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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.
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.
Full- or half-sibling hounds (n = 56).
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.
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.
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.
PMCID: PMC1950129  PMID: 16634999
2.  Clinical and genetic assessments of hip joint laxity in the Boykin spaniel 
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
3.  Canine Hip Dysplasia is Predictable by Genotyping 
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.
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.
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%.
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.
PMCID: PMC3065507  PMID: 21215318
4.  Radiographic evaluation of early periprosthetic acetabular bone contrast and prosthetic head acetabular coverage after uncemented and cemented total hip prosthesis in dogs 
BMC Veterinary Research  2016;12:271.
Coxofemoral osteoarthritis is a chronic, disabling condition affecting people and dogs, with THA providing an excellent return to function in severely affected joints. The principal role of THA is to restore an adequate range of motion to the hip joint while transferring load from the acetabulum in order to improve the survival of the implant and enhance the limb function in the short and long terms. The objectives of the study reported here were, therefore, to radiographically evaluate periprosthetic acetabular bone GV and to assess prosthetic head acetabular coverage after 4 months of uncemented and cemented THA in dogs. Means periprosthetic acetabular GV for each and combined 3 regions of interest (zones 1, 2 and 3) were calculated immediately and 4 months after THA. Prosthetic head Norberg (PHN) angle was also measured to assess the degree of prosthetic head acetabular coverage after 4 months of surgery.
Zones 2 and 3 showed a significant increase in the mean bone GV after 4 months of uncemented THA. No differences in zones 1–3 after 4 months of cemented THA. Combined zones showed a significant increase in overall mean bone GV 4 months after uncemented THA; whereas, no changes were identified after 4 months of cemented THA. The PHN angles did not change after 4 months of uncemented and cemented THA and did not differ significantly between the 2 designs of hip arthroplasty.
Regional periprosthetic acetabular bone GV varies with the design of THA. None of the designs showed periprosthetic acetabular bone lucency. No differences identified in the degree of prosthetic head acetabular coverage in both designs, indicating proper implant stability after 4 months of surgery. Further longer–term investigation on larger population is however still warranted.
PMCID: PMC5135795  PMID: 27912753
Radiographic evaluation; Periprosthetic acetabular contrast; Acetabular coverage; Total hip arthroplasty; Dogs
5.  Genetic Evaluation of the Nine Component Features of Hip Score in UK Labrador Retrievers 
PLoS ONE  2010;5(10):e13610.
The aim of this study was to explore the genetic relationship between the nine component traits comprising the British Veterinary Association (BVA) total hip score in UK registered Labrador Retrievers. Data consisted of 11,928 single records of trait scores of dogs aged between one and four years (365–1459 days) old, from radiographs evaluated between 2000 and 2007. Pedigree information was provided by the UK Kennel Club. The distribution of trait scores showed only small numbers of dogs with visible malformation in the six traits that were scored according to the severity of osteoarthritis. Linear mixed models were fitted using ASREML. Estimates of heritability ranged from 0.15 to 0.38, and litter effects from 0.04 to 0.10. Genetic correlations between all nine traits were extremely high ranging from 0.71 to 1.0, implying considerable genetic similarity. The decomposition demonstrated that aggregate scores of only the 3 traits indicative of laxity in one year old dogs was predictive of the phenotype of the remaining six scored on osteoarthritic severity in dogs at 4+ years old. The application of selection index methodology in selecting against hip dysplasia using the trait scores was explored and potential improvements in accuracy (directly related to response to selection) of over 10% are reported compared to the current total hip score. This study demonstrates that traits descriptive of joint laxity are valuable early-age predictors of osteoarthritis and shows that there is scope for improvement in the way data from the UK hip score scheme are used for selection against hip dysplasia in Labradors. This was verified via use of selection indices, which identified substantial increases in accuracy, not only via optimum coefficients, but also through an easily applicable aggregate of scores of just two or three traits only compared with the current total hip score.
