Genomic Regions and Variant Analysis Reveal Candidate Genes Associated with Age at First Service in Chinese Holstein Heifers

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ABSTRACT Understanding the genetic basis and identifying quantitative trait loci (QTL) for age at first service (AFS) is essential for improving reproductive efficiency and reducing economic costs in heifers rearing. We conducted a genome-wide association study (GWAS) for AFS using the genomic estimated breeding values (GEBVs) of 3,686 Chinese Holstein heifers, genotyped with 7,964,217 single nucleotide polymorphisms (SNPs) after quality control. Significant SNPs and candidate genes were identified and investigated through colocalization analysis of GWAS, expression QTL (eQTL), and splicing QTL (sQTL), and expression analysis in blood RNA sequencing (RNA-seq). The heritability estimate for AFS was moderate at 0.276 ±0.025. Three QTL regions associated with AFS were identified: Region 1 on BTA6 (43688837-45007127 bp, 1.3 Mb with three 200kb windows), explaining 0.47% of genetic variance; Region 2 on BTA6 (62770788-62967316 bp) explaining 0.27% of the genetic variance; and Region 3 on BTA18 (6299721-6498934 bp) explaining 0.17% of the genetic variance. Combining GWAS and colocalization analysis, we identified ANAPC4, RBPJ, SEPSECS, SLC34A2, ZCCHC4 , CCDC149, GNPDA2, GUF1, DHX15, SOD3, GUF1 and GNPDA2 as candidate genes. These genes are enriched in signaling pathways such as progesterone-mediated oocyte maturation, parathyroid hormone synthesis, secretion and action, and selenocompound metabolism. ANAPC4, DHX15, GUF1, SEPSECS , and SOD3 were also differently expressed genes (DEGs) in blood RNA-seq. Integrating the GWAS, colocalization, differential expression analysis, and existing literature, ANAPC4 and rs136363104 were highlighted as the putative causal gene and variant for puberty, respectively. In conclusion, our study identified three candidate regions and 12 candidate genes, confirming ANAPC4 as a putative causal gene influencing AFS. This research enhances the understanding of the genetic basis of AFS in Chinese Holstein heifers. The identified key genomic regions, candidate genes, and variants have the potential to improve reproductive efficiency and reduce economic costs in heifer rearing. Interpretative summary The economic burden of heifer-raising and reproductive inefficiency in dairy cattle is evident. The most important strategy for optimizing heifer-raising is selecting heifers with earlier puberty (sexual maturity) to shorten age at first service (AFS). In this study, we have identified key genomic regions and candidate genes on AFS in Chinese Holstein heifers by genome-wide association study, and validated them by colocalization and RNA-seq analysis. The findings have the potential to enhance the understanding of the genetic basis of reproductive traits, leading to more targeted breeding strategies for improved reproductive efficiency.

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