2126-LB: Mapping Functional Genetic Variants and Disease Heritability on Gene Regulatory Programs in Human Adipocyte Villages under Metabolic Disease–Relevant Stimuli

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Introduction and Objective: Genetic variation and its interaction with environmental cues are crucial in the etiology of metabolic diseases, which are strongly linked to adipocyte dysfunction and are highly cell state- and context-specific. Methods: Here, we leverage a population-scale biobank (CellGenBank) to conduct pooled natural genetic variation screens in primary human adipocyte villages for single-nucleus transcriptomic and chromatin accessibility profiling under various disease-relevant stimuli. Results: Processing 338k nuclei from 118 donors allowed us to identified key cell states characterized by canonical marker genes, including quiescent (PDGFRA) and proliferative (PDGFRA, CDK1, AURKB) adipose tissue-derived mesenchymal stem cells (AMSCs), structural Wnt-regulated adipose tissue-resident (SWAT; DCN, PLAC9, APOD) cells and adipogenic (ADIPOQ, PLIN1) cells, with distinct transcriptional responses to stimuli. By leveraging individual polygenic risk scores, we identified correlations between disease risk and shifts in cell state proportions. These states have been also mapped to metabolic disease relevant traits using single-cell heritability analysis, with body mass index highly enriched in AMSCs, whereas traits informative of metabolic health show strong enrichment in adipogenic cells and a subpopulation of SWAT cells. Furthermore, genome-wide eQTL mapping revealed hundreds of context- and state-specific eQTLs that were enriched in predicted gene-enhancer/promoter regions, linking these variants to their functional transcripts and chromatin accessibility. Conclusion: Collectively, the human adipocyte village approach coupled with single-nucleus functional genomics enabled the discovery of genetic mechanisms underlying metabolic diseases, highlighting its high potential as a tool in the development of effective therapeutic targets. (*Yi Huang and Joaquin Perez-Schindler contribute to this work equally) Disclosure Y. Huang: None. J. Perez-Schindler: None. S. Datta: None. B. Min: None. N. Nambrath: None. M. Murali: None. H. Dashti: None. B. Sharma: None. S. SinghPoma: None. P. Kubitz: None. W. Qiu: None. R. Andersson: None. T. Jones: None. M. Claussnitzer: None.

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