Hip shape is an important determinant of hip osteoarthritis (OA), which occurs more commonly in women. However, it remains unclear to what extent differences in OA prevalence are attributed to sex ...differences in hip shape. Here, we explore sex differences in proximal femur shape in a cohort of adolescents. Hip morphology was quantified using hip DXA scans from the Avon Longitudinal Study of Parents and Children. Independent modes of variation (hip shape mode (HSM) scores) were generated for each image using an adult reference statistical shape model (N = 19,379). Linear regression was used to examine sex differences for the top ten HSMs, adjusting for age, height, lean and fat mass. Complete outcome and covariate data were available for 4,428 and 4,369 participants at ages 14 and 18 years, respectively. Several HSMs showed sex differences at both time points. The combined effect of sex on hip shape at age 14 reflected flatter femoral head and smaller lesser trochanter in females compared with males and, following adjustment for age and body size, these differences became more pronounced. At age 18, smaller lesser trochanter and femoral neck width (FNW) in females still remained although differences in femoral head, femoral shaft and FNW were largely attenuated following adjustment. Sexual dimorphism in proximal femur shape can be discerned in adolescence and early adulthood. Observed differences in proximal femur shape, particularly at age 14 were largely independent of body size, however to what extent differences in hip shape in early life play a role in predisposing to hip OA in later life remains to be determined.
The relationship between circulating total bilirubin and incident non-alcoholic fatty liver disease (NAFLD) is uncertain. We aimed to assess the association of total bilirubin with the risk of ...new-onset NAFLD and investigate any causal relevance to the association using a Mendelian randomization (MR) study. Plasma total bilirubin levels were measured at baseline in the PREVEND prospective study of 3824 participants (aged 28–75 years) without pre-existing cardiovascular disease or NAFLD. Incident NAFLD was estimated using the biomarker-based algorithms, fatty liver index (FLI) and hepatic steatosis index (HSI). Odds ratios (ORs) (95% confidence intervals) for NAFLD were assessed. The genetic variant rs6742078 located in the UDP-glucuronosyltransferase (UGT1A1) locus was used as an instrumental variable. Participants were followed up for a mean duration of 4.2 years. The multivariable adjusted OR (95% CIs) for NAFLD as estimated by FLI (434 cases) was 0.82 (0.73–0.92;
p
= 0.001) per 1 standard deviation (SD) change in log
e
total bilirubin. The corresponding adjusted OR (95% CIs) for NAFLD as estimated by HSI (452 cases) was 0.87 (0.78–0.97;
p
= 0.012). The rs6742078 variant explained 20% of bilirubin variation. The ORs (95% CIs) for a 1 SD genetically elevated total bilirubin level was 0.98 (0.69–1.38;
p
= 0.900) for FLI and 1.14 (0.81–1.59;
p
= 0.451) for HSI. Elevated levels of total bilirubin were not causally associated with decreased risk of NAFLD based on MR analysis. The observational association may be driven by biases such as unmeasured confounding and/or reverse causation. However, due to low statistical power, larger-scale investigations are necessary to draw definitive conclusions.
Scales are mineralised exoskeletal structures that are part of the dermal skeleton. Scales have been mostly lost during evolution of terrestrial vertebrates whilst bony fish have retained a ...mineralised dermal skeleton in the form of fin rays and scales. Each scale is a mineralised collagen plate that is decorated with both matrix-building and resorbing cells. When removed, an ontogenetic scale is quickly replaced following differentiation of the scale pocket-lining cells that regenerate a scale. Processes promoting de novo matrix formation and mineralisation initiated during scale regeneration are poorly understood. Therefore, we performed transcriptomic analysis to determine gene networks and their pathways involved in dermal scale regeneration.
We defined the transcriptomic profiles of ontogenetic and regenerating scales of zebrafish and identified 604 differentially expressed genes (DEGs). These were enriched for extracellular matrix, ossification, and cell adhesion pathways, but not in enamel or dentin formation processes indicating that scales are reminiscent to bone. Hypergeometric tests involving monogenetic skeletal disorders showed that DEGs were strongly enriched for human orthologues that are mutated in low bone mass and abnormal bone mineralisation diseases (P< 2× 10
). The DEGs were also enriched for human orthologues associated with polygenetic skeletal traits, including height (P< 6× 10
), and estimated bone mineral density (eBMD, P< 2× 10
). Zebrafish mutants of two human orthologues that were robustly associated with height (COL11A2, P=6× 10
) or eBMD (SPP1, P=6× 10
) showed both exo- and endo- skeletal abnormalities as predicted by our genetic association analyses; col11a2
mutants showed exoskeletal and endoskeletal features consistent with abnormal growth, whereas spp1
mutants predominantly showed mineralisation defects.
