Genome-Wide Association Studies on Litter Size in Sheep: A Systematic Review and Gene Prioritization Analysis

Sheep litter size is of major economic importance, yet its polygenic nature and low heritability limit the effectiveness of traditional selection methods. Following PRISMA guidelines, this systematic review integrated genome-wide association study (GWAS) evidence for sheep litter size and prioritized candidate genes. Four databases were searched, yielding 24 eligible studies comprising a total effective analytical sample of 7618 animals from 98 breeds/populations across nine countries. Following standardized re-annotation of genomic coordinates, 245 significant variations and 316 candidate genes were extracted. Gene prioritization using ToppGene identified 96 high-priority genes, including 10 core genes: GRIN2A, DLG2, FLT4, ESR2, AMH, ALK, INHBB, NF1, CAMK2D, and ERCC2. These genes collectively operate through four functional axes: the gonadal axis regulation, follicular development, hormonal signal transduction, and DNA damage repair. Functional enrichment analysis revealed significant involvement in protein binding and metal ion binding. Marked breed-specificity was observed, with only the BMPR1B (FecB) locus replicated across three studies. Key limitations include restriction to English-language publications, small median sample sizes in the included studies, and the inherent bias of ToppGene training genes toward previously reported loci. These findings clarify the molecular genetic architecture of sheep litter size and provide a validated candidate gene framework to support precision genomic breeding strategies.