scholarly journals Joint disease-specificity at the regulatory base-pair level

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Pushpanathan Muthuirulan ◽  
Dewei Zhao ◽  
Mariel Young ◽  
Daniel Richard ◽  
Zun Liu ◽  
...  
Keyword(s):  
Hip Dysplasia ◽  
Joint Disease ◽  
Anatomical Site ◽  
Specific Response ◽  
Risk Haplotype ◽  
Regulatory Variants ◽  
Disease Associations ◽  
Causal Variants ◽  
Disease Specificity ◽  
Pair Level

AbstractGiven the pleiotropic nature of coding sequences and that many loci exhibit multiple disease associations, it is within non-coding sequence that disease-specificity likely exists. Here, we focus on joint disorders, finding among replicated loci, that GDF5 exhibits over twenty distinct associations, and we identify causal variants for two of its strongest associations, hip dysplasia and knee osteoarthritis. By mapping regulatory regions in joint chondrocytes, we pinpoint two variants (rs4911178; rs6060369), on the same risk haplotype, which reside in anatomical site-specific enhancers. We show that both variants have clinical relevance, impacting disease by altering morphology. By modeling each variant in humanized mice, we observe joint-specific response, correlating with GDF5 expression. Thus, we uncouple separate regulatory variants on a common risk haplotype that cause joint-specific disease. By broadening our perspective, we finally find that patterns of modularity at GDF5 are also found at over three-quarters of loci with multiple GWAS disease associations.

scholarly journals The Genetics of Inherited Cholestatic Disorders in Neonates and Infants: Evolving Challenges

Genes ◽  
2021 ◽  
Vol 12 (11) ◽  
pp. 1837
Author(s):  
Rebecca Jeyaraj ◽  
Kirsten McKay Bounford ◽  
Nicola Ruth ◽  
Carla Lloyd ◽  
Fiona MacDonald ◽  
...  
Keyword(s):  
Liver Disease ◽  
Phenotypic Variability ◽  
Bile Secretion ◽  
Disease Associations ◽  
Paediatric Liver Disease ◽  
Causal Variants ◽  
Potential Benefits ◽  
Infantile Cholestasis ◽  
Neonates And Infants ◽  
Patient Subgroups

Many inherited conditions cause cholestasis in the neonate or infant. Next-generation sequencing methods can facilitate a prompt diagnosis in some of these cases; application of these methods in patients with liver diseases of unknown cause has also uncovered novel gene-disease associations and improved our understanding of physiological bile secretion and flow. By helping to define the molecular basis of certain cholestatic disorders, these methods have also identified new targets for therapy as well patient subgroups more likely to benefit from specific therapies. At the same time, sequencing methods have presented new diagnostic challenges, such as the interpretation of single heterozygous genetic variants. This article discusses those challenges in the context of neonatal and infantile cholestasis, focusing on difficulties in predicting variant pathogenicity, the possibility of other causal variants not identified by the genetic screen used, and phenotypic variability among patients with variants in the same genes. A prospective, observational study performed between 2010–2013, which sequenced six important genes (ATP8B1, ABCB11, ABCB4, NPC1, NPC2 and SLC25A13) in an international cohort of 222 patients with infantile liver disease, is given as an example of potential benefits and challenges that clinicians could face having received a complex genetic result. Further studies including large cohorts of patients with paediatric liver disease are needed to clarify the spectrum of phenotypes associated with, as well as appropriate clinical response to, single heterozygous variants in cholestasis-associated genes.

scholarly journals TreeMap: a structured approach to fine mapping of eQTL variants

2020 ◽  
Author(s):  
Li Liu ◽  
Pramod Chandrashekar ◽  
Biao Zeng ◽  
Maxwell D Sanderford ◽  
Sudhir Kumar ◽  
...  
Keyword(s):  
Long Range ◽  
Fine Mapping ◽  
Regulation Of Gene Expression ◽  
R Package ◽  
Supplementary Information ◽  
Cis Acting ◽  
Regulatory Variants ◽  
Daunting Task ◽  
The Hierarchical Structure ◽  
Causal Variants

