Meta-analysis of genome-wide association studies for litter size in sheep

Litter size and ovulation rate are important reproduction traits in sheep and have important impacts on the profitability of farm animals. To investigate the genetic architecture of litter size, we report the first meta-analysis of genome-wide association studies (GWAS) using 522 ewes and 564,377 SNPs from six sheep breeds. We identified 29 significant associations for litter size which 27 of which have not been reported in individual GWAS for each population. However, we could confirm the role of BMPR1B in prolificacy. Our gene set analysis discovered biological pathways related to cell signaling, communication, and adhesion. Functional clustering and enrichment using protein databases identified epidermal growth factor-like domain affecting litter size. Through analyzing protein-protein interaction data, we could identify hub genes like CASK, PLCB4, RPTOR, GRIA2, and PLCB1 that were enriched in most of the significant pathways. These genes have a role in cell proliferation, cell adhesion, cell growth and survival, and autophagy. Notably, identified SNPs were scattered on several different chromosomes implying different genetic mechanisms underlying variation of prolificacy in each breed. Given the different layers that make up the follicles and the need for communication and transfer of hormones and nutrients through these layers to the oocyte, the significance of pathways related to cell signaling and communication seems logical. Our results provide genetic insights into the litter size variation in different sheep breeds.