3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity

eLife, Год журнала: 2024, Номер 13

Опубликована: Авг. 5, 2024

The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts revealed 19 independent signals trait; however, mechanism action these loci remains to be elucidated. To molecularly characterize loci, we sought determine underlying causal variants corresponding effector genes within diverse cellular contexts. Integrating GWAS summary statistics existing 3D genomic datasets 57 human cell types, consisting high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, RNA-seq, applied stratified LD score regression calculated proportion SNP heritability attributable type-specific features, revealing pancreatic alpha enrichment as most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out significant their linkage disequilibrium proxies implicate genes, yielded abundant number candidate target at BDNF, ADCY3, TMEM18, FTO skeletal muscle myotubes beta-cell line, EndoC-BH1. One novel implicated gene, ALKAL2 - an inflammation-responsive gene nerve nociceptors observed key TMEM18 locus across multiple immune types. Interestingly, this observation also supported through colocalization analysis using expression quantitative trait (eQTL) derived from Genotype-Tissue Expression (GTEx) dataset, supporting inflammatory neurologic component pathogenesis obesity. Our comprehensive appraisal generated myriad different types provides insights into pediatric pathogenesis.

Язык: Английский

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Characterization of non-coding variants associated with transcription factor binding through ATAC-seq-defined footprint QTLs in liver

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 25, 2024

Non-coding variants discovered by genome-wide association studies (GWAS) are enriched in regulatory elements harboring transcription factor (TF) binding motifs, strongly suggesting a connection between disease and the disruption of cis-regulatory sequences. Occupancy TF inside region open chromatin can be detected ATAC-seq where bound TFs block transposase Tn5, leaving pattern relatively depleted Tn5 insertions known as "footprint". Here, we sought to identify associated with TF-binding, or "footprint quantitative trait loci" (fpQTLs) data generated from 170 human liver samples. We used computational tools scan reads quantify likelihood scores" at derived whole genome sequencing same tested for genotype footprint score observed 693 fpQTLs footprint-inferred (FDR < 5%). Given that insertion sites measured base-pair resolution, show aid GWAS QTL fine-mapping precisely pinpointing activity within broad trait-associated loci underlying causal variant is unknown. Liver were across ChIP-seq peaks, expression QTLs (eQTLs), liver-related loci, their inferred effect on was concordant sequence motifs 80% cases. conclude reveal variants, define role site provide functional insights into non-coding ultimately informing novel treatments common diseases.

Язык: Английский

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Cross-species evidence for a developmental origin of adult hypersomnia with loss of synaptic adhesion molecules beat-Ia/CADM2

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Сен. 26, 2024

Idiopathic hypersomnia (IH) is a poorly-understood sleep disorder characterized by excessive daytime sleepiness despite normal nighttime sleep. Combining human genomics with behavioral and mechanistic studies in fish flies, we uncover role for

Язык: Английский

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Mapping chromatin interactions at melanoma susceptibility loci and cell-type specific dataset integration uncovers distant gene targets ofcis-regulation

medRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Ноя. 15, 2024

ABSTRACT Genome-wide association studies (GWAS) of melanoma risk have identified 68 independent signals at 54 loci. For most loci, specific functional variants and their respective target genes remain to be established. Capture-HiC is an assay that links fine-mapped candidate by comprehensively mapping cell-type chromatin interactions. We performed a GWAS region-focused capture-HiC in human primary melanocytes identify physical interactions between potential causal susceptibility genes. Overall, interaction data alone nominated for 61 the signals, identifying many candidates beyond those reported previous studies. further integrated these with epigenomic (chromatin state, accessibility), gene expression (eQTL/TWAS), DNA methylation (meQTL/MWAS), massively parallel reporter (MPRA) prioritize potentially cis -regulatory targets. From set across we 140 prioritized linked 195 42 signals. In addition, developed integrative scoring system facilitate prioritization, integrating melanocyte datasets. Notably, several observed long-range connections (500 kb >1 Mb) distant validated such using CRISPR inhibition, providing evidence known cancer driver MDM4 CBL , as well SRY-box transcription factor SOX4 likely

Язык: Английский

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3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity

Опубликована: Ноя. 27, 2024

The prevalence of childhood obesity is increasing worldwide, along with the associated common comorbidities type 2 diabetes and cardiovascular disease in later life. Motivated by evidence for a strong genetic component, our prior genome-wide association study (GWAS) efforts revealed 19 independent signals trait; however, mechanism action these loci remains to be elucidated. To molecularly characterize we sought determine underlying causal variants corresponding effector genes within diverse cellular contexts. Integrating GWAS summary statistics existing 3D genomic datasets 57 human cell types, consisting high-resolution promoter-focused Capture-C/Hi-C, ATAC-seq, RNA-seq, applied stratified LD score regression calculated proportion SNP heritability attributable type-specific features, revealing pancreatic alpha enrichment as most statistically significant. Subsequent chromatin contact-based fine-mapping was carried out significant their linkage disequilibrium proxies implicate genes, yielded abundant number candidate target at BDNF , ADCY3 TMEM18 FTO skeletal muscle myotubes beta-cell line, EndoC-BH1. One novel implicated gene, ALKAL2 – an inflammation-responsive gene nerve nociceptors observed key locus across multiple immune types. Interestingly, this observation also supported through colocalization analysis using expression quantitative trait (eQTL) derived from Genotype-Tissue Expression (GTEx) dataset, supporting inflammatory neurologic component pathogenesis obesity. Our comprehensive appraisal generated myriad different types provides insights into pediatric pathogenesis.

Язык: Английский

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