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Cascading epigenomic analysis for identifying disease genes from the regulatory landscape of GWAS variants.

ABSTRACT: The majority of genetic variants detected in genome wide association studies (GWAS) exert their effects on phenotypes through gene regulation. Motivated by this observation, we propose a multi-omic integration method that models the cascading effects of genetic variants from epigenome to transcriptome and eventually to the phenome in identifying target genes influenced by risk alleles. This cascading epigenomic analysis for GWAS, which we refer to as CEWAS, comprises two types of models: one for linking cis genetic effects to epigenomic variation and another for linking cis epigenomic variation to gene expression. Applying these models in cascade to GWAS summary statistics generates gene level statistics that reflect genetically-driven epigenomic effects. We show on sixteen brain-related GWAS that CEWAS provides higher gene detection rate than related methods, and finds disease relevant genes and gene sets that point toward less explored biological processes. CEWAS thus presents a novel means for exploring the regulatory landscape of GWAS variants in uncovering disease mechanisms.

SUBMITTER: Ng B

PROVIDER: S-EPMC8648125 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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Cascading epigenomic analysis for identifying disease genes from the regulatory landscape of GWAS variants.

Ng Bernard B Casazza William W Kim Nam Hee NH Wang Chendi C Farhadi Farnush F Tasaki Shinya S Bennett David A DA De Jager Philip L PL Gaiteri Christopher C Mostafavi Sara S

PLoS genetics 20211122 11

The majority of genetic variants detected in genome wide association studies (GWAS) exert their effects on phenotypes through gene regulation. Motivated by this observation, we propose a multi-omic integration method that models the cascading effects of genetic variants from epigenome to transcriptome and eventually to the phenome in identifying target genes influenced by risk alleles. This cascading epigenomic analysis for GWAS, which we refer to as CEWAS, comprises two types of models: one for ...[more]

PMID: 34807913

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Project description:BackgroundGenome-wide association studies (GWASs) have identified multiple risk loci for bipolar disorder (BD). However, pinpointing functional (or causal) variants in the reported risk loci and elucidating their regulatory mechanisms remain challenging.MethodsWe first integrated chromatin immunoprecipitation sequencing (ChIP-Seq) data from human brain tissues (or neuronal cell lines) and position weight matrix (PWM) data to identify functional single-nucleotide polymorphisms (SNPs). Then, we verified the regulatory effects of these transcription factor (TF) binding-disrupting SNPs (hereafter referred to as "functional SNPs") through a series of experiments, including reporter gene assays, allele-specific expression (ASE) analysis, TF knockdown, CRISPR/Cas9-mediated genome editing, and expression quantitative trait loci (eQTL) analysis. Finally, we overexpressed PACS1 (whose expression was most significantly associated with the identified functional SNPs rs10896081 and rs3862386) in mouse primary cortical neurons to investigate if PACS1 affects dendritic spine density.ResultsWe identified 16 functional SNPs (in 9 risk loci); these functional SNPs disrupted the binding of 7 TFs, for example, CTCF and REST binding was frequently disrupted. We then identified the potential target genes whose expression in the human brain was regulated by these functional SNPs through eQTL analysis. Of note, we showed dysregulation of some target genes of the identified TF binding-disrupting SNPs in BD patients compared with controls, and overexpression of PACS1 reduced the density of dendritic spines, revealing the possible biological mechanisms of these functional SNPs in BD.ConclusionsOur study identifies functional SNPs in some reported risk loci and sheds light on the regulatory mechanisms of BD risk variants. Further functional characterization and mechanistic studies of these functional SNPs and candidate genes will help to elucidate BD pathogenesis and develop new therapeutic approaches and drugs.

Project description:Borrelia burgdorferi, the etiological agent of Lyme disease, persists in nature through an enzootic cycle consisting of a vertebrate host and an Ixodes tick vector. The sequence motifs modified by two well-characterized restriction/modification (R/M) loci of B. burgdorferi type strain B31 were recently described, but the methylation profiles of other Lyme disease Borrelia bacteria have not been characterized. Here, the methylomes of B. burgdorferi type strain B31 and 7 clonal derivatives, along with B. burgdorferi N40, B. burgdorferi 297, B. burgdorferi CA-11, B. afzelii PKo, B. afzelii BO23, and B. garinii PBr, were defined through PacBio single-molecule real-time (SMRT) sequencing. This analysis revealed 9 novel sequence motifs methylated by the plasmid-encoded restriction/modification enzymes of these Borrelia strains. Furthermore, while a previous analysis of B. burgdorferi B31 revealed an epigenetic impact of methylation on the global transcriptome, the current data contradict those findings; our analyses of wild-type B. burgdorferi B31 revealed no consistent differences in gene expression among isogenic derivatives lacking one or more restriction/modification enzymes. IMPORTANCE The principal causative agent of Lyme disease in humans in the United States is Borrelia burgdorferi, while B. burgdorferi, B. afzelii, and B. garinii, collectively members of the Borrelia burgdorferi sensu lato species complex, cause Lyme disease in Europe and Asia. Two plasmid-encoded restriction/modification systems have been shown to limit the genetic transformation of B. burgdorferi type strain B31 with foreign DNA, but little is known about the restriction/modification systems of other Lyme disease Borrelia bacteria. This paper describes the methylation motifs present on genomic DNAs of multiple B. burgdorferi, B. afzelii, and B. garinii strains. Contrary to a previous report, we did not find evidence for an epigenetic impact on gene expression by methylation. Knowledge of the motifs recognized and methylated by the restriction/modification enzymes of Lyme disease Borrelia will facilitate molecular genetic investigations of these important human pathogens. Additionally, the similar motifs methylated by orthologous restriction/modification systems of Lyme disease Borrelia bacteria and the presence of these motifs within recombinogenic loci suggest a biological role for these ubiquitous restriction/modification systems in horizontal gene transfer.

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Cascading epigenomic analysis for identifying disease genes from the regulatory landscape of GWAS variants.

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Cascading epigenomic analysis for identifying disease genes from the regulatory landscape of GWAS variants.

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