Disease & heat resistance

Uncovering genetic variants compromising heifer survival at calving in Holstein cattle through HHED analysis

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Abstract

Peri-calving mortality represents a major and costly source of loss in dairy cattle, however, putative deleterious variants remain undetected because of the lack of specificity of their effects. We combined life-history data with medium-density SNP genotypes and employed the Homozygous Haplotype Enrichment/Depletion (HHED) method to identify haplotypes and candidate causal variants associated with increased culling or mortality around first calving. Pedigree, fertility, and mortality records were extracted from the French national bovine database for Holstein. Cases were defined as heifers that either died or were culled within ±14 days around first calving, whereas controls consisted of cows that completed at least two full lactations. Genomic data were available for 411,302 females (9,382 cases and 401,920 controls), including 173,139 with both parents genotyped and 238,163 with the sire and maternal grandsire genotyped. The animals were genotyped using Illumina SNP arrays ranging from 7K to 777K markers. The genotypes were phased and imputed to the BovineSNP50 array using FImpute3. A total of 44,574 informative SNPs were used to compute sliding haplotypes of 20 markers (~1 Mb). In both cases and controls, the observed and expected numbers of homozygous haplotypes were estimated from phased genotypes and pedigree-based transmission probabilities. Only haplotypes with an expected count ≥5 were tested in cases and controls using χ² statistics. To mitigate the effects of population stratification, we retained signals that exhibited significant deviation between observed controls and cases, accounting for the number of haplotypes tested and the inflation observed in the control group. Five distinct haplotypes were identified, with −log₁₀(P) values ranging from 8 to 65.1. Survival analysis on all genotyped animals revealed an increased mortality at first calving for homozygous animals, indicating that these haplotypes likely increase susceptibility to metabolic or infectious disorders associated with parturition. The correlation between each haplotype and sequence variants was assessed in a panel of 1,169 bulls with whole-genome sequence data, including 247 Holsteins. Candidate variants were retained when R² > 0.5 and when VEP predicted a highly deleterious effect; each of the five haplotypes showed a strong candidate variant under these criteria. Importantly, these variants are at least partly tolerated during normal development, allowing homozygous animals to survive until the peripartum period of their first calving. Given the long and costly rearing period before culling, these defects have a particularly high economic impact. Classical methods, such as positional cloning or homozygous deficiency mapping, which rely on the clear presence or absence of homozygotes to detect deleterious alleles, may overlook these variants. By combining life-history records with genomic data, HHED detects these stress-dependent deleterious variants and supports improved management of recessive defects in breeding programs. This work was carried out as part of the Welcow project funded by APIS-GENE.

Keywords: 2026

How to Cite:

Barbat, A., Besnard, F., Boichard, D., Boussaha, M., Capitan, A., Escouflaire, C., Fritz, S., GROHS, C. & Minéry, S., (2026) “Uncovering genetic variants compromising heifer survival at calving in Holstein cattle through HHED analysis”, World Congress on Genetics Applied to Livestock Production Digital Archive 2026(1): 2286320. doi: https://doi.org/10.31274/wcgalp.23924

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