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1.  Associations Between Canine Juvenile Weight Gain and Coxofemoral Joint Laxity at 16 Weeks of Age 
Veterinary surgery : VS  2006;35(3):214-218.
Objective
Evaluation of the relationship between canine weight gain from 6 to 15 weeks of age and passive coxofemoral joint (CFJ) laxity at 16 weeks of age.
Study Design
Longitudinal cohort study.
Animals
Full- or half-sibling hounds (n = 56).
Methods
Hounds were weighed weekly from 6 to 15 weeks of age. Individual average daily gain (ADG) was calculated for each week (weekly) and for the study (overall). PennHIP distraction index (DI) was determined for each CFJ at 16 weeks. Mixed effects linear models were evaluated for associations of DI (highest and mean) with 15-week weight and ADGs (actual or normalized). Left and right DIs were compared with a Student’s paired t-test. Significance was set at P < .05. Trends were considered at P < .10.
Results
Mean (± SD) 16-week DI score and 15-week weight was 0.67 ± 0.16 and 12.5 ± 1.8 kg, respectively. Within animal left and right DIs were not significantly different. There were no significant associations between DI and any of the weight gains evaluated. There was a trend for a negative relationship between normalized 14-week ADG and DI in one statistical model.
Conclusions
Weight gain from 6 to 15 weeks of age was unrelated to 16-week PennHIP DI in a homogenous canine population with moderate-to-severe CFJ joint laxity.
Clinical Relevance
Based on our results, ad libitum feeding between 6 and 15 weeks of age does not appear to have an adverse impact on joint laxity at 16 weeks of age as measured by the PennHIP DI.
doi:10.1111/j.1532-950X.2006.00139.x
PMCID: PMC1950129  PMID: 16634999
2.  Evaluation of gait kinetics in puppies with coxofemoral joint laxity 
Objective
To characterize ground reaction forces (GRFs) and determine whether there were correlations between forces and passive coxofemoral joint laxity in puppies.
Animals
Fifty-one 16-week-old hound-breed dogs.
Procedure
Force-plate gait evaluation and distraction radiographic imaging were performed. Ground reaction forces evaluated included x (mediolateral), y (craniocaudal breaking and propulsion), and z (vertical) peak force and impulse. Z-plane limb loading and unloading rates, loading interval, and weight distribution and y-plane stance time breaking and propulsion percentages were calculated. One-way ANOVA with the Duncan multiple range test was used to evaluate differences in gait variables among limbs. The relationships of left, right, highest, and mean distraction index (DI) with individual limb data of each dog were evaluated with the Spearman rank correlation. Left and right DIs were compared by means of linear regression analysis.
Results
Mean ± SEM DI was 0.67 ± 0.02. Left and right DIs were strongly correlated, but there were no significant relationships between DIs and gait variables. Most fore- and hind limb gait variables differed significantly, whereas paired fore- and hind limb gait variables did not. Asymmetry was most pronounced in the x- and y-planes.
Conclusions and Clinical Relevance
GRFs were consistent with those of clinically normal mature dogs, supporting an absence of association between GRF and DI in young dogs. The GRFs and elucidation of the relationship between GRFs and DI may be useful for future studies in immature dogs.
doi:10.2460/ajvr.67.2.236
PMCID: PMC2094731  PMID: 16454627
3.  Clinical and genetic assessments of hip joint laxity in the Boykin spaniel 
Abstract
Canine hip dysplasia (CHD) is characterized by a malformation of the hip joint that leads to joint laxity and consequential degenerative joint disease. The most widely used method for diagnosis of CHD is the ventrodorsal hip-extended radiologic view, commonly referred to as the Orthopedic Foundation for Animals (OFA) method. The method of the University of Pennsylvania Hip Improvement Program (PennHIP), an alternative technique that is based on hip joint laxity, provides a quantitative assessment, the distraction index (DI), of the likelihood of the development of CHD because of increased laxity in the hip joint. Linear regression analysis showed that, across many breeds of dog, the incidence of CHD, as defined by the OFA, is positively correlated with the mean DI, the determination coefficient (r2) being 26%. We used families of Boykin spaniels (BSs) to determine the level of joint laxity in the breed and to conduct an initial whole-genome screening to identify markers that co-segregate with increased joint laxity. Although there was a positive correlation between the incidence of hip dysplasia and increased joint laxity, we did not find significant linkage in the 28 BSs that underwent genotyping, likely owing to the small size of the pedigree.
PMCID: PMC1410725  PMID: 16639948
4.  Bivariate Linkage Study of Proximal Hip Geometry and Body Size Indices: The Framingham Study 
Calcified tissue international  2007;81(3):162-173.