PMCID: PMC2962649  PMID: 21042594
6.  Bone Mineral Density Variation in Men is influenced by Sex-Specific and Non Sex-Specific Quantitative Trait Loci 
Bone  2009;45(3):443-448.
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.
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).
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.
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.
PMCID: PMC2725190  PMID: 19427925
men; sex- specific QTL; genome-wide scan; linkage
7.  Non-synonymous FGD3 Variant as Positional Candidate for Disproportional Tall Stature Accounting for a Carcass Weight QTL (CW-3) and Skeletal Dysplasia in Japanese Black Cattle 
PLoS Genetics  2015;11(8):e1005433.
Recessive skeletal dysplasia, characterized by joint- and/or hip bone-enlargement, was mapped within the critical region for a major quantitative trait locus (QTL) influencing carcass weight; previously named CW-3 in Japanese Black cattle. The risk allele was on the same chromosome as the Q allele that increases carcass weight. Phenotypic characterization revealed that the risk allele causes disproportional tall stature and bone size that increases carcass weight in heterozygous individuals but causes disproportionately narrow chest width in homozygotes. A non-synonymous variant of FGD3 was identified as a positional candidate quantitative trait nucleotide (QTN) and the corresponding mutant protein showed reduced activity as a guanine nucleotide exchange factor for Cdc42. FGD3 is expressed in the growth plate cartilage of femurs from bovine and mouse. Thus, loss of FDG3 activity may lead to subsequent loss of Cdc42 function. This would be consistent with the columnar disorganization of proliferating chondrocytes in chondrocyte-specific inactivated Cdc42 mutant mice. This is the first report showing association of FGD3 with skeletal dysplasia.
Author Summary
Livestock are typically subjected to intensive artificial selection for traits of economic value to producers. In spite of this strong selection, some major quantitative trait loci (QTLs) for an economically important trait never reach fixation in the population. Several studies have revealed that such QTLs are accompanied with an unfavorable effect on other traits of economic importance, including heritable disease phenotypes. The carcass weight QTL, named CW-3, was previously identified as one of three major QTL in Japanese Black cattle, and it was found to originate from a specific line that had been maintained in a regional subpopulation. Recent efforts to maintain genetic diversity of the Japanese Black breed have resulted in the widespread use of this line throughout Japan. Half-sib QTL analyses of the elite sires repeatedly detected the CW-3 QTL, while skeletal dysplasia has been found in the descendants. Genomic analyses revealed that skeletal dysplasia is inseparably linked with CW-3 and a functional variant of FGD3 was identified as a positional candidate QTN. Further studies such as creating a genetically modified mouse model will be useful to understand a molecular mechanism of FGD3 to modulate bone development.
PMCID: PMC4549114  PMID: 26306008
8.  Radiographic Hip Joint Phenotype of the Pembroke Welsh Corgi 
Veterinary surgery : VS  2012;41(1):10.1111/j.1532-950X.2011.00938.x.
To investigate the radiographic hip joint phenotype of the Pembroke Welsh Corgi.
Study Design
Prospective and retrospective cross-sectional study.
Pembroke Welsh Corgis (n = 399).
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).
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).
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.
PMCID: PMC3842694  PMID: 23253037
9.  Evaluation of gait kinetics in puppies with coxofemoral joint laxity 
To characterize ground reaction forces (GRFs) and determine whether there were correlations between forces and passive coxofemoral joint laxity in puppies.
Fifty-one 16-week-old hound-breed dogs.
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.
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.
