Project description:Sole ulcers (SU) and white line disease (WLD) are noninfectious claw lesions that arise due to compromised horn production and are common causes of lameness in dairy cattle, imposing welfare and profitability concerns. The low to moderate heritability estimates of SU and WLD susceptibility indicate that genetic selection could reduce their prevalence. To identify loci associated with SU and WLD susceptibility, generalized linear mixed model (GLMM) regression and random forest (RF) genome-wide association studies (GWAS) were performed. Cows from five commercial dairies in California were classified as sound controls having no instances of lameness and above six years of age (n = 102) or cases having SU (n = 152), WLD (n = 117), SU and/or WLD (SU+WLD, n = 198), or any type of noninfectious claw lesion (n = 217). Top SNPs were defined as those passing Bonferroni-corrected suggestive and significance thresholds in the GLMM analysis or those that a validated RF model considered important. Effects of top SNPs were quantified using Bayesian estimation. Linkage disequilibrium (LD) blocks defined by top SNPs were explored for candidate genes and previously identified, functionally relevant quantitative trait loci. The GLMM GWAS revealed regions of association on BTA8 for SU and BTA13 common to WLD, SU+WLD, and noninfectious claw lesions. Bayesian estimation of effect sizes indicated that these SNPs had effects significantly different from zero, indicating their small but notable contribution to susceptibility. Promising candidate genes identified in these regions were involved in wound healing, skin lesions, bone growth and mineralization, adipose tissue, and keratinization. The LD block defined by the most significant SNP on BTA8 for SU included a SNP previously reported to be associated with SU. The RF models were overfitted, indicating that SNP effects were very small and thereby preventing meaningful interpretation of SNPs with the highest importance values and downstream analyses. These findings suggested that variants associated with a variety of physiological systems may contribute to susceptibility for noninfectious claw lesions, demonstrating the complexity of genetic predisposition.

Project description:In this study 3 pooling experiments were performed. In each of the 3 cohorts, a 'case' and a 'control' blood pool was compared - the goal being to identify single nucleotide polymorphisms with significantly different estimated pooling allele frequencies between cases and controls. For cohort 1, 100 individuals with blue eye color were placed in one pool (the 'control' pool) and 100 individuals with brown eye color were placed in another pool ( the 'case' pool). In cohort 2, 131 individuals with age-related macular degeneration were placed in one pool, with 216 control individuals in another pool. In cohort 3, 100 individuals with pseudoexfoliation syndrome were placed in a case pool - in this case the cohort 2 control sample was used as 'controls'. The blue/brown pools were hybridized to Illumina HumanHap550 arrays. The cohort 2 and 3 pools were hybridized to Illumina 1M arrays. After processing, the raw data are summarized to give pooling allele frequency estimates for each pool. The abstract from the paper describing these data is as follows: Genome-wide association studies (GWAS) have now successfully identified important genetic variants associated with many human traits and diseases. The high cost of genotyping arrays in large datasets remains the major barrier to wider utilization of GWAS. We have developed a novel method in which whole blood from cases and controls respectively is pooled prior to DNA extraction for genotyping. We demonstrate proof of principle by clearly identifying the associated variants for eye color, age-related macular degeneration and pseudoexfoliation syndrome in cohorts not previously studied. Blood pooling has the potential to reduce GWAS cost by several orders of magnitude and dramatically shorten gene discovery time. This method has profound implications for translation of modern genetic approaches to a multitude of diseases and traits yet to be analysed by GWAS, and will enable developing nations to participate in GWAS. Pools were typed with Illumina arrays. Estimates of pooling allele frequency were obtained.

Project description:In this study 3 pooling experiments were performed. In each of the 3 cohorts, a 'case' and a 'control' blood pool was compared - the goal being to identify single nucleotide polymorphisms with significantly different estimated pooling allele frequencies between cases and controls. For cohort 1, 100 individuals with blue eye color were placed in one pool (the 'control' pool) and 100 individuals with brown eye color were placed in another pool ( the 'case' pool). In cohort 2, 131 individuals with age-related macular degeneration were placed in one pool, with 216 control individuals in another pool. In cohort 3, 100 individuals with pseudoexfoliation syndrome were placed in a case pool - in this case the cohort 2 control sample was used as 'controls'. The blue/brown pools were hybridized to Illumina HumanHap550 arrays. The cohort 2 and 3 pools were hybridized to Illumina 1M arrays. After processing, the raw data are summarized to give pooling allele frequency estimates for each pool. The abstract from the paper describing these data is as follows: Genome-wide association studies (GWAS) have now successfully identified important genetic variants associated with many human traits and diseases. The high cost of genotyping arrays in large datasets remains the major barrier to wider utilization of GWAS. We have developed a novel method in which whole blood from cases and controls respectively is pooled prior to DNA extraction for genotyping. We demonstrate proof of principle by clearly identifying the associated variants for eye color, age-related macular degeneration and pseudoexfoliation syndrome in cohorts not previously studied. Blood pooling has the potential to reduce GWAS cost by several orders of magnitude and dramatically shorten gene discovery time. This method has profound implications for translation of modern genetic approaches to a multitude of diseases and traits yet to be analysed by GWAS, and will enable developing nations to participate in GWAS.

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Pleiotropic loci associated with foot disorders and common periparturient diseases in Holstein cattle

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