Femoral geometry and body size are both characterized by substantial heritability. The purpose of this study was to discern whether hip geometry and body size (height and body mass index, BMI) share quantitative trait loci (QTL). Dual-energy X-ray absorptiometric scans of the proximal femur from 1,473 members in 323 pedigrees (ages 31–96 years) from the Framingham Osteoporosis Study were studied. We measured femoral neck length, neck-shaft angle, subperiosteal width (outer diameter), cross-sectional bone area, and section modulus, at the narrowest section of the femoral neck (NN), intertrochanteric (IT), and femoral shaft (S) regions. In variance component analyses, genetic correlations (ρG) between hip geometry traits and height ranged 0.30–0.59 and between hip geometry and BMI ranged 0.11–0.47. In a genomewide linkage scan with 636 markers, we obtained nominally suggestive linkages (bivariate LOD scores ≥ 1.9) for geometric traits and either height or BMI at several chromosomes (4, 6, 9, 15, and 21). Two loci, on chr. 2 (80 cM, BMI/shaft section modulus) and chr. X (height/shaft outer diameter), yielded bivariate LOD scores ≥ 3.0; although these loci were linked in univariate analyses with a geometric trait, neither was linked with either height or BMI. In conclusion, substantial genetic correlations were found between the femoral geometric traits, height and BMI. Linkage signals from bivariate linkage analyses of bone geometric indices and body size were similar to those obtained in univariate linkage analyses of femoral geometric traits, suggesting that most of the detected QTL primarily influence geometry of the hip.
doi:10.1007/s00223-007-9052-y
PMCID: PMC2376749  PMID: 17674073
Proximal femoral geometry; Body size; Heritability; Bivariate linkage analysis; Quantitative trait locus
5.  The long (and winding) road to gene discovery for canine hip dysplasia 
Hip dysplasia is a common inherited trait of dogs that results in secondary osteoarthritis. In this article the methods used to uncover the mutations contributing to this condition are reviewed, beginning with hip phenotyping. Coarse, genome-wide, microsatellite-based screens of pedigrees of greyhounds and dysplastic Labrador retrievers were used to identify linked quantitative trait loci (QTL). Fine-mapping across two chromosomes (CFA11 and 29) was employed using single nucleotide polymorphism (SNP) genotyping. Power analyses and preferential selection of dogs for ongoing SNP-based genotyping is described with the aim of refining the QTL intervals to 1–2 megabases on these and several additional chromosomes prior to candidate gene screening. The review considers how a mutation or a genetic marker such as a SNP or haplotype of SNPs might be combined with pedigree and phenotype information to create a ‘breeding value’ that could improve the accuracy of predicting a dog’s hip conformation.
doi:10.1016/j.tvjl.2009.02.008
PMCID: PMC2679856  PMID: 19297220
Canine hip dysplasia; Genome wide screen; Microsatellites; Single nucleotide polymorphisms (SNP); Breeding values
6.  Anterior Hip Subluxation due to Lumbar Degenerative Kyphosis and Posterior Pelvic Tilt 
Case Reports in Orthopedics  2014;2014:806157.
Nontraumatic anterior subluxation and dislocation of the hip joint are extremely rare. A 58-year-old woman presented to our outpatient clinic with left hip pain with a duration of 15 years. There was no history of trauma or other diseases. Her hip pain usually occurred only on walking and not at rest. Physical examinations demonstrated no tenderness in the hip joint. The range of motion of both hip joints was almost normal. Laxity of other joints was not observed. The bone mineral density of the lumbar spine and proximal femur confirmed a diagnosis of osteoporosis. A plain radiograph showed osteoarthritic changes of the hip joints, severe posterior pelvic tilt, and superior displacement of both femoral heads, especially in a standing position. Three-dimensional computed tomography (3DCT) revealed anterior subluxation of both femoral heads. Seven years after the initial visit, both hip joints showed progression to severe osteoarthritis. Although the exact cause remains unclear, lumbar kyphosis, posterior pelvic tilt, and a decrease in acetabular coverage may have influenced the current case. We should be aware of these factors when we examine patients with hip osteoarthritis.
doi:10.1155/2014/806157
PMCID: PMC3926232  PMID: 24592346
7.  Effects of intertrochanteric varus osteotomy on Norberg angle and percent coverage of the femoral head in displastic dogs 
Journal of Veterinary Science  2013;14(2):185-191.
This study was conducted to assess the effects of femoral varus osteotomy on joint congruency in dogs affected by early stage hip dysplasia. Preoperative planning to move the femoral head within the acetabulum was carried out. Varisation of the femoral inclination angle (fIA) was achieved by Intertrochanteric Osteotomy (ITO). Norberg angle (NA), percent coverage (PC) of the femoral head by the acetabulum and fIA was measured from preoperative, immediate postoperative and first and second recheck radiographs of seven dogs that underwent an ITO (joint n = 9). There was significant (p < 0.05) improvement of both NA and PC in all patients as indicated by a change in the mean ± standard deviation of 78.9° ± 7.5 and 36.9% ± 5.2 to 92.2° ± 6.7 and 50.6% ± 8.3, respectively. No significant difference (p < 0.05) was observed between the values of the planned femoral inclination angle (pfIA) of the femur and the effective femoral inclination angle (efIA) obtained after surgery (115.9° ± 2.5 and 111.3° ± 6.4, respectively). These findings could encourage the use of ITO in veterinary practice and indicate that intertrochanteric varus osteotomy should be re-considered for the treatment of early stage hip dysplasia in dogs with radiological signs of joint incongruency.
