Consequences of epistasis on growth in an erhualian × white duroc pig cross

Epistasis describes an interaction between the effects of loci. We included epistasis in quantitative trait locus (QTL) mapping of growth at a series of ages in a cross of a Chinese pig breed, Erhualian, with a commercial line, White Duroc. Erhualian pigs have much lower growth rates than White Duroc. We improved a method for genomewide testing of epistasis and present a clear analysis workflow. We also suggest a new approach for interpreting epistasis results where significant additive and dominance effects of a locus in specific backgrounds are determined. In total, seventeen QTL were found and eleven showed epistasis. Loci on chromosomes 2, 3, 4 and 7 were highlighted as affecting growth at more than one age or forming an interaction network. Epistasis resulted in both the QTL on chromosomes 3 and 7 having effects in opposite directions. We believe it is the first time for the chromosome 7 locus that an allele from a Chinese breed has been found to decrease growth. The consequences of epistasis were diverse. Results were impacted by using growth rather than body weight as the phenotype and by correcting for an effect of mother. Epistasis made a considerable contribution to growth in this population and modelling epistasis was important for accurately determining QTL effects

Knowledge-Driven Analysis Identifies a Gene–Gene Interaction Affecting High-Density Lipoprotein Cholesterol Levels in Multi-Ethnic Populations

Total cholesterol, low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol (HDL-C) levels are among the most important risk factors for coronary artery disease. We tested for gene–gene interactions affecting the level of these four lipids based on prior knowledge of established genome-wide association study (GWAS) hits, protein–protein interactions, and pathway information. Using genotype data from 9,713 European Americans from the Atherosclerosis Risk in Communities (ARIC) study, we identified an interaction between HMGCR and a locus near LIPC in their effect on HDL-C levels (Bonferroni corrected Pc = 0.002). Using an adaptive locus-based validation procedure, we successfully validated this gene–gene interaction in the European American cohorts from the Framingham Heart Study (Pc = 0.002) and the Multi-Ethnic Study of Atherosclerosis (MESA; Pc = 0.006). The interaction between these two loci is also significant in the African American sample from ARIC (Pc = 0.004) and in the Hispanic American sample from MESA (Pc = 0.04). Both HMGCR and LIPC are involved in the metabolism of lipids, and genome-wide association studies have previously identified LIPC as associated with levels of HDL-C. However, the effect on HDL-C of the novel gene–gene interaction reported here is twice as pronounced as that predicted by the sum of the marginal effects of the two loci. In conclusion, based on a knowledge-driven analysis of epistasis, together with a new locus-based validation method, we successfully identified and validated an interaction affecting a complex trait in multi-ethnic populations

Evaluation of the safety of C-spine clearance by paramedics: design and methodology

<p>Abstract</p> <p>Background</p> <p>Canadian Emergency Medical Services annually transport 1.3 million patients with potential neck injuries to local emergency departments. Less than 1% of those patients have a c-spine fracture and even less (0.5%) have a spinal cord injury. Most injuries occur before the arrival of paramedics, not during transport to the hospital, yet most patients are transported in ambulances immobilized. They stay fully immobilized until a bed is available, or until physician assessment and/or X-rays are complete. The prolonged immobilization is often unnecessary and adds to the burden of already overtaxed emergency medical services systems and crowded emergency departments.</p> <p>Methods/Design</p> <p>The goal of this study is to evaluate the safety and potential impact of an active strategy that allows paramedics to assess very low-risk trauma patients using a validated clinical decision rule, the Canadian C-Spine Rule, in order to determine the need for immobilization during transport to the emergency department.</p> <p>This cohort study will be conducted in Ottawa, Canada with one emergency medical service. Paramedics with this service participated in an earlier validation study of the Canadian C-Spine Rule. Three thousand consecutive, alert, stable adult trauma patients with a potential c-spine injury will be enrolled in the study and evaluated using the Canadian C-Spine Rule to determine the need for immobilization. The outcomes that will be assessed include measures of safety (numbers of missed fractures and serious adverse outcomes), measures of clinical impact (proportion of patients transported without immobilization, key time intervals) and performance of the Rule.</p> <p>Discussion</p> <p>Approximately 40% of all very low-risk trauma patients could be transported safely, without c-spine immobilization, if paramedics were empowered to make clinical decisions using the Canadian C-Spine Rule. This safety study is an essential step before allowing all paramedics across Canada to selectively immobilize trauma victims before transport. Once safety and potential impact are established, we intend to implement a multi-centre study to study actual impact.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov <a href="http://www.clinicaltrials.gov/ct2/show/NCT01188447">NCT01188447</a></p

Genome-wide analysis of epistasis in body mass index using multiple human populations

We surveyed gene–gene interactions (epistasis) in human body mass index (BMI) in four European populations (n<1200) via exhaustive pair-wise genome scans where interactions were computed as F ratios by testing a linear regression model fitting two single-nucleotide polymorphisms (SNPs) with interactions against the one without. Before the association tests, BMI was corrected for sex and age, normalised and adjusted for relatedness. Neither single SNPs nor SNP interactions were genome-wide significant in either cohort based on the consensus threshold (P=5.0E−08) and a Bonferroni corrected threshold (P=1.1E−12), respectively. Next we compared sub genome-wide significant SNP interactions (P<5.0E−08) across cohorts to identify common epistatic signals, where SNPs were annotated to genes to test for gene ontology (GO) enrichment. Among the epistatic genes contributing to the commonly enriched GO terms, 19 were shared across study cohorts of which 15 are previously published genome-wide association loci, including CDH13 (cadherin 13) associated with height and SORCS2 (sortilin-related VPS10 domain containing receptor 2) associated with circulating insulin-like growth factor 1 and binding protein 3. Interactions between the 19 shared epistatic genes and those involving BMI candidate loci (P<5.0E−08) were tested across cohorts and found eight replicated at the SNP level (P<0.05) in at least one cohort, which were further tested and showed limited replication in a separate European population (n>5000). We conclude that genome-wide analysis of epistasis in multiple populations is an effective approach to provide new insights into the genetic regulation of BMI but requires additional efforts to confirm the findings