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Why breeding values estimated using familial data should not be used for genome-wide association studies.

ABSTRACT: In animal breeding, the genetic potential of an animal is summarized as its estimated breeding value, which is derived from its own performance as well as the performance of related individuals. Here, we illustrate why estimated breeding values are not suitable as a phenotype for genome-wide association studies. We simulated human-type and pig-type pedigrees with a range of quantitative trait loci (QTL) effects (0.5-3% of phenotypic variance) and heritabilities (0.3-0.8). We analyzed 1000 replicates of each scenario with four models: (a) a full mixed model including a polygenic effect, (b) a regression analysis using the residual of a mixed model as a trait score (so called GRAMMAR approach), (c) a regression analysis using the estimated breeding value as a trait score, and (d) a regression analysis that uses the raw phenotype as a trait score. We show that using breeding values as a trait score gives very high false-positive rates (up 14% in human pedigrees and >60% in pig pedigrees). Simulations based on a real pedigree show that additional generations of pedigree increase the type I error. Including the family relationship as a random effect provides the greatest power to detect QTL while controlling for type I error at the desired level and providing the most accurate estimates of the QTL effect. Both the use of residuals and the use of breeding values result in deflated estimates of the QTL effect. We derive the contributions of QTL effects to the breeding value and residual and show how this affects the estimates.

SUBMITTER: Ekine CC

PROVIDER: S-EPMC3931567 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Why breeding values estimated using familial data should not be used for genome-wide association studies.

Ekine Chinyere C CC Rowe Suzanne J SJ Bishop Stephen C SC de Koning Dirk-Jan DJ

G3 (Bethesda, Md.) 20140219 2

In animal breeding, the genetic potential of an animal is summarized as its estimated breeding value, which is derived from its own performance as well as the performance of related individuals. Here, we illustrate why estimated breeding values are not suitable as a phenotype for genome-wide association studies. We simulated human-type and pig-type pedigrees with a range of quantitative trait loci (QTL) effects (0.5-3% of phenotypic variance) and heritabilities (0.3-0.8). We analyzed 1000 replic ...[more]

PMID: 24362310

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Project description:BackgroundOur aim was to identify genomic regions via genome-wide association studies (GWAS) to improve the predictability of genetic merit in Holsteins for 10 calving and 28 body conformation traits. Animals were genotyped using the Illumina Bovine 50 K BeadChip and imputed to the Illumina BovineHD BeadChip (HD). GWAS were performed on 601,717 real and imputed single nucleotide polymorphism (SNP) genotypes using a single-SNP mixed linear model on 4841 Holstein bulls with breeding value predictions and followed by gene identification and in silico functional analyses. The association results were further validated using five scenarios with different numbers of SNPs.ResultsSeven hundred and eighty-two SNPs were significantly associated with calving performance at a genome-wise false discovery rate (FDR) of 5%. Most of these significant SNPs were on chromosomes 18 (71.9%), 17 (7.4%), 5 (6.8%) and 7 (2.4%) and mapped to 675 genes, among which 142 included at least one significant SNP and 532 were nearby one (100 kbp). For body conformation traits, 607 SNPs were significant at a genome-wise FDR of 5% and most of them were located on chromosomes 5 (30%), 18 (27%), 20 (13%), 6 (6%), 7 (5%), 14 (5%) and 13 (3%). SNP enrichment functional analyses for calving traits at a FDR of 1% suggested potential biological processes including musculoskeletal movement, meiotic cell cycle, oocyte maturation and skeletal muscle contraction. Furthermore, pathway analyses suggested potential pathways associated with calving performance traits including tight junction, oxytocin signaling, and MAPK signaling (P < 0.10). The prediction ability of the 1206 significant SNPs was between 78 and 83% of the prediction ability of the BovineSNP50 SNPs for calving performance traits and between 35 and 79% for body conformation traits.ConclusionsVarious SNPs that are significantly associated with calving performance are located within or nearby genes with potential roles in tight junction, oxytocin signaling, and MAPK signaling. Combining the significant SNPs or SNPs within or nearby gene(s) from the HD panel with the BovineSNP50 panel yielded a marginal increase in the accuracy of prediction of genomic estimated breeding values for all traits compared to the use of the BovineSNP50 panel alone.

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Why breeding values estimated using familial data should not be used for genome-wide association studies.

Publications

Why breeding values estimated using familial data should not be used for genome-wide association studies.

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