doi:10.4142/jvs.2013.14.2.185
PMCID: PMC3694190  PMID: 23814471
femoral inclination angle; hip dysplasia; intertrochanteric osteotomy; subluxation
8.  Canine Hip Dysplasia is Predictable by Genotyping 
Summary
Objective
To establish a predictive method using whole genome genotyping for early intervention in canine hip dysplasia (CHD) risk management, for the prevention of the progression of secondary osteoarthritis (OA), and for selective breeding.
Design
Two sets of dogs (6 breeds) were genotyped with dense SNPs covering the entire canine genome. The first set contained 359 dogs upon which a predictive formula for genomic breeding value (GBV) was derived by using their estimated breeding value (EBV) of the Norberg angle (a measure of CHD) and their genotypes. To investigate how well the formula would work for an individual dog with genotype only (without using EBV or phenotype), a cross validation was performed by masking the EBV of one dog at a time. The genomic data and the EBV of the remaining dogs were used to predict the GBV for the single dog that was left out. The second set of dogs included 38 new Labrador retriever dogs, which had no pedigree relationship to the dogs in the first set.
Results
The cross validation showed a strong correlation (r>0.7) between the EBV and the GBV. The independent validation showed a strong correlation (r=0.5) between GBV for the Norberg angle and the observed Norberg angle (no EBV was available for the new 38 dogs). Sensitivity, specificity, positive, and negative predictive value of the genomic data were all above 70%.
Conclusions
Prediction of CHD from genomic data is feasible, and can be applied for risk management of CHD and early selection for genetic improvement to reduce the prevalence of CHD in breeding programs. The prediction can be implemented before maturity, at which age current radiographic screening programs are traditionally applied, and as soon as DNA is available.
doi:10.1016/j.joca.2010.12.011
PMCID: PMC3065507  PMID: 21215318
9.  Collagen Gene Variants Previously Associated With Anterior Cruciate Ligament Injury Risk Are Also Associated With Joint Laxity 
Sports Health  2012;4(4):312-318.
Background:
Genetic association studies demonstrate a relationship between several collagen gene variants and anterior cruciate ligament (ACL) injury, yet the mechanism of these relationships is still unclear. Joint laxity is a heritable trait; increased magnitudes of anterior knee laxity (AKL), genu recurvatum (GR), and general joint laxity (GJL) have been consistently associated with a greater risk of ACL injury. Joint laxity may constitute an important intermediate phenotype for the genetic association with ACL injury that can be measured clinically.
Hypothesis:
To determine if genetic variants within the COL1A1, COL5A1, and COL12A1 genes, previously associated with ACL injury, were also associated with greater magnitudes of AKL, GR, and GJL.
Study Design:
Descriptive laboratory study.
Methods:
Blood samples and measures of AKL, GR, and GJL were obtained from 124 (50 male, 74 female) healthy, recreationally active subjects. Genomic DNA was extracted from the blood samples and genotyped for single-nucleotide polymorphisms previously examined relative to ACL injury. Univariate analyses of variance compared the magnitude of each laxity variable across the 3 genotypes for each single-nucleotide polymorphism in both sex-combined and sex-specific models.
Results:
Specific genotypes were associated with greater GR in all subjects. Some genotypes were associated with greater magnitudes of GR, AKL, and GJL in females only.
Conclusions:
Gene variants previously associated with ACL injury risk were in large part also associated with joint laxity. Sex-specific genetic associations with joint laxity were consistent with those previously reported for ACL injury.
Clinical Relevance:
These data provide insight into potential pathways through which genotypic variants in collagen genes have the potential to alter ligament structure and behavior and, thus, ACL injury risk.
doi:10.1177/1941738112446684
PMCID: PMC3435918  PMID: 23016102
joint laxity; genetic variations; anterior cruciate ligament injury; collagen genes; sex differences
10.  Assessment of the relationship between joint laxity and migration of the hip in children with Down syndrome 
Purpose
The aim of this cross-sectional cohort study is to describe the incidence of joint laxity and the correlation between joint laxity and radiological migration of the hip in children with Down syndrome.
Methods
Sixty-five children (2–19 years) with Down’s syndrome were examined for joint laxity. For each subject, laxity scores for joints were carried out with the Bulbena method. Plane pelvic radiographs were used to determine the migration of the hip, according to Reimer’s migration index.
Results
In this study, 26 out of 65 children with Down’s syndrome (40 %) were diagnosed with general joint laxity. On the radiographs of the hips we found a mean Reimer’s Migration Index of 5.2 % for all the subjects. Children with general joint laxity showed a lower Reimer’s Migration Index (2.1 %). No significant correlation was found between general joint laxity and migration of the hip.
