Fine-mapping causal variants from genome-wide association studies (GWAS) loci is challenging in populations with substantial relatedness, such as livestock, as standard methods often assume unrelatedness, leading to poor fine-mapping accuracy. Here, we introduce a comprehensive Bayesian framework to address this. Our approach features BFMAP-Shotgun Stochastic Search for individual-level data, which uses a linear mixed model (LMM) and shotgun stochastic search with simulated annealing. For summary statistics, we develop FINEMAP-adj and SuSiE-adj, novel strategies that directly use standard FINEMAP and SuSiE for samples of related individuals by employing LMM-derived inputs (particularly a relatedness-adjusted linkage disequilibrium matrix). Furthermore, genomic-feature posterior inclusion probability (PIP), implemented here as gene-level PIP (PIPgene), is proposed to enhance detection power by aggregating variant signals. Extensive simulations based on pig genotypes across diverse heritability levels and population structures (pure-breed and multi-breed) show our methods substantially outperform existing tools (FINEMAP, SuSiE, FINEMAP-inf, SuSiE-inf, and GCTA-COJO) in samples of related individuals, achieving notable improvements in fine-mapping accuracy (e.g. up to several-fold increases in the area under the precision-recall curve). Multi-breed populations greatly enhance fine-mapping accuracy compared to single-breed populations. Additionally, PIPgene markedly improves candidate gene identification. Application to Duroc pig traits demonstrates practical utility, with functional enrichment analysis confirming our methods' superior identification of biologically relevant variants. This work provides robust, validated methods and associated software for accurate fine-mapping in populations with complex relatedness.

MOTIVATION: The amount of genomic data is increasing exponentially. Using many genotyped and phenotyped individuals for genomic prediction is appealing yet challenging. RESULTS: We present SLEMM (short for Stochastic-Lanczos-Expedited Mixed Models), a new software tool, to address the computational challenge. SLEMM builds on an efficient implementation of the stochastic Lanczos algorithm for REML in a framework of mixed models. We further implement SNP weighting in SLEMM to improve its predictions. Extensive analyses on seven public datasets, covering 19 polygenic traits in three plant and three livestock species, showed that SLEMM with SNP weighting had overall the best predictive ability among a variety of genomic prediction methods including GCTA's empirical BLUP, BayesR, KAML, and LDAK's BOLT and BayesR models. We also compared the methods using nine dairy traits of ∼300k genotyped cows. All had overall similar prediction accuracies, except that KAML failed to process the data. Additional simulation analyses on up to 3 million individuals and 1 million SNPs showed that SLEMM was advantageous over counterparts as for computational performance. Overall, SLEMM can do million-scale genomic predictions with an accuracy comparable to BayesR. AVAILABILITY AND IMPLEMENTATION: The software is available at https://github.com/jiang18/slemm.