Multi-omics dissection of the genetic regulation underlying fatty acid composition in cattle.

BACKGROUND: Fatty acid composition is a complex trait governed by a polygenic architecture. Although numerous genetic variants associated with fatty acids have been identified through genome-wide association studies (GWAS), the underlying regulatory mechanisms remain incompletely understood. In this study, we employed a multi-omics approach to deeply dissect the genetic regulation of fatty acids in cattle. RESULTS: Our integrated multi-strategy GWAS framework identifies 118,697 candidate variants spanning 4,234 distinct genes associated with fatty acid compositions. Parallel expression quantitative trait locus analyses across 227 muscle and 116 adipose tissue samples reveal 673,478 significant variant-gene pairs. By integrating multi-omics datasets, including DNA methylation, histone modifications, and chromatin accessibility, we systematically annotate the regulatory landscape of fatty acid associated variants. This comprehensive analysis identifies genes, such as SCD and ACAA2, as key regulators of fatty acid synthesis and metabolism. We further characterize a regulatory variant, chr26:21,274,156, located within the same topologically associating domain as the SCD promoter and enhancer elements, potentially facilitating a 3D chromatin-mediated cis-regulation within the locus. Functional validation through dual-luciferase reporter assays and CRISPR/Cas9-mediated perturbation confirm that this variant enhances transcriptional activity and directly modulates fatty acid profiles. CONCLUSIONS: By integrating multi-omics profiles, this study provides new insights into the genetic regulation of fatty acid synthesis and metabolism. Our findings highlight target genes, regulatory elements, and functional variants that influence fatty acids, offering valuable targets for the genetic improvement of meat quality in livestock. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13059-025-03885-z.