Conclusions
This study showed no relationship between joint laxity and migration of the hip in children with Down’s syndrome. This implicates that we were not able to prove that joint laxity is the major factor in developing hip migration in children with Down’s syndrome.
doi:10.1007/s11832-012-0427-x
PMCID: PMC3468730  PMID: 24082952
Down’s syndrome; Children; Joint laxity; Hip dysplasia; Migration of the hip
11.  Mouse BMD Quantitative Trait Loci Show Improved Concordance With Human Genome-wide Association Loci When Recalculated on a New, Common Mouse Genetic Map 
Journal of Bone and Mineral Research  2010;25(8):1808-1820.
Bone mineral density (BMD) is a heritable trait, and in mice, over 100 quantitative trait loci (QTLs) have been reported, but candidate genes have been identified for only a small percentage. Persistent errors in the mouse genetic map have negatively affected QTL localization, spurring the development of a new, corrected map. In this study, QTLs for BMD were remapped in 11 archival mouse data sets using this new genetic map. Since these QTLs all were mapped in a comparable way, direct comparisons of QTLs for concordance would be valid. We then compared human genome-wide association study (GWAS) BMD loci with the mouse QTLs. We found that 26 of the 28 human GWAS loci examined were located within the confidence interval of a mouse QTL. Furthermore, 14 of the GWAS loci mapped to within 3 cM of a mouse QTL peak. Lastly, we demonstrated that these newly remapped mouse QTLs can substantiate a candidate gene for a human GWAS locus, for which the peak single-nucleotide polymorphism (SNP) fell in an intergenic region. Specifically, we suggest that MEF2C (human chromosome 5, mouse chromosome 13) should be considered a candidate gene for the genetic regulation of BMD. In conclusion, use of the new mouse genetic map has improved the localization of mouse BMD QTLs, and these remapped QTLs show high concordance with human GWAS loci. We believe that this is an opportune time for a renewed effort by the genetics community to identify the causal variants regulating BMD using a synergistic mouse-human approach. © 2010 American Society for Bone and Mineral Research.
doi:10.1002/jbmr.72
PMCID: PMC3153351  PMID: 20200990
genetic linkage; quantitative trait loci; mouse; human
12.  Genetic Mapping of Fixed Phenotypes: Disease Frequency as a Breed Characteristic 
Journal of Heredity  2009;100(Suppl 1):S37-S41.
Traits that have been stringently selected to conform to specific criteria in a closed population are phenotypic stereotypes. In dogs, Canis familiaris, such stereotypes have been produced by breeding for conformation, performance (behaviors), etc. We measured phenotypes on a representative sample to establish breed stereotypes. DNA samples from 147 dog breeds were used to characterize single nucleotide polymorphism allele frequencies for association mapping of breed stereotypes. We identified significant size loci (quantitative trait loci [QTLs]), implicating candidate genes appropriate to regulation of size (e.g., IGF1, IGF2BP2 SMAD2, etc.). Analysis of other morphological stereotypes, also under extreme selection, identified many additional significant loci. Behavioral loci for herding, pointing, and boldness implicated candidate genes appropriate to behavior (e.g., MC2R, DRD1, and PCDH9). Significant loci for longevity, a breed characteristic inversely correlated with breed size, were identified. The power of this approach to identify loci regulating the incidence of specific polygenic diseases is demonstrated by the association of a specific IGF1 haplotype with hip dysplasia, patella luxation, and pacreatitis.
doi:10.1093/jhered/esp011
PMCID: PMC3139361  PMID: 19321632
association; canine; disease; longevity; morphology; QTL
13.  Trunk rotation and hip joint range of rotation in adolescent girls with idiopathic scoliosis: does the "dinner plate" turn asymmetrically ? 
Scoliosis  2008;3:1.
Background
In patients with structural idiopathic scoliosis the body asymmetries involve the pelvis and the lower limbs; they are included in many theories debating the pathogenesis of idiopathic scoliosis.
Methods
Hip joint range of motion was studied in 158 adolescent girls, aged 10–18 years (mean 14.2 ± 2.0) with structural idiopathic scoliosis of 20–83° of Cobb angle (mean 43.0° ± 14.5°) and compared to 57 controls, sex and age matched. Hip range of rotation was examined in prone position, the pelvis level controlled with an inclinometer; hip adduction was tested in five different positions.
Results
In girls with structural scoliosis the symmetry of hip rotation was less frequent (p = 0.0047), the difference between left and right hip range of internal rotation was significantly higher (p = 0.0013), and the static rotational offset of the pelvis, calculated from the mid-points of rotation, revealed significantly greater (p = 0.0092) than in healthy controls. The detected asymmetries comprised no limitation of hip range of motion, but a transposition of the sector of motion, mainly towards internal rotation in one hip and external rotation in the opposite hip. The data failed to demonstrate the curve type, the Cobb angle, the angle of trunk rotation or the curve progression factor to be related to the hip joint asymmetrical range of motion.