PMCID: PMC2094731  PMID: 16454627
10.  Identifying the genetic determinants of transcription factor activity 
Genome-wide messenger RNA expression levels are highly heritable. However, the molecular mechanisms underlying this heritability are poorly understood.The influence of trans-acting polymorphisms is often mediated by changes in the regulatory activity of one or more sequence-specific transcription factors (TFs). We use a method that exploits prior information about the DNA-binding specificity of each TF to estimate its genotype-specific regulatory activity. To this end, we perform linear regression of genotype-specific differential mRNA expression on TF-specific promoter-binding affinity.Treating inferred TF activity as a quantitative trait and mapping it across a panel of segregants from an experimental genetic cross allows us to identify trans-acting loci (‘aQTLs') whose allelic variation modulates the TF. A few of these aQTL regions contain the gene encoding the TF itself; several others contain a gene whose protein product is known to interact with the TF.Our method is strictly causal, as it only uses sequence-based features as predictors. Application to budding yeast demonstrates a dramatic increase in statistical power, compared with existing methods, to detect locus-TF associations and trans-acting loci. Our aQTL mapping strategy also succeeds in mouse.
Genetic sequence variation naturally perturbs mRNA expression levels in the cell. In recent years, analysis of parallel genotyping and expression profiling data for segregants from genetic crosses between parental strains has revealed that mRNA expression levels are highly heritable. Expression quantitative trait loci (eQTLs), whose allelic variation regulates the expression level of individual genes, have successfully been identified (Brem et al, 2002; Schadt et al, 2003). The molecular mechanisms underlying the heritability of mRNA expression are poorly understood. However, they are likely to involve mediation by transcription factors (TFs). We present a new transcription-factor-centric method that greatly increases our ability to understand what drives the genetic variation in mRNA expression (Figure 1). Our method identifies genomic loci (‘aQTLs') whose allelic variation modulates the protein-level activity of specific TFs. To map aQTLs, we integrate genotyping and expression profiling data with quantitative prior information about DNA-binding specificity of transcription factors in the form of position-specific affinity matrices (Bussemaker et al, 2007). We applied our method in two different organisms: budding yeast and mouse.
In our approach, the inferred TF activity is explicitly treated as a quantitative trait, and genetically mapped. The decrease of ‘phenotype space' from that of all genes (in the eQTL approach) to that of all TFs (in our aQTL approach) increases the statistical power to detect trans-acting loci in two distinct ways. First, as each inferred TF activity is derived from a large number of genes, it is far less noisy than mRNA levels of individual genes. Second, the number of trait/marker combinations that needs to be tested for statistical significance in parallel is roughly two orders of magnitude smaller than for eQTLs. We identified a total of 103 locus-TF associations, a more than six-fold improvement over the 17 locus-TF associations identified by several existing methods (Brem et al, 2002; Yvert et al, 2003; Lee et al, 2006; Smith and Kruglyak, 2008; Zhu et al, 2008). The total number of distinct genomic loci identified as an aQTL equals 31, which includes 11 of the 13 previously identified eQTL hotspots (Smith and Kruglyak, 2008).
To better understand the mechanisms underlying the identified genetic linkages, we examined the genes within each aQTL region. First, we found four ‘local' aQTLs, which encompass the gene encoding the TF itself. This includes the known polymorphism in the HAP1 gene (Brem et al, 2002), but also novel predictions of trans-acting polymorphisms in RFX1, STB5, and HAP4. Second, using high-throughput protein–protein interaction data, we identified putative causal genes for several aQTLs. For example, we predict that a polymorphism in the cyclin-dependent kinase CDC28 antagonistically modulates the functionally distinct cell cycle regulators Fkh1 and Fkh2. In this and other cases, our approach naturally accounts for post-translational modulation of TF activity at the protein level.
We validated our ability to predict locus-TF associations in yeast using gene expression profiles of allele replacement strains from a previous study (Smith and Kruglyak, 2008). Chromosome 15 contains an aQTL whose allelic status influences the activity of no fewer than 30 distinct TFs. This locus includes IRA2, which controls intracellular cAMP levels. We used the gene expression profile of IRA2 replacement strains to confirm that the polymorphism within IRA2 indeed modulates a subset of the TFs whose activity was predicted to link to this locus, and no other TFs.
