3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity DOI Open Access
Bao Khanh Trang, Matthew C. Pahl, James A. Pippin

и другие.

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

Circadian clock gene polymorphisms implicated in human pathologies DOI Creative Commons

Jesse R. Janoski,

Ignacio Aiello, C. Lundberg

и другие.

Trends in Genetics, Год журнала: 2024, Номер 40(10), С. 834 - 852

Опубликована: Июнь 12, 2024

Circadian rhythms, ~24 h cycles of physiological and behavioral processes, can be synchronized by external signals (e.g., light) persist even in their absence. Consequently, dysregulation circadian rhythms adversely affects the well-being organism. This timekeeping system is generated sustained a genetically encoded endogenous mechanism composed interlocking transcriptional/translational feedback loops that generate rhythmic expression core clock genes. Genome-wide association studies (GWAS) forward genetic show SNPs genes influence gene regulation correlate with risk developing various conditions. We discuss variations are associated phenotypes, implications for human health, stress need thorough this domain regulation.

Язык: Английский

Процитировано

6
Implicating type 2 diabetes effector genes in relevant metabolic cellular models using promoter-focused Capture-C DOI Creative Commons

Nicholas A Wachowski,

James A. Pippin, Keith D. Boehm

и другие.

Diabetologia, Год журнала: 2024, Номер unknown

Опубликована: Сен. 6, 2024

Язык: Английский

Процитировано

5
3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity DOI Creative Commons
Bao Khanh Trang, Matthew C. Pahl, James A. Pippin

и другие.

eLife, Год журнала: 2025, Номер 13

Опубликована: Янв. 15, 2025

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

Процитировано

0
Characterization of non-coding variants associated with transcription-factor binding through ATAC-seq-defined footprint QTLs in liver DOI
Max F. Dudek,

Brandon M. Wenz,

Christopher D. Brown

и другие.

The American Journal of Human Genetics, Год журнала: 2025, Номер unknown

Опубликована: Апрель 1, 2025

Язык: Английский

Процитировано

0
GWAS-informed data integration and non-coding CRISPRi screen illuminate genetic etiology of bone mineral density DOI Creative Commons
Mitchell Conery, James A. Pippin, Yadav Wagley

и другие.

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

Опубликована: Март 20, 2024

Over 1,100 independent signals have been identified with genome-wide association studies (GWAS) for bone mineral density (BMD), a key risk factor mortality-increasing fragility fractures; however, the effector gene(s) most remain unknown. Informed by variant-to-gene mapping strategy implicating 89 non-coding elements predicted to regulate osteoblast gene expression at BMD GWAS loci, we executed single-cell CRISPRi screen in human fetal 1.19 cells (hFOBs). The relevance of hFOBs was supported heritability enrichment from cross-cell type stratified LD-score regression involving 98 cell types grouped into 15 tissues. 24 genes showed perturbation screen, four (

Язык: Английский

Процитировано

3
The Genetics of Human Sleep and Sleep Disorders DOI
Xianlin Zou, Louis J. Ptáček, Ying‐Hui Fu

и другие.

Annual Review of Genomics and Human Genetics, Год журнала: 2024, Номер 25(1), С. 259 - 285

Опубликована: Апрель 26, 2024

Healthy sleep is vital for humans to achieve optimal health and longevity. Poor disorders are strongly associated with increased morbidity mortality. However, the importance of good continues be underrecognized. Mechanisms regulating its functions in remain mostly unclear even after decades dedicated research. Advancements gene sequencing techniques computational methodologies have paved way various genetic analysis approaches, which provided some insights into human genetics. This review summarizes our current knowledge basis underlying traits disorders. We also highlight use animal models validate findings from studies discuss potential molecular mechanisms signaling pathways involved regulation sleep.

Язык: Английский

Процитировано

3
Integrative Genomic Analyses Identify LncRNA Regulatory Networks across Pediatric Leukemias and Solid Tumors DOI
Apexa Modi, Gonzalo López, Karina L. Conkrite

и другие.

Cancer Research, Год журнала: 2023, Номер 83(20), С. 3462 - 3477

Опубликована: Авг. 16, 2023

Abstract Long noncoding RNAs (lncRNA) play an important role in gene regulation and contribute to tumorigenesis. While pan-cancer studies of lncRNA expression have been performed for adult malignancies, the landscape across pediatric cancers remains largely uncharted. Here, we curated RNA sequencing data 1,044 leukemia extracranial solid tumors integrated paired tumor whole genome epigenetic relevant cell line models explore expression, regulation, association with cancer. A total 2,657 lncRNAs were robustly expressed six cancers, including 1,142 exhibiting histotype-elevated expression. DNA copy number alterations contributed dysregulation at a proportion comparable protein coding genes. Application multidimensional framework identify prioritize impacting networks revealed that dysregulated cancer are associated proliferation, metabolism, damage hallmarks. Analysis upstream via type–specific transcription factors further implicated distinct developmental lncRNAs. Integration these analyses prioritized experimental validation, silencing TBX2-AS1, top-prioritized neuroblastoma-specific lncRNA, resulted significant growth inhibition neuroblastoma cells, confirming computational predictions. Taken together, provide comprehensive characterization function pave way future mechanistic studies. Significance: Comprehensive leads identification highly childhood annotation showing histotype-specific elevated prediction regulatory networks.