Abstract Motivation Expression quantitative trait loci (eQTL) harbor genetic variants modulating gene transcription. Fine mapping of regulatory variants at these loci is a daunting task due to the juxtaposition of causal and linked variants at a locus as well as the likelihood of interactions among multiple variants. This problem is exacerbated in genes with multiple cis-acting eQTL, where superimposed effects of adjacent loci further distort the association signals. Results We developed a novel algorithm, TreeMap, that identifies putative causal variants in cis-eQTL accounting for multisite effects and genetic linkage at a locus. Guided by the hierarchical structure of linkage disequilibrium, TreeMap performs an organized search for individual and multiple causal variants. Via extensive simulations, we show that TreeMap detects co-regulating variants more accurately than current methods. Furthermore, its high computational efficiency enables genome-wide analysis of long-range eQTL. We applied TreeMap to GTEx data of brain hippocampus samples and transverse colon samples to search for eQTL in gene bodies and in 4 Mbps gene-flanking regions, discovering numerous distal eQTL. Furthermore, we found concordant distal eQTL that were present in both brain and colon samples, implying long-range regulation of gene expression. Availability and implementation TreeMap is available as an R package enabled for parallel processing at https://github.com/liliulab/treemap. Supplementary information Supplementary data are available at Bioinformatics online.

Early detection of canine hip dysplasia: comparison of two palpation and five radiographic methods

1998 ◽  
Vol 34 (4) ◽  
pp. 339-347 ◽  
Author(s):  
WM Adams ◽  
RT Dueland ◽  
J Meinen ◽  
RT O'Brien ◽  
E Giuliano ◽  
...  
Keyword(s):  
Hip Dysplasia ◽  
Degenerative Joint Disease ◽  
Angle Measurement ◽  
Joint Disease ◽  
Radiographic Measurement ◽  
Neutral Position ◽  
Reliable Predictor ◽  
Radiographic Measurements ◽  
One Year ◽  
Norberg Angle

Hip joint laxity was evaluated in four breeds (i.e., greyhound, Labrador retriever, Irish setter, hound mixed-breed) of puppies (n=32) by Ortolani's and Bardens' maneuvers, by subjective assessment of radiographs (Orthopedic Foundation for Animals [OFA] method), and by four radiographic measurement indices. Puppies were studied at four, six-to-10, 16-to-18, and 52 weeks of age. The purpose of this study was to compare palpation and radiographic methods of hip laxity detection in puppies for predicting the development of degenerative joint disease (DJD) by one year of age. Twenty-seven (42%) hips developed DJD. Ortolani's method was not a reliable predictor of hip dysplasia at six-to-10 weeks; it was significantly predictive at 16-to-18 weeks but had a high incidence of false negatives. Bardens' and subjective (OFA) assessment methods were not reliable at six-to-10 or 16-to-18 weeks. Radiographic measurements taken with femurs in a neutral position and hips distracted (distraction index [DI] and Norberg angle) and measurements taken with femurs extended in OFA position (Norberg angle) of six- to 10-week-old puppies accurately predicted DJD occurrence by one year of age (p less than 0.01). Distraction index measurement (PennHIP method) was the most accurate in predicting the development of DJD (p less than 0.001). Distraction index radiography in puppies six-to-10 and 16-to-18 weeks of age was the most reliable predictor of hip dysplasia. Norberg angle measurement was more reliable during hip distraction than when hips were measured in the OFA position in 16- to 18-week-old puppies, but had similar reliability in six- to 10-week-old puppies.

scholarly journals Statistical Colocalization of Genetic Risk Variants for Related Autoimmune Diseases in the Context of Common Controls