Application of our approach to mouse data identified an aQTL modulating the activity of a specific TF in liver cells. We identified an aQTL on mouse chromosome 7 for Zscan4, a transcription factor containing four zinc finger domains and a SCAN domain. Even though we could not detect a candidate causal gene for Zscan4p because of lack of information about the mouse genome, our result demonstrates that our method also works in higher eukaryotes.
In summary, aQTL mapping has a greatly improved sensitivity to detect molecular mechanisms underlying the heritability of gene expression. The successful application of our approach to yeast and mouse data underscores the value of explicitly treating the inferred TF activity as a quantitative trait for increasing statistical power of detecting trans-acting loci. Furthermore, our method is computationally efficient, and easily applicable to any other organism whenever prior information about the DNA-binding specificity of TFs is available.
Analysis of parallel genotyping and expression profiling data has shown that mRNA expression levels are highly heritable. Currently, only a tiny fraction of this genetic variance can be mechanistically accounted for. The influence of trans-acting polymorphisms on gene expression traits is often mediated by transcription factors (TFs). We present a method that exploits prior knowledge about the in vitro DNA-binding specificity of a TF in order to map the loci (‘aQTLs') whose inheritance modulates its protein-level regulatory activity. Genome-wide regression of differential mRNA expression on predicted promoter affinity is used to estimate segregant-specific TF activity, which is subsequently mapped as a quantitative phenotype. In budding yeast, our method identifies six times as many locus-TF associations and more than twice as many trans-acting loci as all existing methods combined. Application to mouse data from an F2 intercross identified an aQTL on chromosome VII modulating the activity of Zscan4 in liver cells. Our method has greatly improved statistical power over existing methods, is mechanism based, strictly causal, computationally efficient, and generally applicable.
PMCID: PMC2964119  PMID: 20865005
gene expression; gene regulatory networks; genetic variation; quantitative trait loci; transcription factors
11.  Genome-wide QTL mapping for three traits related to teat number in a White Duroc × Erhualian pig resource population 
BMC Genetics  2009;10:6.
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.
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.
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.
PMCID: PMC2672953  PMID: 19226448
12.  Meta-Analysis of Genome-Wide Scans Provides Evidence for Sex- and Site-Specific Regulation of Bone Mass 
Several genome-wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta-analysis of genome-wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner.
BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied.
Materials and Methods
Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing.
For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p = 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24.31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p = 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14q13.1-q24.1, 9q21.32-q31.1, and 5q14.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct.
This large-scale meta-analysis provided evidence for replication of several QTLs identified in previous studies and also identified a QTL on chromosome 18p11-q12.3, which had not been detected by individual studies. However, despite the large sample size, none of the individual loci identified reached genome-wide significance.
PMCID: PMC4016811  PMID: 17228994
osteoporosis; BMD; linkage; meta-analysis; genome search; genome scan
13.  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.
PMCID: PMC2376749  PMID: 17674073
Proximal femoral geometry; Body size; Heritability; Bivariate linkage analysis; Quantitative trait locus
14.  Genetic Correlations among Canine Hip Dysplasia Radiographic Traits in a Cohort of Australian German Shepherd Dogs, and Implications for the Design of a More Effective Genetic Control Program 
PLoS ONE  2013;8(11):e78929.
