J. Jiang1, P.M. VanRaden2, J.B. Cole2, and L. Ma1
1Department of Animal and Avian Sciences, University of Maryland, College Park, Maryland 20742, USA
2Animal Genomics and Improvement Laboratory, USDA, Building 5, Beltsville, Maryland, 20705, USA
2018 PLoS Genetics. (?)
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Imputation has been routinely applied to ascertain sequence variants in large genotyped populations based on reference populations of sequenced individuals. With increasing numbers of animals sequenced and the implementation of the 1000 Bull Genomes Project, fine-mapping of causal variants for complex traits is becoming possible in cattle. After quality control and LD pruning, we imputed 3 million selected sequence variants to over 27,000 Holstein bulls. These bulls were selected to have highly reliable phenotype (breeding values) for 35 production, reproduction, and body conformation traits. We first performed whole-genome single-marker scan for the 35 traits using the mixed-model based association tests. The single-trait association statistics were then merged into multi-trait analyses of 3 groups of traits, production, reproduction, and body conformation, respectively. Both single- and multi-trait GWAS results were used to pick 2-Mb candidate genomic regions for fine-mapping studies. We developed a fast Bayesian Fine-MAPping approach (BFMAP) to fine-map the candidate genomic regions to single-gene resolution and to integrate fine-mapping with functional enrichment analysis. Our fine-mapping identified many promising candidate genes for dairy traits, including ABCC9 VPS13B, MGST1, SCD, MKL1, CSN1S1 for production traits, CHEK2, GC, KALRN for reproduction traits, and TMTC2, ARRDC3, ZNF613, CCND2, FGF6 for body conformation traits. Based on existing functional annotation data available for the cattle genome, we revealed biologically meaningful enrichment in our fine-mapped variants that can be readily tested for future functional validation. Collectively, we developed a fast Bayesian approach for fine-mapping and enrichment analysis, generated a list of candidate genes and variants of complex traits for functional studies, and expanded our understanding of the genetic basis of complex traits in dairy cattle