Genome-wide association and functional annotation analyses reveal candidate genes and pathways associated with various ewe longevity indicators in U.S. Katahdin sheep

Luis F B Pinto^1,2*Ronald M Lewis³Artur O Rocha²Brad A Freking⁴Tom W Murphy⁴Carrie S Wilson⁵Sara M Nilson³Joan M Burke⁶Luiz F Brito²

• ¹Federal University of Bahia (UFBA), Salvador, Brazil
• ²Purdue University, West Lafayette, Indiana, United States
• ³University of Nebraska-Lincoln, Lincoln, Nebraska, United States
• ⁴U.S. Meat Animal Research Center, Agricultural Research Service (USDA), Clay Center, Nebraska, United States
• ⁵Range Sheep Production Efficiency Research Unit, Agricultural Research Service (USDA), Dubois, Idaho, United States
• ⁶Dale Bumpers Small Farms Research Center, Agricultural Research Service (USDA), Booneville, Arizona, United States

Ewe longevity indicators are complex traits that are lowly heritable, expressed late in life, and sex-limited, which makes them a challenge to include in breeding programs. In this context, genome-wide association studies can provide more information about the complex genetic control of these traits. Therefore, the primary objective of this study was to carry out association analyses for eight longevity-related traits in 12,734 Katahdin ewes. A total of 126 associations at the chromosome-wide level and three at genome-wide level were found. These associations involved 86 single nucleotide polymorphisms (SNP) located across 22 chromosomes, and 24 of these SNP were associated with two or more traits. The variants overlap with genes previously associated with prolificacy (APOH, NLRP9, H3PXD2A, CKB, HERC4), ovarian follicle pool (GALNT13, TMEM150B, BRSK1), synthesis and release of reproductive hormones (SULT1B1, LEF1, EIF5), and early pregnancy events (ITGAV, HADH, ZNFX1, ZSCAN4, EPN1, FBXW8, NOS1, ST3GAL4, GFRA1). Moreover, genes related to response to stress or pathological conditions (ADCY5, HADH, ATRNL1, LEP, IL11, NLRP9, PRKCG, PRKCA, NEDD4L, FECH, CTNNA3, HECTD1, LRRTM3, Zinc-finger proteins), growth performance (GRID2, MED13L, DCPS, LEP), and carcass traits (CMYA5, SETD3) were also implicated by association. Metabolic pathways such as oxytocin signaling and cardiac pathways were enriched. These findings suggest that longevity indicators in Katahdin ewes are highly polygenic traits influenced by a combination of voluntary and involuntary culling reasons. Candidate genes and metabolic pathways influencing reproductive performance and health may have a key role in Katahdin ewe functional longevity.