Canine hip dysplasia (CHD) is a common musculoskeletal disease in pedigree dog populations. It can cause severe pain and dysfunction which may require extensive medication and/or surgical treatment and often ultimately requires humane euthanasia. CHD has been found to be moderately heritable and, given its impact on welfare, should be considered an imperative breeding priority. The British Veterinary Association/Kennel Club scoring method is one of several measures used to assess the genetic propensity of potential breeding stock for dysplastic changes to the hips based on radiographic examination. It is a complex measure composed of nine ordinal traits, intended to evaluate both early and late dysplastic changes. It would be highly desirable if estimated breeding values (EBVs) for these nine traits were consolidated into a simpler, EBV-based, selection index more easily usable by breeders. A multivariate analysis on the phenotype scores from an Australian cohort of 13,124 German Shepherd Dogs (GSDs) returned genetic correlations between 0.48–0.97 for the nine traits which fell into two trait groups, Group 1 reflecting early changes (“laxity”) and Group 2 reflecting late changes (“osteoarthritis”). Principal components analysis of the ordinal EBVs suggested the same pattern, with strong differentiation between “laxity” and “osteoarthritis” traits in the second component. Taking account of all results, we recommend interim use of two selection indexes: the first being the average of ordinal EBVs for “laxity” traits and the second being the average of ordinal EBVs for “osteoarthritis” traits. The correlation between these two selection indexes (0.771–0.774) is sufficiently less than unity enabling the selection of dogs with different genetic propensity for laxity and for osteoarthritic CHD changes in GSDs; this may also be applicable in other breeds. Dogs with low propensity for severe osteoarthritic change in the presence of laxity may be of interest both in molecular research and breeding programs.
PMCID: PMC3820674  PMID: 24244386
15.  Heritability and Tissue Specificity of Expression Quantitative Trait Loci 
PLoS Genetics  2006;2(10):e172.
Variation in gene expression is heritable and has been mapped to the genome in humans and model organisms as expression quantitative trait loci (eQTLs). We applied integrated genome-wide expression profiling and linkage analysis to the regulation of gene expression in fat, kidney, adrenal, and heart tissues using the BXH/HXB panel of rat recombinant inbred strains. Here, we report the influence of heritability and allelic effect of the quantitative trait locus on detection of cis- and trans-acting eQTLs and discuss how these factors operate in a tissue-specific context. We identified several hundred major eQTLs in each tissue and found that cis-acting eQTLs are highly heritable and easier to detect than trans-eQTLs. The proportion of heritable expression traits was similar in all tissues; however, heritability alone was not a reliable predictor of whether an eQTL will be detected. We empirically show how the use of heritability as a filter reduces the ability to discover trans-eQTLs, particularly for eQTLs with small effects. Only 3% of cis- and trans-eQTLs exhibited large allelic effects, explaining more than 40% of the phenotypic variance, suggestive of a highly polygenic control of gene expression. Power calculations indicated that, across tissues, minor differences in genetic effects are expected to have a significant impact on detection of trans-eQTLs. Trans-eQTLs generally show smaller effects than cis-eQTLs and have a higher false discovery rate, particularly in more heterogeneous tissues, suggesting that small biological variability, likely relating to tissue composition, may influence detection of trans-eQTLs in this system. We delineate the effects of genetic architecture on variation in gene expression and show the sensitivity of this experimental design to tissue sampling variability in large-scale eQTL studies.
The combined application of genome-wide expression profiling from microarray experiments with genetic linkage analysis enables the mapping of expression quantitative trait loci (eQTLs), which are primary control points for gene expression across the genome. This approach has been called “genetical genomics”, and recent technological and methodological advances have made its large-scale application feasible in humans and model organisms. Using this approach, the authors have carried out an extensive analysis of the genetic architecture underlying variation in gene expression using a panel of 30 rat recombinant inbred strains. The results are used to explore the relationship between heritability of gene expression, cis- and trans-acting genetic effects, tissue heterogeneity, and statistical cut-offs of significance, which are important factors for large-scale eQTL studies. By examining large eQTL data from four tissues, the authors provide a detailed picture of cis- and trans-eQTL features that may help understanding of the genetic regulation of transcription on a genomic scale. The results also show the sensitivity of this approach to discriminate between cis and trans regulation and the value of the rat system in studying large eQTL datasets from multiple tissues.
PMCID: PMC1617131  PMID: 17054398
16.  The Relationship Between Lower Extremity Alignment Characteristics and Anterior Knee Joint Laxity 
Sports health  2009;1(1):54-60.
Lower extremity alignment may influence the load distribution at the knee, potentially predisposing the anterior cruciate ligament to greater stress. We examined whether lower extremity alignment predicted the magnitude of anterior knee laxity in men and women.
