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

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

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Journal
eLife
Published
2024-08-05
DOI
https://doi.org/10.7554/elife.95411
Citations
3
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
1.65

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article

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

Megan K. Levings, Klaus H. Kaestner, Alessandra Chesi, Kurt D. Hankenson et al.
3 citations
eLife
Genetic Associations and Epidemiology
1.65
article

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

Megan K. Levings, Klaus H. Kaestner, Alessandra Chesi, Kurt D. Hankenson, Ashley Jermusyk, Prabhat Sharma, Louis R. Ghanem, Laufey T. Ámundadóttir, Kevin M. Brown, Paul M. Titchenell, Patrick Seale, Andrew D. Wells, Sheridan H. Littleton, Chun Su, Bao Khanh Trang, Babette S. Zemel, Laura E. Cook, James A. Pippin, Struan F.A. Grant, Yadav Wagley, Jason W. Hoskins, Joan M. O’Brien, Wenli Yang, Natalie A. Terry, Nikhil N Kulkarni, Matthew C. Pahl, Stewart A. Anderson, Mai Xu
article en
3 citations

Abstract

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

eLifeVol. 13
Children's Hospital of Philadelphia (US), University of British Columbia (CA), Penn Presbyterian Medical Center (US), The University of Melbourne (AU), University of Michigan (US), Peter Doherty Institute (AU), University of Pennsylvania Health System (US), Division of Cancer Epidemiology and Genetics, University of Pennsylvania (US)
Children's Hospital of Philadelphia, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Child Health and Human Development, Eunice Kennedy Shriver National Institute of Child Health and Human Development
Good health and well-being
Openalex Percentile: Top 15%
Genetic Associations and Epidemiology
1.65
DOIOpen Access PDFOpenAlex
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