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Inferring quantitative trait pathways associated with bull fertility from a genome-wide association study.

ABSTRACT: Whole-genome association studies typically focus on genetic markers with the strongest evidence of association. However, single markers often explain only a small component of the genetic variance and hence offer a limited understanding of the trait under study. As such, the objective of this study was to perform a pathway-based association analysis in Holstein dairy cattle in order to identify relevant pathways involved in bull fertility. The results of a single-marker association analysis, using 1,755 bulls with sire conception rate data and genotypes for 38,650 single nucleotide polymorphisms (SNPs), were used in this study. A total of 16,819 annotated genes, including 2,767 significantly associated with bull fertility, were used to interrogate a total of 662 Gene Ontology (GO) terms and 248 InterPro (IP) entries using a test of proportions based on the cumulative hypergeometric distribution. After multiple-testing correction, 20 GO categories and one IP entry showed significant overrepresentation of genes statistically associated with bull fertility. Several of these functional categories such as small GTPases mediated signal transduction, neurogenesis, calcium ion binding, and cytoskeleton are known to be involved in biological processes closely related to male fertility. These results could provide insight into the genetic architecture of this complex trait in dairy cattle. In addition, this study shows that quantitative trait pathways inferred from single-marker analyses could enhance our interpretations of the results of genome-wide association studies.

SUBMITTER: Penagaricano F

PROVIDER: S-EPMC3542705 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Inferring quantitative trait pathways associated with bull fertility from a genome-wide association study.

Peñagaricano Francisco F Weigel Kent A KA Rosa Guilherme J M GJ Khatib Hasan H

Frontiers in genetics 20130111

Whole-genome association studies typically focus on genetic markers with the strongest evidence of association. However, single markers often explain only a small component of the genetic variance and hence offer a limited understanding of the trait under study. As such, the objective of this study was to perform a pathway-based association analysis in Holstein dairy cattle in order to identify relevant pathways involved in bull fertility. The results of a single-marker association analysis, usi ...[more]

PMID: 23335935

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Project description:BackgroundFertility is one of the most critical factors controlling biological and financial performance of animal production systems and genetic improvement of lines. The objective of this study was to identify molecular defects in the sperm that are responsible for uncompensable fertility in Holstein bulls. We performed a comprehensive genome wide analysis of single nucleotide polymorphisms (SNP) for bull fertility followed by a second-stage replication in additional bulls for a restricted set of markers.ResultsIn the Phase I association study, we genotyped the genomic sperm DNA of 10 low-fertility and 10 high-fertility bulls using Bovine SNP Gene Chips containing approximately 10,000 random SNP markers. In these animals, 8,207 markers were found to be polymorphic, 97 of which were significantly associated with fertility (p < 0.01). In the Phase II study, we tested the four most significant SNP from the Phase I study in 101 low-fertility and 100 high-fertility bulls, with two SNPs (rs29024867 and rs41257187) significantly replicated. Rs29024867 corresponds to a nucleotide change of C --> G 2,190 bp 3' of the collagen type I alpha 2 gene on chromosome 4, while the rs41257187 (C --> T) is in the coding region of integrin beta 5 gene on chromosome 1. The SNP rs41257187 induces a synonymous (Proline --> Proline), suggesting disequilibrium with the true causative locus (i), but we found that the incubation of bull spermatozoa with integrin beta 5 antibodies significantly decreased the ability to fertilize oocytes. Our findings suggest that the bovine sperm integrin beta 5 protein plays a role during fertilization and could serve as a positional or functional marker of bull fertility.ConclusionWe have identified molecular markers associated with bull fertility and established that at least one of the genes harboring such variation has a role in fertility. The findings are important in understanding mechanisms of uncompensatory infertility in bulls, and in other male mammals. The findings set the stage for more hypothesis-driven research aimed at discovering the role of variation in the genome that affect fertility and that can be used to identify molecular mechanisms of development.

