Introduction:Sheep reproductive traits are among the most important economic traits that directly determine production costs and economic benefits of sheep production. Ewes that produce more lambs per birth can increase the number of lambs and thus enhance economic efficiency. Therefore, identifying molecular markers that affect the birth rate in sheep is crucial. Reproductive function is one of the significant economic features in the sheep breeding industry. Litter size is the most important production trait among economic traits, accounting for 70-90% of the industry’s economic value. Due to the high economic importance of fertility and reproduction traits in sheep, genome-wide association studies (GWAS) have been frequently performed as a standard method for mapping QTL, discovering new single nucleotide polymorphisms (SNPs), and identifying candidate genes for economically important traits in animals. In this study, a GWAS analysis was performed to identify biological pathways and genes associated with the litter size trait in 12 sheep breeds. Materials and Methods:In this study, the litter size information of 12 sheep breeds was collected from various sources and articles. Based on the average litter size, these breeds were categorized into three groups: breeds with high litter size (2.52) (Finnsheep, Santa Ines, and Black Headed Mountain), five breeds with medium litter size (1.96) (Barbados Black Belly, Chinese Merino, Sakiz, Scottish Blackface, and Valais Blacknose Sheep), and four breeds with low litter size (1.17) (Cyprus Fat Tail, Karakas, Moghani, and Red Maasai). The data used in this research was genotypes from the 50K SNPChip belonging to the HapMap project were obtained from the study by Kijas et al. (Kijas et al., 2012). Genotype quality control (QC) was performed using PLINK v1.9 software (Purcell et al., 2007). SNPs with a missing genotype rate of more than 10%, MAF (minor allele frequency) less than 0.02, markers with a genotype loss rate of more than 2%, individuals with more than 1% missing genotypes, and SNPs that failed the Hardy-Weinberg Equilibrium (HWE) test at a significance level of 0.005 were excluded from the analysis. We ranked the genome-wide association studies (GWAS) for all breeds using Plink software based on their litter size percentage from highest to lowest. In the next step, to identify significant genes and biological pathways, the DAVID server version 6.8 was used. Results and Discussion:Based on the findings of the present study, pathways associated with the litter size trait were identified through candidate genes in the studied breeds. Further studies are necessary to validate these findings. The results highlight that a genome-wide association study conducted in these breeds revealed a panel of genes potentially linked to reproductive traits and litter size of interest. Specifically, GTF2A1,PHACTR1,KHDRBS3,SCMH1,FOXP1,ELMO1,KCNN3, BEST3, METTL14, PRDM2 and EFNA5 were identified as significant candidate genes. These genes may play roles in regulating the genetic architecture of twinning and litter size. This study underscores the genes associated with litter size traits and their involvement in pathways crucial for litter size and ovulation rate. The findings suggest that these candidate genes could influence the genetic basis of litter size and fertility. Despite limitations in data volume in the current study, it provides insights into the genetic mechanisms underlying birth rate and reproductive traits, potentially informing future sheep breeding programs. Conclusion:The current study revealed genes associated with litter size in sheep and pathways that play an important role in litter size and ovulation rates. Among these, the genes ATG5, NCKAP1L, CERK,AGPS,DCK, EPHA7,DOCK5,FOXN2,SOX6,PIGN, and ONECUT2 were introduced for the first time as effective genes in litter size in sheep. The results of this research can be used as a guide for sheep breeding programs and might lead to improvements in reproductive traits.

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