Conclusion
Numerous asymmetries around the hip were detected, most of them were expressed equally in scoliotics and in controls. Pathogenic implications concern producing a "torsional offset" of muscles patterns of activation around the spine in adolescent girls with structural idiopathic scoliosis during gait.
doi:10.1186/1748-7161-3-1
PMCID: PMC2246099  PMID: 18205943
14.  Total Hip Arthroplasty after Treatment of Pseudojoint Infection in a Patient with a Highly Dislocated Hip 
Case Reports in Orthopedics  2013;2013:947121.
Infection at the pseudoacetabulum in a patient with a high hip dislocation has not been reported previously in the English literature. We report a case of total hip arthroplasty in a 28-year-old female who presented to us with hip pain following debridement of the infected pseudojoint in a case of neglected developmental dysplasia of the hip. The infection was treated with thorough debridement and drainage. However, even after achieving complete infection control, this patient complained of disabling right hip joint pain. Total hip arthroplasty with subtrochanteric osteotomy was performed to relieve the pain and improve gait. After surgery, the patient's symptoms were relieved. We consider that in this case of acute pseudojoint infection simple arthrotomy and debridement combined with irrigation and drainage provide effective treatment. But muscle weakness and more increased joint laxity can cause hip pain even after infection control. So total hip arthroplasty is likely to be necessary after the infection has been controlled in a patient with a highly dislocated hip.
doi:10.1155/2013/947121
PMCID: PMC3708414  PMID: 23878754
15.  Genome-wide QTL mapping for three traits related to teat number in a White Duroc × Erhualian pig resource population 
BMC Genetics  2009;10:6.
Background
Teat number is an important fertility trait for pig production, reflecting the mothering ability of sows. It is also a discrete and often canalized trait presenting bilateral symmetry with minor differences between the two sides, providing a potential power to evaluate fluctuating asymmetry and developmental instability. The knowledge of its genetic control is still limited. In this study, a genome-wide scan was performed with 183 microsatellites covering the pig genome to identify quantitative trait loci (QTL) for three traits related to teat number including the total teat number (TTN), the teat number at the left (LTN) and right (RTN) sides in a large scale White Duroc × Erhualian resource population.
Results
A sex-average linkage map with a total length of 2350.3 cM and an average marker interval of 12.84 cM was constructed. Eleven genome-wide significant QTL for TTN were detected on 8 autosomes including pig chromosomes (SSC) 1, 3, 4, 5, 6, 7, 8 and 12. Six suggestive QTL for this trait were detected on SSC6, 9, 13, 14 and 16. Eight chromosomal regions each on SSC1, 3, 4, 5, 6, 7, 8 and 12 showed significant associations with LTN. These regions were also evidenced as significant QTL for RTN except for those on SSC6 and SSC8. The most significant QTL for the 3 traits were all located on SSC7. Erhualian alleles at most of the identified QTL had positive additive effects except for three QTL on SSC1 and SSC7, at which White Duroc alleles increased teat numbers. On SSC1, 6, 9, 13 and 16, significant dominance effects were observed on TTN, and predominant imprinting effect on TTN was only detected on SSC12.
Conclusion
The results not only confirmed the QTL regions from previous experiments, but also identified five new QTL for the total teat number in swine. Minor differences between the QTL regions responsible for LTN and RTN were validated. Further fine mapping should be focused on consistently identified regions with small confidence intervals, such as those on SSC1, SSC7 and SSC12.
doi:10.1186/1471-2156-10-6
PMCID: PMC2672953  PMID: 19226448
16.  Bone Mineral Density Variation in Men is influenced by Sex-Specific and Non Sex-Specific Quantitative Trait Loci 
Bone  2009;45(3):443-448.
Introduction
A major predictor of age-related osteoporotic fracture is peak areal bone mineral density (aBMD) which is a highly heritable trait. However, few linkage and association studies have been performed in men to identify the genes contributing to normal variation in aBMD. The aim of this study was to perform a genome wide scan in healthy men to identify quantitative trait loci (QTL) that were significantly linked to aBMD and to test whether any of these might be sex-specific.
Methods
aBMD at the spine and hip were measured in 515 pairs of brothers, aged 18-61 (405 white pairs, 110 black pairs). Linkage analysis in the brother sample was compared with results in a previously published sample of 774 sister pairs to identify sex-specific quantitative trait loci (QTL).
Results
A genome wide scan identified significant QTL (LOD>3.6) for aBMD on chromosomes 4q21 (hip), 7q34 (spine), 14q32 (hip), 19p13 (hip), 21q21 (hip), and 22q13 (hip). Analysis suggested that the QTL on chromosome 7q34, 14q32, and 21q21 were male-specific whereas the others were not sex-specific.