Язык: Английский

Процитировано

7
Perturbation of the insomnia WDR90 genome-wide association studies locus pinpoints rs3752495 as a causal variant influencing distal expression of neighboring gene, PIG-Q DOI
Shilpa Sonti, Sheridan H. Littleton, Matthew C. Pahl

и другие.

SLEEP, Год журнала: 2024, Номер 47(7)

Опубликована: Апрель 4, 2024

Abstract Although genome-wide association studies (GWAS) have identified loci for sleep-related traits, they do not directly uncover the underlying causal variants and corresponding effector genes. The majority of such reside in non-coding regions are therefore presumed to impact cis-regulatory elements. Our previously reported ‘variant-to-gene mapping’ effort human induced pluripotent stem cell (iPSC)-derived neural progenitor cells (NPCs), combined with validation both Drosophila zebrafish, implicated phosphatidyl inositol glycan (PIG)-Q as a functionally relevant gene at insomnia “WDR90” GWAS locus. However, importantly that did characterize variant. Specifically, our previous 3D genomic datasets nominated shortlist three neighboring single nucleotide polymorphisms (SNPs) strong linkage disequilibrium within an intronic enhancer region WDR90 contacted open PIG-Q promoter. We sought investigate influence these SNPs collectively then individually on modulation pinpoint “regulatory” Starting gross level perturbation, deletion entire NPCs via CRISPR-Cas9 editing subsequent RNA sequencing revealed expression changes specific transcripts. Results from individual luciferase reporter assays each SNP iPSCs rs3752495 risk allele (RA) ~2.5-fold increase expression. Importantly, also exhibited allele-specific effect, RA increasing by ~2-fold versus non-RA. In conclusion, variant-to-function approach vitro implicate variant embedded while modulating distally located PIG-Q.

Язык: Английский

Процитировано

2
Pleiotropic effects of a high confidence Autism Spectrum Disorder gene, arid1b, on zebrafish sleep DOI Creative Commons
Fusun Doldur-Balli, Amber Zimmerman, Brendan T Keenan

и другие.

Neurobiology of Sleep and Circadian Rhythms, Год журнала: 2023, Номер 14, С. 100096 - 100096

Опубликована: Май 1, 2023

Sleep fulfills critical functions in neurodevelopment, such as promoting synaptic plasticity, neuronal wiring, and brain connectivity which are phenomena Autism Spectrum Disorder (ASD) pathophysiology. disturbance, specifically insomnia, accompanies ASD is associated with more severe core symptoms (e.g., social impairment). It possible that focusing on identifying effective ways to treat sleep problems can help alleviate other ASD-related symptoms. A body of evidence indicates shared mechanisms neurobiological substrates between investigation these may inform therapeutic effects improving at both behavioral molecular levels. In this study, we tested if behavior were different a zebrafish model the arid1b gene mutated compared controls. This was selected for study expert curations conducted Simons Foundation Research Institute (SFARI) Gene database define it 'high confidence' (i.e., clearly implicated) encoding chromatin remodeling protein. Homozygous mutants displayed increased arousability light their heterozygous wild type counterparts, based testing mechano-acoustic stimulus presenting vibration frequencies increasing intensity detect depth. addition, decreased preference observed homozygous mutant zebrafish. The phenotypes reported our line findings from mouse models human studies demonstrate utility vertebrate system high throughput phenotyping changes relevant ASD. Furthermore, importance including assessments arousal threshold when studying using vivo models.

Язык: Английский

Процитировано

6
Validation of Candidate Sleep Disorder Risk Genes Using Zebrafish DOI Creative Commons
Steven Tran, David A. Prober

Frontiers in Molecular Neuroscience, Год журнала: 2022, Номер 15

Опубликована: Апрель 7, 2022

Sleep disorders and chronic sleep disturbances are common associated with cardio-metabolic diseases neuropsychiatric disorders. Several genetic pathways neuronal mechanisms that regulate have been described in animal models, but the genes underlying human variation largely unknown. Identifying these is essential order to develop effective therapies for their comorbidities. To address this unmet health problem, genome-wide association studies (GWAS) identified numerous variants traits However, most cases, it unclear which gene responsible a phenotype variant. As result, necessary experimentally validate candidate by GWAS using an model. Rodents ill-suited endeavor due poor amenability high-throughput assays high costs generating, maintaining, testing large numbers of mutant lines. Zebrafish (

Язык: Английский

Процитировано

8