2015 ◽  
Author(s):  
Mary D Fortune ◽  
Hui Guo ◽  
Oliver Burren ◽  
Ellen Schofield ◽  
Neil M Walker ◽  
...  
Keyword(s):  
Autoimmune Diseases ◽  
Genetic Risk ◽  
Control Design ◽  
Causal Variant ◽  
The Other ◽  
Risk Variants ◽  
Immune Attack ◽  
Disease Associations ◽  
Causal Variants

Identifying whether potential causal variants for related diseases are shared can increase understanding of the shared etiology between diseases. Colocalization methods are designed to disentangle shared and distinct causal variants in regions where two diseases show association, but existing methods are limited by assuming independent datasets. We extended existing methods to allow for the shared control design common in GWAS and applied them to four autoimmune diseases: type 1 diabetes (T1D); rheumatoid arthritis; celiac disease (CEL) and multiple sclerosis (MS). Ninety regions associated with at least one disease. In 22 regions (24%), we identify association to precisely one of our four diseases and can find no published association of any other disease to the same region; some of these may reflect effects mediated by the target of immune attack. Thirty-three regions (37%) were associated with two or more, but in 14 of these there was evidence that causal variants differed between diseases. By leveraging information across datasets, we identified novel disease associations to 12 regions previously associated with one or more of the other three autoimmune disorders. For instance, we link the CEL-associatedFASLGregion to T1D and identify a single SNP, rs78037977, as a likely causal variant. We also highlight several particularly complex association patterns, including theCD28-CTLA4-ICOSregion, in which it appears that three distinct causal variants associate with three diseases in three different patterns. Our results underscore the complexity in genetic variation underlying related but distinct autoimmune diseases and help to approach its dissection.

scholarly journals Disentangling effects of colocalizing genomic annotations to functionally prioritize non-coding variants within complex trait loci

2014 ◽  
Author(s):  
Gosia Trynka ◽  
Harm-Jan Westra ◽  
Kamil Slowikowski ◽  
Xinli Hu ◽  
Han Xu ◽  
...  
Keyword(s):  
Embryonic Stem ◽  
Complex Trait ◽  
Transcription Start Sites ◽  
Regulatory Variants ◽  
Hypersensitive Sites ◽  
Causal Variants ◽  
Gene Regulatory ◽  
Disease Loci ◽  
Independent Effects ◽  
Coding Variants

Identifying genomic annotations that differentiate causal from associated variants is critical to fine-map disease loci. While many studies have identified non-coding annotations overlapping disease variants, these annotations colocalize, complicating fine-mapping efforts. We demonstrate that conventional enrichment tests are inflated and cannot distinguish causal effects from colocalizing annotations. We developed a sensitive and specific statistical approach that is able to identify independent effects from colocalizing annotations. We first confirm that gene regulatory variants map to DNase-I hypersensitive sites (DHS) near transcription start sites. We then show that (1) 15-35% of causal variants within disease loci map to DHS independent of other annotations; (2) breast cancer and rheumatoid arthritis loci harbor potentially causal variants near the summits of histone marks rather than full peak bodies; and (3) variants associated with height are highly enriched for embryonic stem cell DHS sites. We highlight specific loci where we can most effectively prioritize causal variation.

scholarly journals Fine mapping spatiotemporal mechanisms of genetic variants underlying cardiac traits and disease

2021 ◽  
Author(s):  
Matteo D'Antonio ◽  
Timothy D. Arthur ◽  
Jennifer P. Nguyen ◽  
Hiroko Matsui ◽  
Agnieszka D'Antonio-Chronowska ◽  
...  
Keyword(s):  
Fine Mapping ◽  
Cell Types ◽  
Eqtl Analysis ◽  
Regulatory Variants ◽  
Spatiotemporal Information ◽  
Cardiac Gene ◽  
Causal Variants ◽  
Trait Locus ◽  
Context Specific ◽  
The Uk

