Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture

Bone mineral density (BMD) is the most widely used predictor of fracture risk. We performed the largest meta-analysis to date on lumbar spine and femoral neck BMD, including 17 genome-wide association studies and 32,961 individuals of European and east Asian ancestry. We tested the top BMD-associated markers for replication in 50,933 independent subjects and for association with risk of low-trauma fracture in 31,016 individuals with a history of fracture (cases) and 102,444 controls. We identified 56 loci (32 new) associated with BMD at genome-wide significance (P < 5 × 10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal stem cell differentiation, endochondral ossification and Wnt signaling pathways. However, we also discovered loci that were localized to genes not known to have a role in bone biology. Fourteen BMD-associated loci were also associated with fracture risk (P < 5 × 10−4, Bonferroni corrected), of which six reached P < 5 × 10−8, including at 18p11.21 (FAM210A), 7q21.3 (SLC25A13), 11q13.2 (LRP5), 4q22.1 (MEPE), 2p16.2 (SPTBN1) and 10q21.1 (DKK1). These findings shed light on the genetic architecture and pathophysiological mechanisms underlying BMD variation and fracture susceptibility.

Common variants in the region around Osterix are associated with bone mineral density and growth in childhood

Peak bone mass achieved in adolescence is a determinant of bone mass in later life. In order to identify genetic variants affecting bone mineral density (BMD), we performed a genome-wide association study of BMD and related traits in 1518 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). We compared results with a scan of 134 adults with high or low hip BMD. We identified associations with BMD in an area of chromosome 12 containing the Osterix (SP7) locus, a transcription factor responsible for regulating osteoblast differentiation (ALSPAC: P = 5.8 × 10-4; Australia: P = 3.7 × 10-4). This region has previously shown evidence of association with adult hip and lumbar spine BMD in an Icelandic population, as well as nominal association in a UK population. A meta-analysis of these existing studies revealed strong association between SNPs in the Osterix region and adult lumbar spine BMD (P = 9.9 × 10-11). In light of these findings, we genotyped a further 3692 individuals from ALSPAC who had whole body BMD and confirmed the association in children as well (P = 5.4 × 10-5). Moreover, all SNPs were related to height in ALSPAC children, but not weight or body mass index, and when height was included as a covariate in the regression equation, the association with total body BMD was attenuated. We conclude that genetic variants in the region of Osterix are associated with BMD in children and adults probably through primary effects on growth.

Site and gender specificity of inheritance of bone mineral density

Differences in genetic control of BMD by skeletal sites and genders were examined by complex segregation analysis in 816 members of 147 families with probands with extreme low BMD. Spine BMD correlated more strongly in male-male comparisons and hip BMD in female-female comparisons, consistent with gender- and site-specificity of BMD heritability. Introduction: Evidence from studies in animals and humans suggests that the genetic control of bone mineral density (BMD) may differ at different skeletal sites and between genders. This question has important implications for the design and interpretation of genetic studies of osteoporosis. Methods: We examined the genetic profile of 147 families with 816 individuals recruited through probands with extreme low BMD (T-score < −2.5, Z-score < −2.0). Complex segregation analysis was performed using the Pedigree Analysis Package. BMD was measured by DXA at both lumbar spine (L1-L4) and femoral neck. Results: Complex segregation analysis excluded purely monogenic and environmental models of segregation of lumbar spine and femoral neck BMD in these families. Pure polygenic models were excluded at the lumbar spine when menopausal status was considered as a covariate, but not at the femoral neck. Mendelian models with a residual polygenic component were not excluded. These models were consistent with the presence of a rare Mendelian genotype of prevalence 3–19 %, causing high BMD at the hip and spine in these families, with additional polygenic effects. Total heritability range at the lumbar spine was 61–67 % and at the femoral neck was 44–67 %. Significant differences in correlation of femoral neck and lumbar spine BMD were observed between male and female relative pairs, with male-male comparisons exhibiting stronger lumbar spine BMD correlation than femoral neck, and female-female comparisons having greater femoral neck BMD correlation than lumbar spine. These findings remained true for parent-offspring correlations when menopausal status was taken into account. The recurrence risk ratio for siblings of probands of a Z-score < −2.0 was 5.4 at the lumbar spine and 5.9 at the femoral neck. Conclusions: These findings support gender- and site-specificity of the inheritance of BMD. These results should be considered in the design and interpretation of genetic studies of osteoporosis.

