Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. 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, an...