We show that scales have a strong osteogenic expression profile comparable to other elements of the dermal skeleton, enriched in genes that favour collagen matrix growth. Despite the many differences between scale and endoskeletal developmental processes, we also show that zebrafish scales express an evolutionarily conserved sub-population of genes that are relevant to human skeletal disease.
Individuals with high bone mass (HBM) have a greater odds of prevalent radiographic hip osteoarthritis (OA), reflecting an association with bone-forming OA sub-phenotypes (e.g. osteophytosis, ...subchondral sclerosis). As the role of bone mineral density (BMD) in hip OA progression is unclear, we aimed to determine if individuals with HBM have increased incidence and/or progression of bone-forming OA sub-phenotypes.
We analysed an adult cohort with and without HBM (L1 and/or total hip BMD Z-score > + 3.2) with pelvic radiographs collected at baseline and 8-year follow-up. Sub-phenotypes were graded using the OARSI atlas. Superior/inferior acetabular/femoral osteophyte and medial/superior joint space narrowing (JSN) grades were summed and Δosteophyte and ΔJSN derived. Pain and functional limitations were quantified using the WOMAC questionnaire. Associations between HBM status and change in OA sub-phenotypes were determined using multivariable linear/logistic regression, adjusting for age, sex, height, total body fat mass, follow-up time and baseline sub-phenotype grade. Generalised estimating equations accounted for individual-level clustering.
Of 136 individuals, 62% had HBM at baseline, 72% were female and mean (SD) age was 59 (10) years. HBM was positively associated with both Δosteophytes and ΔJSN (adjusted mean grade differences between individuals with and without HBM β
= 0.30 0.01, 0.58, p = 0.019 and β
= 0.10 0.01, 0.18, p = 0.019). Incident subchondral sclerosis was rare. HBM individuals had higher WOMAC hip functional limitation scores (β = 8.3 0.7, 15.98, p = 0.032).
HBM is associated with the worsening of hip osteophytes and JSN over an average of 8 years, as well as increased hip pain and functional limitation.
Epidemiological studies have identified many risk factors for osteoporosis, however it is unclear whether these observational associations reflect true causal effects, or the effects of latent ...confounding or reverse causality. Mendelian randomization (MR) enables causal relationships to be evaluated, by examining the relationship between genetic susceptibility to the risk factor in question, and the disease outcome of interest. This has been facilitated by the development of two-sample MR analysis, where the exposure and outcome are measured in different studies, and by exploiting summary result statistics from large well-powered genome-wide association studies that are available for thousands of traits. Though MR has several inherent limitations, the field is rapidly evolving and at least 14 methodological extensions have been developed to overcome these. The present paper aims to discuss some of the limitations in the MR analytical framework, and how this method has been applied to the osteoporosis field, helping to reinforce conclusions about causality, and discovering potential new regulatory pathways, exemplified by our recent MR study of sclerostin.
Abstract Background Pubertal timing is heritable, varies between individuals, and has implications for life-course health. There are many different indicators of pubertal timing, and how they relate ...to each other is unclear. Our aim was to quantitatively compare nine indicators of pubertal timing. Methods We used data from questionnaires and height, weight, and bone measurements from ages 7–17 y in a population-based cohort of 4267 females and 4251 males to compare nine growth and development-based indicators of pubertal timing. We summarise age of each indicator, their phenotypic and genetic correlations, and how they relate to established genetic risk score (GRS) for puberty timing, and phenotypic childhood body composition measures. Results We show that pubic hair in males (mean: 12.6 y) and breasts in females (11.5 y) are early indicators of puberty, and voice breaking (14.2 y) and menarche (12.7 y) are late indicators however, there is substantial variation between individuals in pubertal age. All indicators show evidence of positive phenotypic intercorrelations (e.g., r = 0.49: male genitalia and pubic hair ages), and positive genetic intercorrelations. An age at menarche GRS positively associates with all other pubertal age indicators (e.g., difference in female age at peak height velocity per SD higher GRS: 0.24 y, 95%CI: 0.21 to 0.26), as does an age at voice breaking GRS (e.g., difference in age at male axillary hair: 0.11 y, 0.07 to 0.15). Higher childhood fat mass and lean mass associated with earlier puberty timing. Conclusions Our findings provide insights into the measurements of the timing of pubertal growth and development and illustrate value of various pubertal timing indicators in life-course research.
