3D genomic features across >50 diverse cell types reveal insights into the genomic architecture of childhood obesity
Authors: Trang Khanh B. , Pahl Matthew C. , Pippin James A. , Su Chun , Littleton Sheridan H. , Sharma Prabhat , Kulkarni Nikhil N. , Ghanem Louis R. , Terry Natalie A. , O’Brien Joan M. , Wagley Yadav , Hankenson Kurt D. , Jermusyk Ashley , Hoskins Jason W. , Amundadottir Laufey T. , Xu Mai , Brown Kevin M , Anderson Stewart A. , Yang Wenli , Titchenell Paul M. , Seale Patrick , Cook Laura , Levings Megan K. , Zemel Babette S. , Chesi Alessandra , Wells Andrew D. , Grant Struan F.A. 
Published: August 2023

ABSTRACTThe 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 theBDNF,ADCY3,TMEM18andFTOloci in skeletal muscle myotubes and the pancreatic beta-cell line, EndoC-BH1. One novel implicated effector gene,ALKAL2– an inflammation-responsive gene in nerve nociceptors – was observed at the key TMEM18 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.KEY POINTSQuestionWhat are the causal variants and corresponding effector genes conferring pediatric obesity susceptibility in different cellular contexts?FindingsOur method of assessing 3D genomic data across a range of cell types revealed heritability enrichment of childhood obesity variants, particularly within pancreatic alpha cells. The mapping of putative causal variants to cis-regulatory elements revealed candidate effector genes for cell types spanning metabolic, neural, and immune systems.MeaningWe gain a systemic view of childhood obesity genomics by leveraging 3D techniques that implicate regulatory regions harboring causal variants, providing insights into the disease pathogenesis across different cellular systems.