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Although traditional genome-wide association studies (GWAS) are capable of localizing genetic variants associated with specific traits, they are insufficient to elucidate the underlying physiological mechanisms. An integrated analysis of multi-trait GWAS and multi-transcriptomic data systematically identifies key tissues and cell types influencing complex traits in beef cattle and elucidates their genetic regulatory basis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We systematically mapped tissue- and cell-type-specific regulatory architectures underlying 20 economically important traits in beef cattle. Tissue-level analyses revealed distinct trait-tissue associations: fatty acid traits, including C16:0 and C20:4, were enriched in liver; carcass traits, including marbling score and carcass weight, in renal cortex\/medulla and longissimus dorsi muscle; meat-quality traits such as pH in cartilaginous tissues; and total fat content in bone marrow. At cellular resolution, analysis of eight trait-associated tissues identified 38 discrete cell types. Myofibers were significantly associated with most carcass traits, including rib-eye area and backfat thickness, whereas hepatocytes emerged as key regulators of fatty acid and meat-quality traits, such as C16:0 and crude protein content. Transcription factor analysis identified cell-type-specific regulators: TBX15, SOX6, and TCF12 in myofibers; FOXA2 and NR1H4 in hepatocytes; and IRF8 and IKZF1 in microglia. Notably, hepatocytes and microglia showed complementary, trait-specific association patterns: hepatocytes were enriched for C16:0 associated saturated fatty-acid metabolic pathways, while microglia were enriched for C16:1 and unsaturated fatty-acid\u2013related pathways, suggesting potential cross-tissue coordination in lipid regulation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Our study links specific tissues and cell types to phenotypic variation in beef cattle and identifies core transcriptional regulators and pathways driving trait variation. These cell-resolved maps provide mechanistic insight into how genetic variation shapes economically important traits, offering a valuable resource for functional studies, cell-informed precision breeding strategies, and the design of large-scale molecular phenotyping.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s40104-026-01471-2","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T23:02:48Z","timestamp":1785193368000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Integrating bulk and single-cell RNA sequencing with GWAS reveals regulatory networks underpinning complex traits in beef cattle"],"prefix":"10.1186","volume":"17","author":[{"given":"Boyu","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shiyuan","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenwei","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hao","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingxiao","family":"Su","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anyi","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Binwu","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyang","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zezhao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lupei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijiang","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junya","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caihong","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"issue":"D1","key":"1471_CR1","doi-asserted-by":"publisher","first-page":"D956","DOI":"10.1093\/nar\/gkab1116","volume":"50","author":"ZL Hu","year":"2022","unstructured":"Hu ZL, Park CA, Reecy JM. 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