Greater anterior pelvic angle, hip anteversion, tibiofemoral angle, genu recurvatum, and navicular drop will predict greater anterior knee laxity.
Study Design
Descriptive laboratory study.
Women (n = 122) and men (n = 97) were measured for anterior knee laxity and 7 lower extremity alignment variables on their dominant stance leg. Linear regression determined the extent to which the alignment variables predicted anterior knee laxity for each sex.
Lower anterior pelvic tilt and tibiofemoral angle, and greater genu recurvatum and navicular drop were related to greater anterior knee laxity in women, explaining 28.1% of the variance (P < .001). Lower anterior pelvic tilt and greater hip anteversion, genu recurvatum and navicular drop were predictors of greater anterior knee laxity in men, explaining 26.5% of the variance (P < .001).
Lower anterior pelvic tilt, greater knee hyperextension, and foot pronation predicted greater anterior knee laxity in both men and women, with genu recurvatum and navicular drop having the greatest impact on anterior knee laxity. Greater hip anteversion was also a strong predictor in men, while a lower tibiofemoral angle was a significant predictor in women.
Clinical Relevance
The associations between lower extremity alignment and anterior knee laxity suggest that alignment of the hip, knee, and ankle may be linked to or contribute to abnormal loading patterns at the knee, potentially stressing the capsuloligamentous structures and promoting greater joint laxity.
PMCID: PMC2952959  PMID: 20948985
posture; alignment; anterior cruciate ligament; joint laxity
17.  The Relationship between Lower Extremity Alignment Characteristics and Anterior Knee Joint Laxity 
Sports Health  2009;1(1):54-60.
Lower extremity alignment may influence the load distribution at the knee, potentially predisposing the anterior cruciate ligament to greater stress. We examined whether lower extremity alignment predicted the magnitude of anterior knee laxity in men and women.
Greater anterior pelvic angle, hip anteversion, tibiofemoral angle, genu recurvatum, and navicular drop will predict greater anterior knee laxity.
Study Design:
Descriptive laboratory study.
Women (n = 122) and men (n = 97) were measured for anterior knee laxity and 7 lower extremity alignment variables on their dominant stance leg. Linear regression determined the extent to which the alignment variables predicted anterior knee laxity for each sex.
Lower anterior pelvic tilt and tibiofemoral angle, and greater genu recurvatum and navicular drop were related to greater anterior knee laxity in women, explaining 28.1% of the variance (P < .001). Lower anterior pelvic tilt and greater hip anteversion, genu recurvatum and navicular drop were predictors of greater anterior knee laxity in men, explaining 26.5% of the variance (P < .001).
Lower anterior pelvic tilt, greater knee hyperextension, and foot pronation predicted greater anterior knee laxity in both men and women, with genu recurvatum and navicular drop having the greatest impact on anterior knee laxity. Greater hip anteversion was also a strong predictor in men, while a lower tibiofemoral angle was a significant predictor in women.
Clinical Relevance:
The associations between lower extremity alignment and anterior knee laxity suggest that alignment of the hip, knee, and ankle may be linked to or contribute to abnormal loading patterns at the knee, potentially stressing the capsuloligamentous structures and promoting greater joint laxity.
PMCID: PMC2952959  PMID: 20948985
posture; alignment; anterior cruciate ligament; joint laxity
18.  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.
PMCID: PMC3139361  PMID: 19321632
association; canine; disease; longevity; morphology; QTL
19.  Meta - and combined - QTL analysis of different experiments on immune traits in chickens 
Journal of Applied Genetics  2013;54(4):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.
PMCID: PMC3825546  PMID: 24114202
Chicken; Combined; Immune response; Meta QTL analysis
20.  Identifying Multiplanar Knee Laxity Profiles and Associated Physical Characteristics 
Journal of Athletic Training  2012;47(2):159-169.
A single measure of knee laxity (ie, measurement of laxity in a single plane of motion) is probably inadequate to fully describe how knee joint laxity is associated with anterior cruciate ligament injury.