Conclusions
This study demonstrates that six QTL were significantly linked with aBMD in men. One was linked to spine and five were linked to hip. When compared to published data in women from the same geographical region, the QTL on chromosomes 7, 14 and 21 were male-specific. The occurrence of sex-specific genes in humans for aBMD has important implications for the pathogenesis and treatment of osteoporosis.
doi:10.1016/j.bone.2009.05.002
PMCID: PMC2725190  PMID: 19427925
men; sex- specific QTL; genome-wide scan; linkage
17.  Joint linkage and segregation analysis under multiallelic trait inheritance: Simplifying interpretations for complex traits 
Genetic epidemiology  2010;34(4):344-353.
Identification of the genetic basis of common traits may be hindered by underlying complex genetic architectures that are inadequately captured by existing models, including both multiallelic and multilocus modes of inheritance (MOI). One useful approach for localizing genes underlying continuous complex traits is the joint oligogenic linkage and segregation analysis implemented in the package Loki. The method uses reversible jump Markov chain Monte Carlo to eliminate the need to prespecify the number of quantitative trait loci (QTLs) in the trait model, thus providing posterior distributions for the number of QTLs in a Bayesian framework. The current implementation assumes QTLs are diallelic, and therefore can overestimate the number of linked QTLs in the presence of a multiallelic QTL. To address the possibility of multiple alleles, we extended the QTL model to allow for a variable number of additive alleles at each locus. Application to simulated data shows that, under a diallelic MOI, the multiallelic and diallelic analysis models give similar results. Under a multiallelic MOI, the multiallelic analysis model provides better mixing and improved convergence, and leads to a more accurate estimate of the underlying trait MOI and model parameter values, than does the diallelic model. Application to real data shows the multiallelic model results in fewer estimated linked QTLs and that the predominant QTL model is similar to one of two predominant models estimated from the diallelic analysis. Our results indicate that use of a multiallelic analysis model can lead to better understanding of the genetic architecture underlying complex traits.
doi:10.1002/gepi.20490
PMCID: PMC2914272  PMID: 20091797
complex trait; MCMC; pedigree; continuous trait; Bayesian
18.  Meta - and combined - QTL analysis of different experiments on immune traits in chickens 
Journal of Applied Genetics  2013;54:483-487.
Meta and/or combined QTL analysis from multiple studies can improve quantitative trait loci (QTL) position estimates compared to the individual experiments. Hereby we present results of a meta-analysis of QTL on chicken chromosome 9, 14 and 18 using data from three separate experiments and joint QTL analysis for chromosome 14 and 18. Meta QTL analysis uses information from multiple QTLs studies. Joint QTL analysis is based on combining raw data from different QTL experimental populations. QTLs under the study were related to specific antibody response to keyhole lymphet hemocyanin (KLH), and natural antibodies to environmental antigens, lipopolisaccharide (LPS) and lipoteichoic acid (LTA). Meta QTL analysis resulted in narrowing down the confidence interval for two QTLs on GGA14. The first one for natural antibodies against LTA and the second one for specific antibody response toward KLH. Also, a confidence interval of a QTL for natural antibodies against LPS located on GGA18 was narrowed down. Combined QTL analysis was successful for two QTLs: for specific antibody response toward KLH on GGA14, and for natural antibodies against LPS on GGA18. The greatest statistical power for QTL detection in joint analysis was achieved when raw data from segregating half–sib families from different populations under the study was used.
doi:10.1007/s13353-013-0177-6
PMCID: PMC3825546  PMID: 24114202
Chicken; Combined; Immune response; Meta QTL analysis
19.  Radiographic Hip Joint Phenotype of the Pembroke Welsh Corgi 
Veterinary surgery : VS  2012;41(1):10.1111/j.1532-950X.2011.00938.x.
Objective
To investigate the radiographic hip joint phenotype of the Pembroke Welsh Corgi.
Study Design
Prospective and retrospective cross-sectional study.
Animals
Pembroke Welsh Corgis (n = 399).
Methods
Ventrodorsal, hip-extended radiographs were evaluated for subluxation, osteoarthritis (OA), caudolateral curvilinear osteophytes (CCO), and circumferential femoral head osteophytes (CFHO) of PennHIP evaluated Corgis. Joint laxity was measured by distraction index (DI).
Results
All Corgis had DI > 0.30 (mean, 0.66), 6.8% had OA, 18% had subluxation, 22.3% had CCO, and 74.4% had CFHO. Higher DI increased the odds for subluxation and canine hip dysplasia (CHD) but not for OA, CCO, or CFHO. The presence of CCO increased the odds for OA by 4.6 times (P = .002) and 2.2 times (P = .01) for hip dysplasia. All dogs with OA had CFHO. The presence of CFHO increased the odds for subluxation by 8.7 times (p < .001) and 8.9 times (P < .001) for hip dysplasia. Subluxation increased the odds for OA by 15.4 times (P < .001).
