Population structure, including population stratification and cryptic relatedness, can cause spurious associations in genome-wide association studies (GWAS). Usually, the scaled median or mean test statistic for association calculated from multiple single-nucleotide-polymorphisms across the genome is used to assess such effects, and 'genomic control' can be applied subsequently to adjust test statistics at individual loci by a genomic inflation factor. Published GWAS have clearly shown that there are many loci underlying genetic variation for a wide range of complex diseases and traits, implying that a substantial proportion of the genome should show inflation of the test statistic. Here, we show by theory, simulation and analysis of data that in the absence of population structure and other technical artefacts, but in the presence of polygenic inheritance, substantial genomic inflation is expected. Its magnitude depends on sample size, heritability, linkage disequilibrium structure and the number of causal variants. Our predictions are consistent with empirical observations on height in independent samples of ~4000 and ~133,000 individuals.

Genomic inflation factors under polygenic inheritance

Body weight is an important economic trait for sheep and it is vital for their successful production and breeding. Therefore, identifying the genomic regions and biological pathways that contribute to understanding variability in body weight traits is significant for selection purposes. In this study, the genome-wide associations of birth, weaning, yearling, and adult weights of 460 fine-wool sheep were determined using resequencing technology. The results showed that 113 single nucleotide polymorphisms (SNPs) reached the genome-wide significance levels for the four body weight traits and 30 genes were annotated effectively, including AADACL3, VGF, NPC1, and SERPINA12. The genes annotated by these SNPs significantly enriched 78 gene ontology terms and 25 signaling pathways, and were found to mainly participate in skeletal muscle development and lipid metabolism. These genes can be used as candidate genes for body weight in sheep, and provide useful information for the production and genomic selection of Chinese fine-wool sheep.

https://www.mdpi.com/2076-2615/10/1/170/pdf

Genome-Wide Association Study of Body Weight Traits in Chinese Fine-Wool Sheep.

Sheep are considered as a major contributor of global food security. Moreover, sheep preweaning growth traits as well as in vivo carcass composition traits such as ultrasonic measurements of Longissimus dorsi muscle depth (UMD) and back-fat thickness (UFD) are crucially important indicators of meat yield and hot carcass composition. Despite their relative importance for productivity and profitability of a sheep production system, detected QTL for these traits are quite scarce. Therefore, we implemented GWAS for these traits using animal mixed model-based association approach provided by GenABEL in Esme sheep. Three genome-wide and 14 individual chromosome-wide associated SNPs were discovered. As a result, ESRP1, LOC105613082, ZNF641, DUSP5, TEAD1, SMOX, PTPRT, RALYL, POM121C, PHIP, LOC101106051, ZIM3, PEG3, TRPC7, FBXL4, LOC105610397, LOC105616489 and DNAAF2 were suggested as candidates. Some of the discovered genes and involved pathways were already annotated to contribute growth and development in various species including human, mice and cattle. All in all, the results of this study are expected to strongly contribute to shed a light on the underlying molecular mechanisms behind growth and carcass composition traits, with potential implications on studies aiming faster genetic improvement, targeted low-resolution SNP panel designs and genome-editing studies.

Genome-wide association studies of preweaning growth and in vivo carcass composition traits in Esme sheep

Qira black sheep is a famous indigenous sheep breed in China. The objectives of this study are to identify candidate genes related to body size, and to estimate the level of inbreeding depression on body size based on runs of homozygosity in Qira black sheep. Here, 188 adult Qira black sheep were genotyped with a high density (630 K) SNP chip and genome-wide association study for body weight and body size traits (including withers height, body slanting length, tail length, chest girth, chest width, and chest depth) were performed using an additive linear model. In consequence, 12 genome- and chromosome-wide significant SNPs and, accordingly, six candidate genes involved in muscle differentiation, metabolism and cell processes were identified. Of them, ZNF704 (zinc finger protein 704) was identified for body weight; AK2 (adenylate kinase 2) and PARK2 (parkin RBR E3 ubiquitin protein ligase) for tail length; MOCOS (molybdenum cofactor sulfurase) and ELP2 (elongator acetyltransferase complex subunit 2) for chest width; and MFAP1 (microfibril associated protein 1) for chest girth. Additionally, inbreeding depressions on body size were observed in the current herd. These results will provide insightful understandings into the genetic mechanisms of adult body size, and into the conservation and utilization of Qira black sheep.

