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. 2025 Jul 3:16:1600587.
doi: 10.3389/fgene.2025.1600587. eCollection 2025.

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 Lewis  3 , Artur O Rocha  2 , Brad A Freking  4 , Tom W Murphy  4 , Carrie S Wilson  5 , Sara M Nilson  3 , Joan M Burke  6 , Luiz F Brito  2
Affiliations

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 et al. Front Genet. .

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.

Keywords: genes; genome-wide associate study; lifespan; longevity; ovine; productive life.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.

Figures

FIGURE 1
FIGURE 1
Manhattan and Q–Q plots of the genome-wide association analysis for age at last lambing (ALL) and length of productive life (LPL) in U.S. Katahdin sheep. The significant SNP at the chromosome-wide threshold are highlighted in green. The horizontal red line indicates the significance of the genome-wide threshold.
FIGURE 2
FIGURE 2
Manhattan and Q–Q plots of the genome-wide association analysis for total number of litters (TNL), lambs born (TNB), and lambs weaned (TNW) over ewe lifetime in U.S. Katahdin sheep. The significant SNP at the chromosome-wide threshold are highlighted in green. The horizontal red line indicates the significance of the genome-wide threshold.
FIGURE 3
FIGURE 3
Manhattan and Q–Q plots of the genome-wide association analysis for total lamb weight at birth (TLB), total lamb weight at weaning (TLW), and total lamb weight at weaning divided by the ewe’s post-weaning weight (TLWadj) in U.S. Katahdin sheep. The significant SNP at the chromosome-wide threshold are highlighted in green. The horizontal red line indicates the significance of the genome-wide threshold.
FIGURE 4
FIGURE 4
Protein–protein network interaction and color legends.
See this image and copyright information in PMC

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