Genetic control of bone density and turnover: Role of the collagen 1α1, estrogen receptor, and vitamin D receptor genes

Genetic factors are known to influence both the peak bone mass and probably the rate of change in bone density. A range of regulatory and structural genes has been proposed to be involved including collagen 1α1 (COL1A1), the estrogen receptor (ER), and the vitamin D receptor (VDR), but the actual genes involved are uncertain. We therefore studied the role of the COL1A1 and VDR loci in control of bone density by linkage in 45 dizygotic twin pairs and 29 nuclear families comprising 120 individuals. The influences on bone density of polymorphisms of COL1A1, VDR, and ER were studied by association both cross-sectionally and longitudinally in 193 elderly postmenopausal women (average age, 69 years) over a mean follow-up time of 6.3 years. Weak linkage of the COL1A1 locus with bone density was observed in both twins and families (p = 0.02 in both data sets), confirming previous observations of linkage of this locus with bone density. Association between the MscI polymorphism of COL1A1 and rate of lumbar spine bone loss was observed with significant gene-environment interaction related to dietary calcium intake (p = 0.0006). In the lowest tertile of dietary calcium intake, carriers of "s" alleles lost more bone than "SS" homozygotes (p = 0.01), whereas the opposite was observed in the highest dietary calcium intake (p = 0.003). Association also was observed between rate of bone loss at both the femoral neck and the lumbar spine and the TaqI VDR polymorphism (p = 0.03). This association was strongest in those in the lowest tertile of calcium intake, also suggesting the presence of gene-environment interaction involving dietary calcium and VDR, influencing bone turnover. No significant association was observed between the PvuII ER polymorphism alone or in combination with VDR or COL1A1 genotypes, with either bone density or its rate of change. These data support the involvement of COL1A1 in determination of bone density and the interaction of both COL1A1 and VDR with calcium intake in regulation of change of bone density over time.

Cost effectiveness of bone density measurements

Objective. To assess the cost-effectiveness of bone density screening programmes for osteoporosis. Study design. Using published and locally available data regarding fracture rates and treatment costs, the overall costs per fracture prevented, cost per quality of life year (QALY) saved and cost per year of life gained were estimated for different bone density screening and osteoporosis treatment programmes. Main outcome measures. Cost per fracture prevented, cost per QALY saved, and cost per year of life gained. Results. In women over the age of 50 years, the costs per fracture prevented of treating all women with hormone replacement therapy, or treating only if osteoporosis is demonstrated on bone density screening were £32,594 or £23,867 respectively. For alendronate therapy for the same groups, the costs were £171,067 and £14,067 respectively. Once the background rate of treatment with alendronate reaches 18%, bone density screening becomes cost-saving. Costs estimates per QALY saved ranged from £1,514 to £39,076 for osteoporosis treatment with alendronate following bone density screening. Conclusions. For relatively expensive medications such as alendronate, treatment programmes with prior bone density screening are far more cost effective than those without, and in some circumstances become cost-saving. Costs per QALY of life saved and per year of life gained for osteoporosis treatment with prior bone density screening compare favourably with treatment of hypertension and hypercholesterolemia.

Submission to the Senate Economics References Committee Inquiry into affordable housing 20 August 2014: De-risking development of medium density housing to improve housing affordability and boost supply

This submission addresses the problem of housing price inflation, the chronic under-supply of new housing stock, and the resultant decline in housing affordability for low and middle income households. It specifically focusses on the supply of medium density housing (multi-unit development) in Melbourne, although we believe that the observations made about housing in supply in Melbourne are relevant in other urban centres and to other types of housing supply. In terms of medium density housing (MDH) our concern also extends to the poor quality and design. Why the market tends to deliver generic apartments of poor quality and design which are uncompetitive with lower density housing and amenity despite planning objectives, and how this apparently intractable problem can be overcome is the topic of this submission...

Effects of fish density distribution and effort distribution on catchability

The effects of fish density distribution and effort distribution on the overall catchability coefficient are examined. Emphasis is also on how aggregation and effort distribution interact to affect overall catch rate [catch per unit effort (cpue)]. In particular, it is proposed to evaluate three indices, the catchability index, the knowledge parameter, and the aggregation index, to describe the effectiveness of targeting and the effects on overall catchability in the stock area. Analytical expressions are provided so that these indices can easily be calculated. The average of the cpue calculated from small units where fishing is random is a better index for measuring the stock abundance. The overall cpue, the ratio of lumped catch and effort, together with the average cpue, can be used to assess the effectiveness of targeting. The proposed methods are applied to the commercial catch and effort data from the Australian northern prawn fishery. The indices are obtained assuming a power law for the effort distribution as an approximation of targeting during the fishing operation. Targeting increased catchability in some areas by 10%, which may have important implications on management advice.