Conclusion
Corgis had a low frequency of conventional OA despite having hip laxity that has been shown to correlate with hip OA and hip dysplasia in large-breed dogs. The relationship between CCO and OA was similar to published findings in nonchondrodystrophic large-breed dogs and the CFHO was significantly associated with subluxation. Both CCO and CFHO are associated with hip dysplasia in this small chondrodystrophic breed.
doi:10.1111/j.1532-950X.2011.00938.x
PMCID: PMC3842694  PMID: 23253037
20.  A non-human primate system for large-scale genetic studies of complex traits 
Human Molecular Genetics  2012;21(15):3307-3316.
Non-human primates provide genetic model systems biologically intermediate between humans and other mammalian model organisms. Populations of Caribbean vervet monkeys (Chlorocebus aethiops sabaeus) are genetically homogeneous and large enough to permit well-powered genetic mapping studies of quantitative traits relevant to human health, including expression quantitative trait loci (eQTL). Previous transcriptome-wide investigation in an extended vervet pedigree identified 29 heritable transcripts for which levels of expression in peripheral blood correlate strongly with expression levels in the brain. Quantitative trait linkage analysis using 261 microsatellite markers identified significant (n = 8) and suggestive (n = 4) linkages for 12 of these transcripts, including both cis- and trans-eQTL. Seven transcripts, located on different chromosomes, showed maximum linkage to markers in a single region of vervet chromosome 9; this observation suggests the possibility of a master trans-regulator locus in this region. For one cis-eQTL (at B3GALTL, beta-1,3-glucosyltransferase), we conducted follow-up single nucleotide polymorphism genotyping and fine-scale association analysis in a sample of unrelated Caribbean vervets, localizing this eQTL to a region of <200 kb. These results suggest the value of pedigree and population samples of the Caribbean vervet for linkage and association mapping studies of quantitative traits. The imminent whole genome sequencing of many of these vervet samples will enhance the power of such investigations by providing a comprehensive catalog of genetic variation.
doi:10.1093/hmg/dds160
PMCID: PMC3392106  PMID: 22556363
21.  Are radiological joint space widths of normal hips asymmetrical? 
Annals of the Rheumatic Diseases  1999;58(4):246-249.
BACKGROUND—To be certain that the joint space width is abnormal in the case of hip joint pain when compared with the contralateral hip requires knowledge of physiological dissymmetry.
AIM OF THE STUDY—To assess interindividual variability and dissymmetry in pelvic radiological joint space width.
METHODS—Pelvic radiographs of subjects without hip joint disease. Measurement with a 0.1 mm graduated magnifying glass and 0.5 mm graduated flat ruler at the hip superointermediate site (vertical going through the femoral head centre). After randomisation of the side to measure, analysis of nine groups of 19 plain films by one investigator blind for the result of the contralateral side.
RESULTS—The difference between the left and right hip was plotted against the corresponding mean for all 171 normal subjects This shows the frequency and the limits of the asymmetry at each measurement site. The asymmetry is independent of interindividual variability of the joint space width and greater than the measurement error in most subjects.
CONCLUSION—This study confirms the interindividual variability of hip joint space width, shows the frequency of hip joint space asymmetry and defines its limit.

 Keywords: hip joint; joint space width; measurement
PMCID: PMC1752859  PMID: 10364904
22.  Relationships of hip joint volume ratios with degrees of joint laxity and degenerative disease from youth to maturity in a canine population predisposed to hip joint osteoarthritis 
Objective
To assess relationships of acetabular volume (AV), femoral head volume (FV), and portion of the femoral head within in the acetabulum (FVIA) with each other and with degrees of hip joint laxity and degenerative joint disease from youth to maturity in dogs predisposed to developing hip joint osteoarthritis (OA).
Animals
46 mixed-breed half- or full-sibling hound-type dogs.
Procedures
The distraction index (DI), AV, FV, FVIA, and degree of osteoarthritis (OA score) were quantified in 1 hip joint at 16, 32, and 104 weeks of age. Relationships among variables were evaluated within and between ages. Ratios corresponding to OA scores were compared within ages. Differences among 16-week ratios corresponding to 32-week OA scores and among 16- and 32-week ratios corresponding to 104-week OA scores were evaluated.
Results
Significant positive relationships existed between FV and AV across ages as well as between FVIA/FV and FVIA/AV and between DI and OA score across and within most ages. Such relationships also existed within these variables across most ages. Negative relationships of DI and OA scores with FVIA/FV and FVIA/AV within and among all ages were significant. Sixteen-week AVs, FVs, and FVIAs were greater and FV/AVs and OA scores were less than 32- and 104-week values. The 32-week FVIA/FV was less than 16- and 104-week values, and the 32-week FVIA/AV was less than the 104-week value. The FVIA/FV and FVIA/AV were lower and the DI was higher with higher OA scores within and among most ages.
Conclusions and Clinical Relevance
Structural volumes in lax canine hip joints changed predictably relative to each other during growth, despite degenerative changes. Measures developed in this study may augment current diagnosis and treatment strategies for hip dysplasia in dogs.
doi:10.2460/ajvr.72.3.376
PMCID: PMC3711502  PMID: 21355741
23.  The pathogenesis and diagnosis of canine hip dysplasia: a review. 
The Canadian Veterinary Journal  1995;36(8):494-502.