Project description:There is considerable evidence that human genetic variation influences gene expression. Genome-wide studies have revealed that mRNA levels are associated with genetic variation in or close to the gene coding for those mRNA transcripts - cis effects, and elsewhere in the genome - trans effects. The role of genetic variation in determining protein levels has not been systematically assessed. Using a genome-wide association approach we show that common genetic variation influences levels of clinically relevant proteins in human serum and plasma. We evaluated the role of 496,032 polymorphisms on levels of 42 proteins measured in 1200 fasting individuals from the population based InCHIANTI study. Proteins included insulin, several interleukins, adipokines, chemokines, and liver function markers that are implicated in many common diseases including metabolic, inflammatory, and infectious conditions. We identified eight Cis effects, including variants in or near the IL6R (p = 1.8x10(-57)), CCL4L1 (p = 3.9x10(-21)), IL18 (p = 6.8x10(-13)), LPA (p = 4.4x10(-10)), GGT1 (p = 1.5x10(-7)), SHBG (p = 3.1x10(-7)), CRP (p = 6.4x10(-6)) and IL1RN (p = 7.3x10(-6)) genes, all associated with their respective protein products with effect sizes ranging from 0.19 to 0.69 standard deviations per allele. Mechanisms implicated include altered rates of cleavage of bound to unbound soluble receptor (IL6R), altered secretion rates of different sized proteins (LPA), variation in gene copy number (CCL4L1) and altered transcription (GGT1). We identified one novel trans effect that was an association between ABO blood group and tumour necrosis factor alpha (TNF-alpha) levels (p = 6.8x10(-40)), but this finding was not present when TNF-alpha was measured using a different assay , or in a second study, suggesting an assay-specific association. Our results show that protein levels share some of the features of the genetics of gene expression. These include the presence of strong genetic effects in cis locations. The identification of protein quantitative trait loci (pQTLs) may be a powerful complementary method of improving our understanding of disease pathways.

Project description:BackgroundThe genetics of male fertility is complex and not fully understood. Male subfertility can adversely affect the economics of livestock production. For example, inadvertently mating bulls with poor fertility can result in reduced annual liveweight production and suboptimal husbandry management. Fertility traits, such as scrotal circumference and semen quality are commonly used to select bulls before mating and can be targeted in genomic studies. In this study, we conducted genome-wide association analyses using sequence-level data targeting seven bull production and fertility traits measured in a multi-breed population of 6,422 tropically adapted bulls. The beef bull production and fertility traits included body weight (Weight), body condition score (CS), scrotal circumference (SC), sheath score (Sheath), percentage of normal spermatozoa (PNS), percentage of spermatozoa with mid-piece abnormalities (MP) and percentage of spermatozoa with proximal droplets (PD).ResultsAfter quality control, 13,398,171 polymorphisms were tested for their associations with each trait in a mixed-model approach, fitting a multi-breed genomic relationship matrix. A Bonferroni genome-wide significance threshold of 5 × 10- 8 was imposed. This effort led to identifying genetic variants and candidate genes underpinning bull fertility and production traits. Genetic variants in Bos taurus autosome (BTA) 5 were associated with SC, Sheath, PNS, PD and MP. Whereas chromosome X was significant for SC, PNS, and PD. The traits we studied are highly polygenic and had significant results across the genome (BTA 1, 2, 4, 6, 7, 8, 11, 12, 14, 16, 18, 19, 23, 28, and 29). We also highlighted potential high-impact variants and candidate genes associated with Scrotal Circumference (SC) and Sheath Score (Sheath), which warrants further investigation in future studies.ConclusionThe work presented here is a step closer to identifying molecular mechanisms that underpin bull fertility and production. Our work also emphasises the importance of including the X chromosome in genomic analyses. Future research aims to investigate potential causative variants and genes in downstream analyses.

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Inferring quantitative trait pathways associated with bull fertility from a genome-wide association study.

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Inferring quantitative trait pathways associated with bull fertility from a genome-wide association study.

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