Modelling growth rate of Penaeus monodon Fabricius in intensively managed ponds: effects of temperature, pond age and stocking density

Records of shrimp growth and water quality made during 12 crops from each of 48 ponds, over a period of 6.5 years, were provided by a Queensland, Australia, commercial shrimp farm, These data were analysed with a new growth model derived from the Gompertz model. The results indicate that water temperature, mortality and pond age significantly affect growth rates. After 180 days, shrimp reach 34 g at constant 30 degrees C, but only 15 g after the same amount of time at 20 degrees C. Mortality, through thinning the density of shrimp in the ponds, increased the growth rate, but the effect is small. With continual production, growth rates at first remained steady, then appeared to decrease for the sixth and seventh crop, after which they have increased steadily with each crop. It appears that conservative pond management, together with a gradual improvement in husbandry techniques, particularly feed management, brought about this change. This has encouraging implications for the long-term sustainability of the farming methods used. The growth model can be used to predict productivity, and hence, profitability, of new aquaculture locations or new production strategies.

The effects of +Gz force on the bone mineral density of fighter pilots

HYPOTHESIS Bone is a metabolically active tissue which responds to high strain loading. The purpose of this study was to examine the bone response to high +Gz force loading generated during high performance flying. METHODS The bone response to +Gz force loading was monitored in 10 high performance RAAF pilots and 10 gender-, age-, height-, weight-matched control subjects. The pilots were stationed at the RAAF base at Pearce, Western Australia, all completing the 1-yr flight training course. The pilots flew the Pilatus PC-9 aircraft, routinely sustaining between 2.0 and 6.0 +Gz. Bone mineral density (BMD) and bone mineral content (BMC) were measured at baseline and 12 mo, using the Hologic QDR 2000+ bone densitometer. RESULTS After controlling for change in total body weight and fat mass, the pilots experienced a significant increase in BMD and BMC for thoracic spine, pelvis, and total body, in the magnitude of 11.0%, 4.9%, and 3.7%, respectively. However, no significant changes in bone mineral were observed in the pilots lumbar spine, arms or legs. The control group experienced a significant decrease in pelvic BMC, with no other bone mineral changes observed at any site. CONCLUSIONS These findings suggest that site specific BMD is increased in response to high +Gz forces generated during high performance flying in a PC-9.

High-density fine-mapping of a chromosome 10q26 linkage peak suggests association between endometriosis and variants close to CYP2C19

OBJECTIVE To refine a previously reported linkage peak for endometriosis on chromosome 10q26, and conduct follow-up analyses and a fine-mapping association study across the region to identify new candidate genes for endometriosis. DESIGN Case-control study. SETTING Academic research. PATIENT(S) Cases=3,223 women with surgically confirmed endometriosis; controls=1,190 women without endometriosis and 7,060 population samples. INTERVENTION(S) Analysis of 11,984 single nucleotide polymorphisms on chromosome 10. MAIN OUTCOME MEASURE(S) Allele frequency differences between cases and controls. RESULT(S) Linkage analyses on families grouped by endometriosis symptoms (primarily subfertility) provided increased evidence for linkage (logarithm of odds score=3.62) near a previously reported linkage peak. Three independent association signals were found at 96.59 Mb (rs11592737), 105.63 Mb (rs1253130), and 124.25 Mb (rs2250804). Analyses including only samples from linkage families supported the association at all three regions. However, only rs11592737 in the cytochrome P450 subfamily C (CYP2C19) gene was replicated in an independent sample of 2,079 cases and 7,060 population controls. CONCLUSION(S) The role of the CYP2C19 gene in conferring risk for endometriosis warrants further investigation.

A high-density association screen of 155 ion transport genes for involvement with common migraine

The clinical overlap between monogenic Familial Hemiplegic Migraine (FHM) and common migraine subtypes, and the fact that all three FHM genes are involved in the transport of ions, suggest that ion transport genes may underlie susceptibility to common forms of migraine. To test this leading hypothesis, we examined common variation in 155 ion transport genes using 5257 single nucleotide polymorphisms (SNPs) in a Finnish sample of 841 unrelated migraine with aura cases and 884 unrelated non-migraine controls. The top signals were then tested for replication in four independent migraine case-control samples from the Netherlands, Germany and Australia, totalling 2835 unrelated migraine cases and 2740 unrelated controls. SNPs within 12 genes (KCNB2, KCNQ3, CLIC5, ATP2C2, CACNA1E, CACNB2, KCNE2, KCNK12, KCNK2, KCNS3, SCN5A and SCN9A) with promising nominal association (0.00041 < P < 0.005) in the Finnish sample were selected for replication. Although no variant remained significant after adjusting for multiple testing nor produced consistent evidence for association across all cohorts, a significant epistatic interaction between KCNB2 SNP rs1431656 (chromosome 8q13.3) and CACNB2 SNP rs7076100 (chromosome 10p12.33) (pointwise P = 0.00002; global P = 0.02) was observed in the Finnish case-control sample. We conclude that common variants of moderate effect size in ion transport genes do not play a major role in susceptibility to common migraine within these European populations, although there is some evidence for epistatic interaction between potassium and calcium channel genes, KCNB2 and CACNB2. Multiple rare variants or trans-regulatory elements of these genes are not ruled out.