To characterize interparticipant differences in the absolute and relative magnitudes of multiplanar knee laxity (ie, sagittal, frontal, and transverse planes) and examine physical characteristics that may contribute to these differences.
Descriptive laboratory study.
University research laboratory.
Patients or Other Participants:
140 participants (90 women, 50 men).
Main Outcome Measure(s):
Using cluster analysis, we grouped participants into distinct multiplanar knee laxity profiles based on the absolute and relative magnitudes of their anterior knee laxity (AKL), genu recurvatum (GR), and varusvalgus (VV) and internal-external rotation (IER) knee laxity. Using multinomial logistic regression, we then examined associations between the different laxity profile clusters and physical characteristics of sex, age, activity level, general joint laxity, body mass index, thigh strength, and 8 measures of lower extremity anatomical alignment.
Six clusters were identified: low (LOW), moderate (MOD) and high (HIGH) laxity overall and disproportionally higher VV/IER (MODVV/IER), GR (HIGHGR), and AKL (HIGHAKL) laxity. Once all other physical characteristics were accounted for, the LOW cluster was more likely to be older, with longer femur length. Clusters with greater magnitudes of VV and IER laxity were more likely to be younger and to have lower body mass index, smaller Q-angle, and shorter femur length (MOD, HIGH, MODVV/IER) and less thigh strength (HIGH). The HIGHGR cluster was more likely to be female and to have a smaller tibiofemoral angle and longer femur length. The HIGHAKL cluster was more likely to have greater hip anteversion and navicular drop.
The absolute and relative magnitudes of a person's multiplanar knee laxity are not always uniform across planes of motion and can be influenced by age, body composition, thigh strength, and structural alignment. Except in HIGHGR, sex was not a significant predictor of cluster membership once other physical characteristics were taken into account.
PMCID: PMC3418127  PMID: 22488281
hypermobility; anterior cruciate ligament injury risk factors; body composition; strength; lower extremity alignment; age; sex
21.  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.
PMCID: PMC3694190  PMID: 23814471
femoral inclination angle; hip dysplasia; intertrochanteric osteotomy; subluxation
22.  Impact of QTL minor allele frequency on genomic evaluation using real genotype data and simulated phenotypes in Japanese Black cattle 
BMC Genetics  2015;16:134.
Genetic variance that is not captured by single nucleotide polymorphisms (SNPs) is due to imperfect linkage disequilibrium (LD) between SNPs and quantitative trait loci (QTLs), and the extent of LD between SNPs and QTLs depends on different minor allele frequencies (MAF) between them. To evaluate the impact of MAF of QTLs on genomic evaluation, we performed a simulation study using real cattle genotype data.
In total, 1368 Japanese Black cattle and 592,034 SNPs (Illumina BovineHD BeadChip) were used. We simulated phenotypes using real genotypes under different scenarios, varying the MAF categories, QTL heritability, number of QTLs, and distribution of QTL effect. After generating true breeding values and phenotypes, QTL heritability was estimated and the prediction accuracy of genomic estimated breeding value (GEBV) was assessed under different SNP densities, prediction models, and population size by a reference-test validation design.
The extent of LD between SNPs and QTLs in this population was higher in the QTLs with high MAF than in those with low MAF. The effect of MAF of QTLs depended on the genetic architecture, evaluation strategy, and population size in genomic evaluation. In genetic architecture, genomic evaluation was affected by the MAF of QTLs combined with the QTL heritability and the distribution of QTL effect. The number of QTL was not affected on genomic evaluation if the number of QTL was more than 50. In the evaluation strategy, we showed that different SNP densities and prediction models affect the heritability estimation and genomic prediction and that this depends on the MAF of QTLs. In addition, accurate QTL heritability and GEBV were obtained using denser SNP information and the prediction model accounted for the SNPs with low and high MAFs. In population size, a large sample size is needed to increase the accuracy of GEBV.
