(1) Background: Litter size traits are critical for pig breeding efficiency but pose challenges due to low heritability and sex-limited influences. This study aimed to elucidate the genetic architecture and identify candidate genes for these traits in Large White pigs using genomic selection (GS) and genome-wide association analyses (GWAS). (2) Methods: This study utilized phenotypic data from nine litter size traits in Large White sows. Genotyping-by-sequencing (GBS) was performed to obtain genotype data, retaining 153,782 high-quality SNPs after quality control. Genetic evaluation was conducted using single-step genomic best linear unbiased prediction (ssGBLUP), with genetic parameters (heritability and genetic correlations) estimated via an animal model (repeatability model). To assess prediction accuracy, 10-fold cross-validation was employed to compare traditional BLUP with ssGBLUP. Furthermore, a single-step genome-wide association study (ssGWAS) integrated genomic information and pedigree-based relationship matrices to screen for significant SNPs associated with litter size traits across the genome. Functional analysis of key candidate genes was subsequently conducted based on ssGWAS results. (3) Results: Heritabilities for litter traits ranged from 0.01 to 0.06. ssGBLUP improved genomic prediction accuracy by 6.38–13.33% over BLUP. Six genomic windows explaining 1.07–1.77% of genetic variance were identified via ssGWAS, highlighting GPR12 on SSC11 as a key candidate gene linked to oocyte development. (4) Conclusions: This study demonstrates the efficacy of ssGBLUP for low-heritability traits and identifies GPR12 as a pivotal gene for litter size. Prioritizing NHB and LBWT in breeding programs could enhance genetic gains while mitigating adverse effects on piglet health. These findings advance genomic strategies for improving reproductive efficiency in swine.

(1) Background: Reproductive performance is crucial for the pork industry’s success. The Large White pig is central to this, yet the genetic factors influencing its reproductive traits are not well understood, highlighting the need for further research. (2) Methods: This study utilized Genome-Wide Association Studies to explore the genetic basis of reproductive traits in the Large White pig. We collected data from 2237 Large White sows across four breeding herds in southern China, focusing on eight reproductive traits. Statistical analyses included principal component analysis, linkage disequilibrium analysis, and univariate linear mixed models to identify significant single-nucleotide polymorphisms and candidate genes. (3) Results: Forty-five significantly related SNPs and 17 potential candidate genes associated with litter traits were identified. Individuals with the TT genotype at SNP rs341909772 showed an increase of 1.24 in the number of piglets born alive (NBA) and 1.25 in the number of healthy births (NHBs) compared with those with the CC genotype. (4) Conclusions: The SNPs and genes identified in this study offer insights into the genetics of reproductive traits in the Large White pig, potentially guiding the development of breeding strategies to improve litter size.