Association of a low density lipoprotein receptor microsatellite variant with obesity

OBJECTIVE: To determine whether a microsatellite polymorphism located towards the 3' end of the low density lipoprotein receptor gene (LDLR) is associated with obesity. DESIGN: A cross-sectional case-control study. SUBJECTS: One hundred and seven obese individuals, defined as a body mass index (BMI) > or = 26 kg/m2, and 163 lean individuals, defined as a BMI < 26 kg/m2. MEASUREMENTS: BMI, blood pressure, serum lipids, alleles of LDLR microsatellite (106 bp, 108 bp and 112 bp). RESULTS: There was a significant association between variants of the LDLR microsatellite and obesity, in the overall tested population, due to a contributing effect in females (chi 2 = 12.3, P = 0.002), but not in males (chi 2 = 0.3, P = 0.87). In females, individuals with the 106 bp allele were more likely to be lean, while individuals with the 112 bp and/or 108 bp alleles tended to be obese. CONCLUSIONS: These results suggest that in females, LDLR may play a role in the development of obesity.

Cross-sectional study of a microsatellite marker in the low density lipoprotein receptor gene in obese normotensives

1. The low density lipoprotein receptor is an important regulator of serum cholesterol which may have implications for the development of both hypertension and obesity. In this study, genotypes for a low density lipoprotein receptor gene (LDLR) dinucleotide polymorphism were determined in both lean and obese normotensive populations. 2. In previous cross-sectional association studies an ApaLI and a HincII polymorphism for LDLR were shown to be associated with obesity in essential hypertensives. However, these polymorphisms did not show an association with obesity in normotensives. 3. In contrast, this study reports that preliminary results for an LDLR microsatellite marker, located more towards the 3' end of the gene, show a significant association with obesity in the normotensive population studied. These results indicate that LDLR could play an important role in the development of obesity, which might be independent of hypertension.

Small nerve fiber quantification in the diagnosis of diabetic sensorimotor polyneuropathy: Comparing corneal confocal microscopy with intraepidermal nerve fiber density

OBJECTIVE Quantitative assessment of small fiber damage is key to the early diagnosis and assessment of progression or regression of diabetic sensorimotor polyneuropathy (DSPN). Intraepidermal nerve fiber density (IENFD) is the current gold standard, but corneal confocal microscopy (CCM), an in vivo ophthalmic imaging modality, has the potential to be a noninvasive and objective image biomarker for identifying small fiber damage. The purpose of this study was to determine the diagnostic performance of CCM and IENFD by using the current guidelines as the reference standard. RESEARCH DESIGN AND METHODS Eighty-nine subjects (26 control subjects and 63 patients with type 1 diabetes), with and without DSPN, underwent a detailed assessment of neuropathy, including CCM and skin biopsy. RESULTS Manual and automated corneal nerve fiber density (CNFD) (P < 0.0001), branch density (CNBD) (P < 0.0001) and length (CNFL) (P < 0.0001), and IENFD (P < 0.001) were significantly reduced in patients with diabetes with DSPN compared with control subjects. The area under the receiver operating characteristic curve for identifying DSPN was 0.82 for manual CNFD, 0.80 for automated CNFD, and 0.66 for IENFD, which did not differ significantly (P = 0.14). CONCLUSIONS This study shows comparable diagnostic efficiency between CCM and IENFD, providing further support for the clinical utility of CCM as a surrogate end point for DSPN.

Defining the density debate in Brisbane: how urban consolidation is represented in the media

Rapid population growth, changing demographic profiles and increased focus on sustainable urban form has led to significant changes in settlement patterns in Australian cities. Growth management strategies are increasingly employed to help cities manage strain on infrastructure, housing and ecosystems. Urban consolidation is one such strategy and has been adopted by all Australian capital cities. Despite strong governmental support, urban consolidation has triggered much academic debate and has often been accompanied by staunch community opposition and complaints from the development industry about barriers to the provision of higher density housing. Greater understanding of stakeholder representations of higher density housing is important for planning, given the strong policy focus on urban consolidation nationally. This paper contributes to existing urban consolidation literature by empirically demonstrating how urban consolidation is represented in Brisbane’s newspaper media through the use of metaphors. Its conceptual departure point is Social Representations Theory, drawing on the theory’s notion of objectification to illustrate how the media translates the abstract notion of urban consolidation into a tangible and understandable object. The objectification of urban consolidation is identified and discussed relative to four themes: land use conflict; growth; neighbourhood change and apartment living. This paper argues that understanding stakeholder representations is important for planners seeking to promote and negotiate delivery of higher density development. It concludes that stakeholder representations can highlight key areas of contention to be addressed by planners, provide indications on the likelihood of public acceptance of increased housing densities and delineate the boundaries of urban consolidation debates.