The causal variants and genes underlying thousands of cardiac GWAS signals have yet to be identified. To address this issue, we leveraged spatiotemporal information on 966 RNA-seq cardiac samples and performed an expression quantitative trait locus (eQTL) analysis detecting ~26,000 eQTL signals associated with more than 11,000 eGenes and 7,000 eIsoforms. Approximately 2,500 eQTLs were associated with specific cardiac stages, organs, tissues and/or cell types. Colocalization and fine mapping of eQTL and GWAS signals of five cardiac traits in the UK BioBank identified variants with high posterior probabilities for being causal in 210 GWAS loci. Over 50 of these loci represent novel functionally annotated cardiac GWAS signals. Our study provides a comprehensive resource mapping regulatory variants that function in spatiotemporal context-specific manners to regulate cardiac gene expression, which can be used to functionally annotate genomic loci associated with cardiac traits and disease.

Traumatic Coxofemoral Luxation in Dysplastic Dogs Managed with a Triple Pelvic Osteotomy: Results in four Dogs

1997 ◽  
Vol 10 (03) ◽  
pp. 136-140 ◽  
Author(s):  
D. D. Lewis ◽  
S. C. Kerwin ◽  
S. T. Murphy
Keyword(s):  
Femoral Head ◽  
Hip Dysplasia ◽  
External Rotation ◽  
Pelvic Osteotomy ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Contralateral Limb ◽  
Norberg Angle

SummaryTriple pelvic osteotomy (TPO) was used in the treatment for traumatic coxofemoral luxations in four adult, large breed dogs with hip dysplasia. Initial closed reductions failed in three and one dog had an initial closed reduction and subsequent open reduction of the coxofemoral luxation that failed. Hip dysplasia was thought to be a prominent factor contributing to the reluxation. TPO successfully maintained reduction of the coxofemoral luxation in all of the dogs. An increase in dorsal acetabular coverage of the femoral head following TPO was demonstrated by an increased Norberg angle. The improved congruency was thought to maintain reduction of the femoral head in the acetabulum and decrease stresses on the joint capsule, allowing healing to occur. Long-term (median: 343, mean ± SD: 406 ± 226 days follow-up) function of the affected limb was comparable to the contralateral limb. Three of the four dogs did not have radiographic progression of coxofemoral degenerative joint disease of the affected joint and differences in the progression of degenerative joint disease were not evident between the affected and the contralateral coxofemoral joint. A decrease in abduction and external rotation and an increase in internal rotation following TPO was noted in the affected coxofemoral joint. Our results establish the utility of this procedure in dysplastic dogs with traumatic coxofemoral luxations.Triple pelvic osteotomy used in the treatment for traumatic coxofemoral luxation in four adult, large breed dogs with hip dysplasia successfully maintained reduction and resulted in satisfactory limb function in all patients.

scholarly journals Relation between type and local of orthopedic injuries with physical activity in horses

2017 ◽  
Vol 47 (2) ◽  
Author(s):  
Nicole Ruas de Sousa ◽  
Stelio Pacca Loureiro Luna ◽  
Dietrich Pizzigatti ◽  
Mayra Teixeira Alas Martins ◽  
Fabio Sossai Possebon ◽  
...  
Keyword(s):  
Physical Activities ◽  
Joint Disease ◽  
Anatomical Site ◽  
Shoulder Injuries ◽  
Exact Test ◽  
Hind Limbs ◽  
Age Related ◽  
History Of ◽  
Orthopedic Injuries ◽  
Type Of Injury

