Population-scale single-nucleus multi-omic profiling of skeletal muscle reveals extensive context-specific genetic regulation
Open accessAbstract
Skeletal muscle tissue underlies several polygenic metabolic traits and diseases. Identifying their genetic mechanisms requires pinpointing cell types, regulatory elements, target genes and causal variants. Here we use genetic multiplexing to generate population-scale single-nucleus chromatin accessibility (single-nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq)) and transcriptome (single-nucleus RNA sequencing (snRNA-seq)) maps across 287 frozen human skeletal muscle biopsies. We identify 13 cell types and integrate genetic variation to discover >7,000 expression quantitative trait loci (eQTLs) and >100,000 chromatin accessibility QTLs (caQTLs) across cell types, including context-specific eQTL/caQTL with significant G × C interaction. We identify nearly 2,000 eGenes colocalized with caQTL and construct causal directional maps for chromatin accessibility and gene expression. Almost 3,500 genome-wide association study (GWAS) signals across 38 relevant traits colocalize with sn-eQTL/caQTL, most in a cell-specific manner. These signals typically colocalize with caQTL and not eQTL, highlighting the importance of population-scale chromatin profiling for GWAS functional studies. The results of this study illuminate the genetic regulatory architecture of human skeletal muscle.
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- Authors
- Varshney, A., Manickam, N., Orchard, P., Tovar, A., Ventresca, C., Zhang, Z., Feng, F., Mears, J., Erdos, M. R., Narisu, N., Nishino, K., Rai, V., Stringham, H. M., Jackson, A. U., Tamsen, T., Gao, C., Yang, M., Koues, O. I., Welch, J. D., Burant, C. F., Williams, L. K., Jenkinson, C., DeFronzo, R. A., Norton, L., Saramies, J., Lakka, T. A., Laakso, M., Tuomilehto, J., Mohlke, K. L., Kitzman, J. O., Koistinen, H. A., Liu, J., Boehnke, M., Collins, F. S., Scott, L. J., & Parker, S. C. J.
- Affiliations
- University of Michigan (US)
- National Institutes of Health (US)
- Henry Ford Health (US)
- The University of Texas Rio Grande Valley (US)
- The University of Texas at San Antonio Health Science Center (US)
- Etelä-Karjalan sosiaali ja terveyspiiri (FI)
- University of Eastern Finland (FI)
- University of Helsinki (FI)
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Parker, Stephen C. J.
- ORCID
- Varshney, Arushi
- Manickam, Nandini
- Orchard, Peter
- Ventresca, Christa
- Feng, Fan
- Erdos, Michael R.
- Narisu, Narisu
- Stringham, Heather M.
- Jackson, Anne U.
- Gao, Chao
- Welch, Joshua D.
- DeFronzo, Ralph A.
- Lakka, Timo A.
- Laakso, Markku
- Mohlke, Karen L.
- Kitzman, Jacob O.
- Koistinen, Heikki A.
- Boehnke, Michael
- Collins, Francis S.
- Scott, Laura J.
- Parker, Stephen C. J.
- Venue
- Nature Genetics
- Published
- 2026-10-28
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W4393524305
- Cited by
- 0
- References
- 0
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Licence
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Zenodo (CERN European Organization for Nuclear Research) (cc-by)
- Funders
- U.S. Department of Health & Human Services | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (R01DK117960, UM1DK126185)
- U.S. Department of Health & Human Services | NIH | National Institute of Arthritis and Musculoskeletal and Skin Diseases (P30AR069620)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- skeletal muscle, single-nucleus multiomics, single-nucleus RNA sequencing, single-nucleus ATAC-seq, cell type-specific gene expression, cis-eQTL, genetic control, muscle fiber type
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