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Genome-Wide Associations and Detection of Potential Candidate Yin and König Genet Sel Evol (2019) 51:4 https://doi.org/10.1186/s12711-018-0444-4 Genetics Selection Evolution RESEARCH ARTICLE Open Access Genome-wide associations and detection of potential candidate genes for direct genetic and maternal genetic efects infuencing dairy cattle body weight at diferent ages Tong Yin and Sven König* Abstract Background: Body weight (BW) at diferent ages are of increasing importance in dairy cattle breeding schemes, because of their strong correlation with energy efciency traits, and their impact on cow health, longevity and farm economy. In total, 15,921 dairy cattle from 56 large-scale test-herds with BW records were genotyped for 45,613 single nucleotide polymorphisms (SNPs). This dataset was used for genome-wide association studies (GWAS), in order to localize potential candidate genes for direct and maternal genetic efects on BW recorded at birth (BW0), at 2 to 3 months of age (BW23), and at 13 to 14 months of age (BW1314). Results: The frst 20 principal components (PC) of the genomic relationship matrix ( G ) grouped the genotyped cattle into three clusters. In the statistical models used for GWAS, correction for population structure was done by including polygenic efects with various genetic similarity matrices, such as the pedigree-based relationship matrix ( A ), the G -matrix, the reduced G-matrix LOCO (i.e. exclusion of the chromosome on which the candidate SNP is located), and LOCO plus chromosome-wide PC. Infation factors for direct genetic efects using A and LOCO were larger than 1.17. For G and LOCO plus chromosome-wide PC, infation factors were very close to 1.0. According to Bonferroni correc- tion, ten, two and seven signifcant SNPs were detected for the direct genetic efect on BW0, BW23, and BW1314, respectively. Seventy-six candidate genes contributed to direct genetic efects on BW with four involved in growth and developmental processes: FGF6, FGF23, TNNT3, and OMD. For maternal genetic efects on BW0, only three signif- cant SNPs (according to Bonferroni correction), and four potential candidate genes, were identifed. The most signif- cant SNP on chromosome 19 explained only 0.14% of the maternal de-regressed proof variance for BW0. Conclusions: For correction of population structure in GWAS, we suggest a statistical model that considers LOCO plus chromosome-wide PC. Regarding direct genetic efects, several SNPs had a signifcant efect on BW at diferent ages, and only two SNPs on chromosome 5 had a signifcant efect on all three BW traits. Thus, diferent potential candidate genes regulate BW at diferent ages. Maternal genetic efects followed an infnitesimal model. Background dairy cows to produce more milk for a given feed con- Some countries with pasture-based production systems sumption [6]. Diferent traits are defned to measure consider dairy cow live weight in overall breeding goals or feed efciency, e.g. the ratio of milk to body weight, in selection indices [1, 2]. Positive genetic correlations of feed intake, residual feed intake [7], and feed saved [8]. body weight (BW) with milk yield and protein yield have Most of these defnitions imply that BW or changes in been reported [3–5]. Feed efciency refects the ability of BW are taken into account. Moreover, dry matter intake and energy balances are favourably correlated with BW *Correspondence: [email protected] [3]. In addition, BW infuences dairy cow fertility and Institute of Animal Breeding and Genetics, Justus-Liebig-University health. For example, survival of new-born calves and Gießen, Ludwigstr. 21b, 35390 Giessen, Germany calving ease are moderately correlated with birth weight © The Author(s) 2019. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creat iveco mmons .org/licen ses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creat iveco mmons .org/ publi cdoma in/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yin and König Genet Sel Evol (2019) 51:4 Page 2 of 14 of calves and BW of cows [9]. Berry et al. [5] reported proofs for direct genetic and maternal genetic efects on that heavier cows had a shorter interval between calv- BW at diferent ages; (2) to correct for population stratif- ing and frst service, but conception rates decreased with cation in GWAS when using pedigree-based or genomic increasing BW. In contrast, in heifers, increasing BW was relationship matrices, or a combination of relationship associated with improved non-return rates after 56 and matrices with principal components; (3) to infer (co)vari- 90 days [4]. Hence, we hypothesize that diferent genes ance components for/between direct genetic and mater- are involved in BW at diferent ages, as indicated in