The MAF of QTL had an impact on heritability estimation and prediction accuracy. Most genetic variance can be captured using denser SNPs and the prediction model accounted for MAF, but a large sample size is needed to increase the accuracy of GEBV under all QTL MAF categories.
Electronic supplementary material
The online version of this article (doi:10.1186/s12863-015-0287-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4653875  PMID: 26586567
BovineHD; Genomic prediction; Heritability estimation; Japanese Black cattle; Minor allele frequency; Simulation study
23.  Detection of multiple quantitative trait loci and their pleiotropic effects in outbred pig populations 
Simultaneous detection of multiple QTLs (quantitative trait loci) may allow more accurate estimation of genetic effects. We have analyzed outbred commercial pig populations with different single and multiple models to clarify their genetic properties and in addition, we have investigated pleiotropy among growth and obesity traits based on allelic correlation within a gamete.
Three closed populations, (A) 427 individuals from a Yorkshire and Large White synthetic breed, (B) 547 Large White individuals and (C) 531 Large White individuals, were analyzed using a variance component method with one-QTL and two-QTL models. Six markers on chromosome 4 and five to seven markers on chromosome 7 were used.
Population A displayed a high test statistic for the fat trait when applying the two-QTL model with two positions on two chromosomes. The estimated heritabilities for polygenic effects and for the first and second QTL were 19%, 17% and 21%, respectively. The high correlation of the estimated allelic effect on the same gamete and QTL test statistics suggested that the two separate QTL which were detected on different chromosomes both have pleiotropic effects on the two fat traits. Analysis of population B using the one-QTL model for three fat traits found a similar peak position on chromosome 7. Allelic effects of three fat traits from the same gamete were highly correlated suggesting the presence of a pleiotropic QTL. In population C, three growth traits also displayed similar peak positions on chromosome 7 and allelic effects from the same gamete were correlated.
Detection of the second QTL in a model reduced the polygenic heritability and should improve accuracy of estimated heritabilities for both QTLs.
PMCID: PMC2762464  PMID: 19807906
24.  Sex-specific genetic architecture of human fatness in Chinese: the SAPPHIRe Study 
Human genetics  2010;128(5):501-513.
To dissect the genetic architecture of sexual dimorphism in obesity-related traits, we evaluated the sex–genotype interaction, sex-specific heritability and genome-wide linkages for seven measurements related to obesity. A total of 1,365 non-diabetic Chinese subjects from the family study of the Stanford Asia–Pacific Program of Hypertension and Insulin Resistance were used to search for quantitative trait loci (QTLs) responsible for the obesity-related traits. Pleiotropy and co-incidence effects from the QTLs were also examined using the bivariate linkage approach. We found that sex-specific differences in heritability and the genotype–sex interaction effects were substantially significant for most of these traits. Several QTLs with strong linkage evidence were identified after incorporating genotype by sex (G × S) interactions into the linkage mapping, including one QTL for hip circumference [maximum LOD score (MLS) = 4.22, empirical p = 0.000033] and two QTLs: for BMI on chromosome 12q with MLS 3.37 (empirical p = 0.0043) and 3.10 (empirical p = 0.0054). Sex-specific analyses demonstrated that these linkage signals all resulted from females rather than males. Most of these QTLs for obesity-related traits replicated the findings in other ethnic groups. Bivariate linkage analyses showed several obesity traits were influenced by a common set of QTLs. All regions with linkage signals were observed in one gender, but not in the whole sample, suggesting the genetic architecture of obesity-related traits does differ by gender. These findings are useful for further identification of the liability genes for these phenotypes through candidate genes or genome-wide association analysis.
PMCID: PMC4446122  PMID: 20725740
25.  Trunk rotation and hip joint range of rotation in adolescent girls with idiopathic scoliosis: does the "dinner plate" turn asymmetrically ? 
Scoliosis  2008;3:1.
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.
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.
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.
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.
PMCID: PMC2246099  PMID: 18205943

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