 publications

References 51 publications

Multi-tissue analysis reveals short tandem repeats as ubiquitous regulators of gene expression and complex traits

Multi-tissue analysis reveals short tandem repeats as ubiquitous regulators of gene expression and complex traits

Functional genomic approaches to elucidate the role of enhancers during development

A gene-level methylome-wide association analysis identifies novel Alzheimer’s disease genes

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