Genome-wide association study and inbreeding depression on body size traits in Qira black sheep (Ovis aries)

Variants that regulate transcription, such as expression quantitative trait loci (eQTL), have shown enrichment in genome-wide association studies (GWAS) for mammalian complex traits. However, no study has reported eQTL in sheep, although it is an important agricultural species for which many GWAS of complex meat traits have been conducted. Using RNA sequence data produced from liver and muscle from 149 sheep and imputed whole-genome single nucleotide polymorphisms (SNPs), our aim was to dissect the genetic architecture of the transcriptome by associating sheep genotypes with three major molecular phenotypes including gene expression (geQTL), exon expression (eeQTL) and RNA splicing (sQTL). We also examined these three types of eQTL for their enrichment in GWAS of multi-meat traits and fatty acid profiles. Whereas a relatively small number of molecular phenotypes were significantly heritable (h2 > 0, P < 0.05), their mean heritability ranged from 0.67 to 0.73 for liver and from 0.71 to 0.77 for muscle. Association analysis between molecular phenotypes and SNPs within ± 1 Mb identified many significant cis-eQTL (false discovery rate, FDR < 0.01). The median distance between the eQTL and transcription start sites (TSS) ranged from 68 to 153 kb across the three eQTL types. The number of common variants between geQTL, eeQTL and sQTL within each tissue, and the number of common variants between liver and muscle within each eQTL type were all significantly (P < 0.05) larger than expected by chance. The identified eQTL were significantly (P < 0.05) enriched in GWAS hits associated with 56 carcass traits and fatty acid profiles. For example, several geQTL in muscle mapped to the FAM184B gene, hundreds of sQTL in liver and muscle mapped to the CAST gene, and hundreds of sQTL in liver mapped to the C6 gene. These three genes are associated with body composition or fatty acid profiles. We detected a large number of significant eQTL and found that the overlap of variants between eQTL types and tissues was prevalent. Many eQTL were also QTL for meat traits. Our study fills a gap in the knowledge on the regulatory variants and their role in complex traits for the sheep model.

/pdf/expression-quantitative-trait-loci-in-sheep-liver-and-muscle-3dg5s7hnk5.pdf

Expression quantitative trait loci in sheep liver and muscle contribute to variations in meat traits.

Abstract The aim was to study the effect of the threshold number on the accuracy of genomic evaluation of the threshold traits using support vector machine (SVM), genomic best linear unbiased prediction (GBLUP) and Bayesian method B (BayesB). For this purpose, a genome consisting of three chromosomes was simulated for 1000 individuals on which 3000 bi-allelic single nucleotide polymorphism markers were evenly distributed. Genomic breeding values were predicted in different scenarios of threshold number (1–6 thresholds), QTL number (30 and 300 QTLs) and heritability level (0.1, 0.3 and 0.5). By increasing the number of thresholds from 1 to 6 thresholds, especially at higher levels of heritability, the accuracy of genomic evaluation increased; however, the increase in accuracy was not linear so that it was much more noticeable when the number of thresholds increased from 1 to 2 thresholds. In the most studied scenarios, SVM showed a very poor performance compared to other methods. BayesB ranked first regarding prediction accuracy, though in some cases the observed differences with GBLUP was not significant. While increase in heritability increased the accuracy of genomic evaluation, change in the QTL number had a slight effect on the prediction accuracy. According to the results, the SVM is not recommended for genomic evaluation of threshold traits, especially those which have only one threshold and instead, use of GBLUP and BayesB is recommended. For traits with more than one threshold, fortunately we can achieve accuracy similar to continuous traits by applying traditional genomic evaluation methods. 

Genomic evaluation of threshold traits in different scenarios of threshold number using parametric and non-parametric statistical methods

Birth weight is the earliest available growth trait with considerable impacts on lamb survivability and growth performance traits. This study was conducted to perform a genome-wide association study of birth weight in a meat-type sheep. A total of 132 Lori-Bakhtiari sheep were selected based on estimated of breeding values (EBVs) for BW analyses. The selected animals were genotyped using Illumina Ovine SNP50 Bead Chip. After quality control, a total of 41 323 single-nucleotide polymorphisms (SNPs) and 130 sheep were used for subsequent analyses. Plink 1.90 beta software was used for the analyses. Seven SNPs on chromosomes 1, 16, 19 and 22 were detected based on genome-wide unadjusted P-values (P <10-6), which jointly accounted for 1.2% of total genetic variation. However, based on Bonferroni-adjusted P-values, only three SNPs on chromosome 1 had significant associations with EBVs for birth weight (P <0.05), which jointly explained 0.8% of total genetic variation. A total of seven genes were found in 50 kb intervals from the three significant SNPs on chromosome 1, but only three genes, including RAB6B (a member of RAS oncogene family), Tf serotransferrin and GIGYF2 (a GRB10 interacting GYF protein 2), could be considered as candidate genes for birth weight in future studies. The results of this study may facilitate potential use of the genes involving in growth and production traits for genetic improvement of productivity in sheep.

https://www.cambridge.org/core/services/aop-cambridge-core/content/view/A2DAD843614D595335F7C411A94A0B34/S1751731118003610a.pdf/div-class-title-genome-wide-association-study-of-birth-weight-in-sheep-div.pdf

Genome-wide association study of birth weight in sheep.

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Genomic evaluation of threshold traits in different scenarios of threshold number using parametric and non-parametric statistical methods

Genome-wide association study of birth weight in sheep.