We aimed to create an imaging biomarker for knee shape using knee dual-energy x-ray absorptiometry (DXA) scans and investigate its potential association with subsequent total knee replacement (TKR), ...independently of radiographic features of knee osteoarthritis and established risk factors.
Using a 129-point statistical shape model, knee shape (expressed as a B-score) and minimum joint space width (mJSW) of the medial joint compartment (binarized as above or below the first quartile) were derived. Osteophytes were manually graded in a subset of images and an overall score was assigned. Cox proportional hazards models were used to examine the associations of B-score, mJSW and osteophyte score with TKR risk, adjusting for age, sex, height and weight.
The analysis included 37,843 individuals (mean age 63.7 years). In adjusted models, B-score was associated with TKR: each unit increase in B-score, reflecting one standard deviation from the mean healthy shape, corresponded to a hazard ratio (HR) of 2.25 (2.08, 2.43), while a lower mJSW had a HR of 2.28 (1.88, 2.77). Among the 6719 images scored for osteophytes, mJSW was replaced by osteophyte score in the most strongly predictive model for TKR. In ROC analyses, a model combining B-score, osteophyte score, and demographics outperformed a model including demographics alone (AUC = 0.87 vs 0.73).
Using statistical shape modelling, we derived a DXA-based imaging biomarker for knee shape that was associated with kOA progression. When combined with osteophytes and demographic data, this biomarker may help identify individuals at high risk of TKR, facilitating targeted interventions.
Bones are complex objects with considerable variation in the shape and structure often attributed to anatomical, environmental or genetic differences. In addition, bone shape has been of interest in ...relation to its associations with disease processes. Hip shape is an important determinant of hip osteoarthritis and osteoporotic hip fracture; however, its quantification is difficult. While previous studies largely focused on individual geometrical indices of hip geometry such as neck-shaft angle or femoral neck width, statistical shape modelling offers the means to quantify the entire contour of the proximal femur, including lesser trochanter and acetabular eyebrow. We describe the derivation of independent modes of variation (hip shape mode scores) to characterise variation in hip shape from dual-energy X-ray absorptiometry (DXA) images in the Avon Longitudinal Study of Parents and Children (ALSPAC) offspring, using statistical shape modelling. ALSPAC is a rich source of phenotypic and genotypic data which provides a unique opportunity to investigate the environmental and genetic influences on hip shape in adolescence, as well as comparison with adult hip shape.
Alpha angle (AA) is a widely used imaging measure of hip shape that is commonly used to define cam morphology, a bulging of the lateral aspect of the femoral head. Cam morphology has shown strong ...associations with hip osteoarthritis (OA) making the AA a clinically relevant measure. In both clinical practice and research studies, AA tends to be measured manually which can be inconsistent and time-consuming.
We aimed to (i) develop an automated method of deriving AA from anterior-posterior dual-energy x-ray absorptiometry (DXA) scans; and (ii) validate this method against manual measures of AA.
6,807 individuals with left hip DXAs were selected from UK Biobank. Outline points were manually placed around the femoral head on 1,930 images before training a Random Forest-based algorithm to place the points on a further 4,877 images. An automatic method for calculating AA was written in Python 3 utilising these outline points. An iterative approach was taken to developing and validating the method, testing the automated measures against independent batches of manually measured images in sequential experiments.
Over the course of six experimental stages the concordance correlation coefficient, when comparing the automatic AA to manual measures of AA, improved from 0.28 95% confidence interval 0.13-0.43 for the initial version to 0.88 0.84-0.92 for the final version. The inter-rater kappa statistic comparing automatic versus manual measures of cam morphology, defined as AA ³≥60°, improved from 0.43 80% agreement for the initial version to 0.86 94% agreement for the final version.
We have developed and validated an automated measure of AA from DXA scans, showing high agreement with manually measuring AA. The proposed method is available to the wider research community from Zenodo.
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