Sequenced-based GWAS for linear classification traits in Belgian Blue beef cattle reveals new coding variants in genes regulating body size in mammals

Abstract

Cohorts of individuals that have been genotyped and phenotyped for genomic selection programs offer the opportunity to better understand genetic variation associated with complex traits. Here, we perform an association study for traits related to body size and muscular development in intensively selected beef cattle. We leveraged multiple trait information to refine and interpret the significant associations. After a multiple-step genotype imputation to the sequence-level for 14,762 Belgian Blue beef (BBB) cattle cows, we performed a GWAS for 11 traits related to muscular development and body size. The 37 identified genome-wide significant QTL could be condensed in 11 unique QTL regions based on their position. There was evidence for pleiotropic effects in most of these regions (e.g., correlated association signals, overlap between credible sets of candidate variants - CSCV). We consequently applied a multiple-trait approach to combine information from different traits to refine the CSCV. In several QTL regions, we identified strong candidate genes known to be related to growth and height in other species such as LCORL-NCAPG or CCND2. For some of these genes, relevant candidate variants were identified in the CSCV, including three new missense variants in EZH2, PAPPA2 and ADAM12, possibly two additional coding variants in LCORL, and candidate regulatory variants linked to CCND2 and ARMC12. Strikingly, four other QTL regions were related to five (recessive) deleterious coding variants previously identified. Heterozygotes for several of these mutations have favorable effects for muscular development traits. Our study further supports that a set of common genes controls body size across mammalian species. In particular, we added new genes to the list of those associated with height in both human and cattle. We also identified new strong candidate causing variants in some of those genes, strengthening the evidence of the causality of these genes. Several breed-specific recessive deleterious variants were identified in our QTL regions, probably as a result of the extreme selection for muscular development in BBB cattle.