ABSTRACT: Equine sport modalities influence the prevalence and predisposition of musculoskeletal injuries in horses. This study aimed to evaluate the prevalence of location and type of orthopedic injuries of horses undergoing various physical activities. Data from 116 horses of different breeds and ages was analyzed. Physical activities included dressage, racing, polo pony, jumping, work and western performance. All horses had history of orthopedic lameness diagnosed by radiographs and/or ultrasound scans. The effect of sport on the affected anatomical site and type of lesion was performed using Fisher's exact test. Desmitis was more prevalent in animals that performed western sports than in the working ones. The number of fractures was greater in racing and polo pony animals than in working horses. Stifle lesions were more prevalent in dressage horses than working horses and had lower occurrence of shoulder injuries than jumping horses. Hind limb tendon injuries were lower in jumping than in dressage and western horses. We conclude that there is a relationship between location and type of injury and physical activities. In racing horses there is a predominance of young animals and higher prevalence of orthopedic injuries from traumatic events such as tendonitis, desmitis and fractures. In physical activities that require longer training and that animals were used for longer periods, eg. jumping, polo pony, dressage and work, age-related degenerative, such as joint disease, were predominant. In western sport animals the most common lesion was desmitis. Regarding limbs, forelimb injures were more often observed in racing horses, polo pony, jumping and working animals; whereas, dressage and Western sports horses presented more injuries in hind limbs.

A retrospective study of canine hip dysplasia in 116 military working dogs. Part I: Angle measurements and orthopedic foundation for animals (OFA) grading

1996 ◽  
Vol 32 (5) ◽  
pp. 413-422 ◽  
Author(s):  
CM Banfield ◽  
JE Bartels ◽  
JA Hudson ◽  
JC Wright ◽  
JT Hathcock ◽  
...  
Keyword(s):  
Hip Dysplasia ◽  
Joint Space Width ◽  
Joint Space ◽  
Degenerative Joint Disease ◽  
Joint Disease ◽  
Working Dogs ◽  
Estimated Risk ◽  
Width Measurements ◽  
Military Working Dogs ◽  
Canine Hip Dysplasia

The progression of hip dysplasia was investigated in 116 military working dogs. Serial pelvic radiographs were graded for degree of dysplasia and degenerative joint disease (DJD). Norberg angles, angles of inclination, and joint space widths were measured. There was a significant correlation between the Norberg angle and the degree of dysplasia (p less than 0.0001). Angles of inclination and joint space width measurements did not demonstrate a correlation to canine hip dysplasia. Dysplastic dogs had a significant estimated risk for development of DJD compared to normal dogs (p less than 0.0001; odds ratio of 70.2). Dogs with normal hip conformation at 24 months of age or older did not develop moderate nor severe DJD.

scholarly journals Local joint testing improves power and identifies missing heritability in association studies

2016 ◽  
Author(s):  
Brielin C. Brown ◽  
Alkes L. Price ◽  
Nikolaos A. Patsopoulos ◽  
Noah Zaitlen
Keyword(s):  
Multiple Testing ◽  
Association Studies ◽  
Genetic Association Studies ◽  
Testing Procedure ◽  
Missing Heritability ◽  
Multiple Testing Correction ◽  
Testing Framework ◽  
Genome Wide ◽  
Disease Associations ◽  
Causal Variants

AbstractThere is mounting evidence that complex human phenotypes are highly polygenic, with many loci harboring multiple causal variants, yet most genetic association studies examine each SNP in isolation. While this has lead to the discovery of thousands of disease associations, discovered variants account for only a small fraction of disease heritability. Alternative multi-SNP methods have been proposed, but issues such as multiple testing correction, sensitivity to genotyping error, and optimization for the underlying genetic architectures remain. Here we describe a local joint testing procedure, complete with multiple testing correction, that leverages a genetic phenomenon we call linkage masking wherein linkage disequilibrium between SNPs hides their signal under standard association methods. We show that local joint testing on the original Wellcome Trust Case Control Consortium dataset leads to the discovery of 29% more associated loci that were later found in followup studies containing thousands of additional individuals. These loci double the heritability explained by genome-wide significant associations in the WTCCC dataset, implicating linkage masking as a novel source of missing heritability. Furthermore, we show that local joint testing in a cis-eQTL study of the gEUVADIS dataset increases the number of genes discovered by 10.7% over marginal analyses. Our multiple hypothesis correction and joint testing framework are available in a python software package called jester, available at github.com/brielin/Jester.

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