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

Authors: PINTO, LUIS - Federal University Of Bahia (UFBA); LEWIS, RON - University Of Nebraska; ROCHA, ARTUR - Purdue University; Freking, Bradley; Murphy Jr, Thomas; Wilson, Carrie; NILSON, SARA - University Of Nebraska; Burke, Joan; BRITO, LUIZ - Purdue University

Submitted to: Frontiers in Livestock Genomics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/16/2025
Publication Date: 7/3/2025
Citation: Pinto, L.F.B., Lewis, R.M., Rocha, A.O., Freking, B.A., Murphy, T.W., Wilson, C.S., Nilson, S.M., Burke, J.M., Brito, L.F. 2025. Genome-wide association and functional annotation analyses reveal candidate genes and pathways associated with various ewe longevity indicators in U.S. Katahdin sheep. Frontiers in Livestock Genomics. 16. Article 1600587. https://doi.org/10.3389/fgene.2025.1600587.
DOI: https://doi.org/10.3389/fgene.2025.1600587

Interpretive Summary: Ewe longevity is a key economic driver within most sheep production systems since over 40% of all ewes in the U.S. are culled before age actually becomes a detriment to productivity. The genetic basis for ewe longevity is a poorly understood topic in sheep. Direct genetic improvement is restricted by the fact longevity is measured only in females and also at a very late time point in life. Genomic analysis for ewe longevity traits provides a potential breakthrough for selection by sheep breeders. We report results from the largest genome wide association study conducted in the U.S. Katahdin breed for eight indicator traits of longevity using datasets provided by the National Sheep Improvement Program (NSIP) and recorded by U.S. Katahdin producers on12,734 Katahdin ewes. The most significant genetic association generated by this analysis was from a location on chromosome 4 which was associated with three indicator traits of longevity. An additional 126 associations throughout the rest of genome were identified at a lower level of statistical support which indicated the sheep genome contains many different genes with each contributing relatively small effects for these traits. Our results suggested that candidate genes to improve ewe longevity may also be associated with a wide range of genetic influences ranging from those impacting prolificacy, to responses associated with stress or disease. This novel information together suggests that Katahdin ewe longevity depends on a complex combination of voluntary and involuntary culling reasons and those genetic mechanisms revealed in this association analysis will require further study.

Technical Abstract: Ewe longevity indicators are complex traits that are lowly heritable, expressed late in life, and sex-limited, making them challenging to include in breeding programs. In this context, genome-wide association studies (GWASs) can provide more information on the complex genetic control of these traits. Therefore, the primary objective of this study was to carry out association analyses for 8 longevity-related traits in 12,734 Katahdin ewes. A total of 126 associations at the chromosome-wide level and 3 at genome-wide level were found. These associations involved 86 single-nucleotide polymorphisms (SNPs) located across 22 chromosomes, with 24 of these SNPs associated with two or more traits. The variants overlapped with genes previously associated with prolificacy (APOH, NLRP9, H3PXD2A, CKB, and HERC4), ovarian follicle pool (GALNT13, TMEM150B, and BRSK1), synthesis and release of reproductive hormones (SULT1B1, LEF1, and EIF5), and early pregnancy events (ITGAV, HADH, ZNFX1, ZSCAN4, EPN1, FBXW8, NOS1, ST3GAL4, and GFRA1). Moreover, genes related to response to stress or pathological conditions (ADCY5, HADH, ATRNL1, LEP, IL11, NLRP9, PRKCG, PRKCA, NEDD4L, FECH, CTNNA3, HECTD1, LRRTM3, and zinc-finger proteins), growth performance (GRID2, MED13L, DCPS, and LEP), and carcass traits (CMYA5 and SETD3) were also implicated. Metabolic pathways such as oxytocin signaling and cardiac-related 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 play a key role in the functional longevity of Katahdin ewes.