quan- nal genetic efects on diferent scales (pedigree-based titative genetic studies via random regression models [4]. genetic parameters, whole genome, and single chromo- On the genomic scale, GWAS for BW or BW indicators somes); and (4) to identify associated potential candidate have considered only one time point per animal [10–12]. genes for direct genetic and maternal genetic efects. Zhang et al. [12] analysed longitudinal BW records in cat- tle at 6, 12, 18 and 24 months of age, but BW was predicted Methods from measurements for heart girth and hip height. Te Phenotype data aforementioned publications focussed only on the esti- Body weight records at birth (BW0), 2 to 3 months of mation of direct additive genetic efects on BW. However, age (BW23), and 13 to 14 months of age (BW1314) were especially in early life, BW should be separated into direct available for 250,173, 42,632 and 54,768 female animals, genetic and maternal genetic efects [13]. Dams with high respectively. Te number of animals with phenotypic breeding values for maternal ability provide an improved records at all three age intervals was 15,234. Animals nourishing environment, with an associated positive were born between 2004 and 2016, and kept in 56 large- impact on survival rates and birth weight in ofspring. For scale dairy cattle test-herds, which were located in the a deeper understanding of the mechanisms between direct German federal states of Mecklenburg-Westpommer- and maternal efects, it is imperative to detect the func- ania and Berlin-Brandenburg. For the 250,173 calves, tional segments of the genome that contribute to maternal the gestation length of their dams ranged from 265 to genetic efects on BW, and to study direct-maternal asso- 295 days (average: 279.4 days). For BW0, we discarded ciations on the genomic scale. To date, only a few studies birth weights above 60 kg or below 20 kg. For the detec- [14–16] have addressed such topics. tion of outlier data for BW23 and BW1314, we followed Te power of GWAS contributes to the detection of the approach by Yin et al. [4] and calculated studentized signifcant markers, and, furthermore, has an impact residuals and corresponding Bonferroni p values (using on the identifcation of associated potential candidate the outlier test function in the R package “car” [23]). genes. Linkage disequilibrium (LD) is one of the param- Records were excluded from further analyses when p val- eters that afects the power of GWAS. Te use of a dense ues were lower than 0.05 or higher than 0.95. Te pedi- 50 K single nucleotide polymorphism (SNP) chip implies gree fle included 411,943 animals, born between 1948 that it contains markers that are closely located to the and 2016. functional mutation and contribute to acceptable LD between markers and causal loci [17]. Body weight is a Genotype data trait with a moderate to high pedigree-based heritability Among the Holstein cattle with BW records, 13,827 [4, 5, 18], which is favourable for the detection of QTL. calves with BW0 records, 4246 calves with BW23 Furthermore, currently, the trend is to use large numbers records, and 7920 heifers with BW1314 records, were of female observations for the estimation of SNP efects, genotyped. Genotyping was performed using the Illu- which contributes to an increasing number of phenotypic mina Bovine 50 K SNP BeadChip V2 (4120 animals), or records for GWAS [19], with a positive impact on the the Illumina Bovine Eurogenomics 10 K low-density chip statistical power for the detection of SNP efects. Non- (11,801 animals). Animals with low-density genotypes causative rare alleles with high frequencies in large half- were imputed to the 50 K chip (according to the routine sib daughter groups might contribute to false positive procedure for ofcial national genetic evaluations [24]). signals in GWAS. Usually, the frst principal components Finally, for all the genotyped cattle, 45,613 SNPs were and similarity matrices can be considered in statistical available that had a call rate higher than 95%, a minor modelling to correct for population stratifcation [20]. In allele frequency higher than 0.01, and did not deviate sig- dairy cattle breeding, deep pedigree information is avail- nifcantly from Hardy–Weinberg equilibrium (p > 0.001). able, which enables the use of mixed models for GWAS Only SNPs located on Bos taurus autosomes (BTA) were with random polygenic efects based on pedigree [21] or considered. Furthermore, we discarded animals with on genomic relationship matrices [22]. more than 95% identical genotypes. Quality control of Consequently, the objectives of our study were: (1) SNP data was done by using the GenABEL package in R to perform GWAS using phenotypes and de-regressed [25].
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