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Principal Investigator: KAREN L. MOHLKE
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $638,741
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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Genome-wide association studies (GWAS) have successfully identified thousands of genetic signals associated with common, complex diseases and quantitative traits. However, at most signals, the specific variants and genes, their directions of effect, their cell types of action, and their mechanisms remain to be determined. Subcutaneous adipose tissue buffers lipid energy balance and may protect from metabolic risk. Previously, our analyses of bulk subcutaneous adipose tissue from Metabolic Syndrome in Men (METSIM) study participants identified local expression and splice quantitative trait loci (eQTL, sQTL) colocalized with GWAS signals to suggest new candidate genes; our collaborative eQTL studies based on >2,200 participants identified >1,800 candidate target genes for metabolic traits; and our assays of chromatin accessibility in adipose tissue and differentiating adipocytes identified regulatory elements. However, relatively few regulatory effects have been validated. A more thorough understanding of regulatory mechanisms is needed, including detection and functional characterization of noncoding variants, their target genes, and cell types of action. Our overarching goal is to identify the variants, genes, and mechanisms responsible for metabolic trait GWAS signals. We hypothesize that characterizing regulatory variants in cell types from a disease-relevant tissue will reveal genes and mechanisms that alter metabolic traits.
In the next phase of this study, we will expand identification and functional characterization of regulatory variants for metabolic traits. We will detect allelic differences in adipose cell-type gene expression that colocalize with and mediate variant effects on metabolic trait GWAS signals. At GWAS signals that colocalize with adipose or cell-type eQTL, we will use high-throughput assays to identify regulatory variants that exhibit allelic effects on transcriptional activity in adipose cell types. We will validate variant links to target genes by altering the variant-containing regulatory elements and assaying effects on expression, and for selected genes, we will use cell assays to determine functions. Excellent human tissue resources, innovations in development of high-throughput assays and genome editing, and advanced analytical methods make this project timely and feasible. Together, this study will identify functional variants, genes, and relevant cell types at metabolic trait GWAS signals. While identification of new GWAS signals continues to progress, translating associated variants into underlying genes remains challenging, and this combination of approaches provides a new opportunity to specify which genes, variants, and mechanisms are involved in disease risk. Better understanding of these factors and mechanisms may lead to improved diagnoses and treatments for obesity, T2D, and metabolic syndrome.
Terms: <Abdominal obesity><Acceleration><Adipocytes><Adipose Cell><Adipose tissue><Adult-Onset Diabetes Mellitus><Affect><Allele Frequency><Alleles><Allelomorphs><Android fat distribution><Assay><Basal Transcription Factor><Basal transcription factor genes><Binding><Bioassay><Biological><Biological Assay><Blood Plasma><Body Tissues><Buffers><CRISPR activation><CRISPR activator><CRISPR based activation><CRISPR gene activation><CRISPR interference><CRISPR transcription activation><CRISPR transcriptional activation><CRISPR-Cas-9-mediated gene activation><CRISPR-based gene activation><CRISPR-dCAS9 Activator><CRISPR-dCas9-mediated repression><CRISPR-mediated transcriptional activation><CRISPR/CAS9 activation><CRISPR/CAS9 gene activation><CRISPR/dCas9 activation><CRISPR/dCas9 interference><CRISPR/dCas9-based transcriptional activation><CRISPR/dCas9-mediated transcriptional inhibition><CRISPRa><CRISPRi><Candidate Disease Gene><Candidate Gene><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Assay><Cellular Function><Cellular Physiology><Cellular Process><Central obesity><Centripetal obesity><Cholesterol><Chromatin><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats interference><Complex><DNA><Data><Deoxyribonucleic Acid><Detection><Development><Diabetes Mellitus><Diagnosis><Disease><Disorder><Distal><Enhancers><Exhibits><Fat Cells><Fatty Tissue><Frequencies><Functional RNA><GTEx><GWA study><GWAS><Gene Action Regulation><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Gene Expression Regulation><Gene Frequency><Gene Regulation><Gene Regulation Process><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic><Genetic Transcription><Genetic study><Genotype-Tissue Expression Project><Goals><Hereditary><High Throughput Assay><Humulin R><Individual><Inherited><Insulin><Intracellular Communication and Signaling><Ketosis-Resistant Diabetes Mellitus><Leptin><Link><Lipids><Lipocytes><Mature Lipocyte><Mature fat cell><Maturity-Onset Diabetes Mellitus><Mediating><Mendelian randomization><Meta-Analysis><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic syndrome><Minor><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><NIDDM><Non-Coding><Non-Coding RNA><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Non-translated RNA><Noncoding RNA><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nontranslated RNA><Novolin R><Ob Gene Product><Ob Protein><Obese Gene Product><Obese Protein><Participant><Pathogenicity><Phase><Plasma><Plasma Serum><QTL><Quantitative Trait Loci><RNA Expression><RNA Seq><RNA Splicing><RNA sequencing><RNAseq><Recommendation><Regular Insulin><Regulator Genes><Regulatory Element><Reporter><Research Resources><Resources><Reticuloendothelial System, Serum, Plasma><Risk><Role><Sample Size><Signal Transduction><Signal Transduction Systems><Signaling><Single-Nucleus Sequencing><Slow-Onset Diabetes Mellitus><Specific qualifier value><Specified><Splicing><Stable Diabetes Mellitus><Subcellular Process><T2 DM><T2D><T2DM><Testing><Text><Thesaurismosis><Tissues><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Transcriptional Regulatory Elements><Translating><Triacylglycerol><Triglycerides><Truncal obesity><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><Untranslated RNA><Variant><Variation><Waist-Hip Ratio><Work><activating CRISPR technology><adipocyte development><adipocyte differentiation><adipose><adult onset diabetes><advanced analytics><allelic frequency><analytical method><analyze gene expression><biologic><biological signal transduction><causal allele><causal gene><causal mutation><causal variant><causative mutation><causative variant><cell assay><cell type><developmental><diabetes><disease diagnosis><disease risk><disorder risk><energy balance><entire genome><epigenomics><exome><exomes><experiment><experimental research><experimental study><experiments><full genome><gene expression analysis><gene expression assay><gene function><genetic epidemiologic study><genetic epidemiology><genome editing><genome sequencing><genome wide association><genome wide association scan><genome wide association studies><genome wide association study><genomewide association scan><genomewide association studies><genomewide association study><genomic editing><high throughput screening><high throughput technology><human tissue><improved><innovate><innovation><innovative><ketosis resistant diabetes><maturity onset diabetes><men><metabolism disorder><mortality><noncoding><novel><obesity intervention><obesity therapy><obesity treatment><regulatory gene><repressing CRISPR-dCas9 system><sNuc-Seq><single cell genomics><single nucleus RNA-sequencing><single nucleus seq><single-nucleus RNA-seq><snRNA sequencing><snRNA-seq><social role><subcutaneous><subdermal><success><tissue resource><trait><trans acting element><transcription factor><transcriptional profiling><transcriptome sequencing><transcriptomic sequencing><transcriptomics><type 2 DM><type II DM><type two diabetes><variant detection><visceral obesity><waist-to-hip ratio><white adipose tissue><whole genome><whole genome association analysis><whole genome association studies><whole genome association study><yellow adipose tissue>