Hip dysplasia is a common developmental problem affecting the canine population. Despite extensive research into the condition, many questions remain unanswered and numerous misconceptions are present among the general public. The purpose of this paper is to review the current knowledge on the development of hip dysplasia, factors modifying its development, and current diagnostic techniques. A computerized literature search was conducted for the period of January 1983 to April 1985 using the MEDLINE and CAB databases, and the keywords hip dysplasia, hip, dog, and canine. Other articles, wherever possible original research articles, published before 1983 were also reviewed. Animals affected by hip dysplasia are born with normal hips, but quickly develop subluxation of the femoral head. Degenerative joint disease follows. Hip dysplasia is a complex, inherited, polygenic trait. Selective breeding of only normal dogs with normal littermates, parents, and grandparents is the recommended method of reducing the incidence in the general population. Gene expression in affected individuals may be modified by a number of environmental factors. These factors do not cause hip dysplasia, but they alter manifestations of the trait and its severity. Nutrition is a major environmental factor. Excess energy consumption increases the frequency and severity of hip dysplasia in genetically predisposed dogs. Food intake should be regulated to maintain a slender figure with the ribs and dorsal vertebral spines easily palpable, but not visible. Excess dietary calcium and vitamin D contribute to hip dysplasia in genetically predisposed individuals and should be avoided. High dose vitamin C supplementation in growing puppies does not prevent hip dysplasia, and this practice should be discontinued.(ABSTRACT TRUNCATED AT 250 WORDS)
Images
PMCID: PMC1687006  PMID: 7585436
24.  Identification and Dissection of Four Major QTL Affecting Milk Fat Content in the German Holstein-Friesian Population 
PLoS ONE  2012;7(7):e40711.
Milk composition traits exhibit a complex genetic architecture with a small number of major quantitative trait loci (QTL) explaining a large fraction of the genetic variation and numerous QTL with minor effects. In order to identify QTL for milk fat percentage (FP) in the German Holstein-Friesian (HF) population, a genome-wide association study (GWAS) was performed. The study population consisted of 2327 progeny-tested bulls. Genotypes were available for 44,280 SNPs. Phenotypes in the form of estimated breeding values (EBVs) for FP were used as highly heritable traits. A variance components-based approach was used to account for population stratification. The GWAS identified four major QTL regions explaining 46.18% of the FP EBV variance. Besides two previously known FP QTL on BTA14 (P = 8.91×10−198) and BTA20 (P = 7.03×10−12) within DGAT1 and GHR, respectively, we uncovered two additional QTL regions on BTA5 (P = 2.00×10−13) and BTA27 (P = 9.83×10−5) encompassing EPS8 and GPAT4, respectively. EPS8 and GPAT4 are involved in lipid metabolism in mammals. Re-sequencing of EPS8 and GPAT4 revealed 50 polymorphisms. Genotypes for five of them were inferred for the entire study population. Two polymorphisms affecting potential transcription factor binding sites of EPS8 (P = 1.40×10−12) and GPAT4 (P = 5.18×10−5), respectively, were highly significantly associated with the FP EBV. Our results provide evidence that alteration of regulatory sites is an important aspect of genetic variation of complex traits in cattle.
doi:10.1371/journal.pone.0040711
PMCID: PMC3394711  PMID: 22792397
25.  Secondary Hip Osteoarthritis due to Neurofibroma Treated with Total Hip Replacement 
Case Reports in Orthopedics  2012;2012:173921.
Background. Local plexiform neurofibroma can lead to deformity of the pelvis, valgus deformity of femoral neck, and joint capsule laxity. We report a case of secondary hip osteoarthritis with subluxation and coxa vara deformity resulting from an extra-articular neurofibroma treated with total hip replacement. Case Description. A 39-year-old man had a large benign plexiform neurofibroma at buttock which induced secondary osteoarthritis of the hip. Conservative treatment of tumor was selected because the patient had low chance of malignant transformation due to absence of other neurofibromatosis features. However, due to secondary osteoarthritis he underwent total hip arthroplasty. Anterior capsulotomy was selected to avoid large posterior hip tumor mass. In order to avoid the difficulties associated with setting tension of the abductor muscle, modified trochanteric slide osteotomy with trochanteric advancement, lateralized cup placement, and extended neck offset were used. One year after the surgery, the patient had excellent clinical function, hip stability, leg length equality and was satisfied with the outcome. Clinical Relevance. We concluded that the modified trochanteric slide osteotomy with trochanteric advancement represents a valuable approach for THR in patients with extremely elongation of the hip abductor and secondary hip osteoarthritis resulting from extra-articular neurofibroma.
doi:10.1155/2012/173921
PMCID: PMC3505911  PMID: 23259112

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