Bone mineral density (BMD) is the most important 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-associated BMD markers for replication in 50,933 independent subjects and for risk of low-trauma fracture in 31,016 cases and 102,444 controls. We identified 56 loci (32 novel)associated with BMD atgenome-wide significant level (P<5×10−8). Several of these factors cluster within the RANK-RANKL-OPG, mesenchymal-stem-cell differentiation, endochondral ossification and the Wnt signalling pathways. However, we also discovered loci containing genes not known to play a role in bone biology. Fourteen BMD loci were also associated with fracture risk (P<5×10−4, Bonferroni corrected), of which six reached P<5×10−8 including: 18p11.21 (C18orf19), 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.

SUMMARY The extent to which low-frequency (minor allele frequency [MAF] between 1–5%) and rare (MAF ≤ 1%) variants contribute to complex traits and disease in the general population is largely unknown. Bone mineral density (BMD) is highly heritable, is a major predictor of osteoporotic fractures and has been previously associated with common genetic variants1–8, and rare, population-specific, coding variants9. Here we identify novel non-coding genetic variants with large effects on BMD (ntotal = 53,236) and fracture (ntotal = 508,253) in individuals of European ancestry from the general population. Associations for BMD were derived from whole-genome sequencing (n=2,882 from UK10K), whole-exome sequencing (n= 3,549), deep imputation of genotyped samples using a combined UK10K/1000Genomes reference panel (n=26,534), and de-novo replication genotyping (n= 20,271). We identified a low-frequency non-coding variant near a novel locus, EN1, with an effect size 4-fold larger than the mean of previously reported common variants for lumbar spine BMD8 (rs11692564[T], MAF = 1.7%, replication effect size = +0.20 standard deviations [SD], Pmeta = 2×10−14), which was also associated with a decreased risk of fracture (OR = 0.85; P = 2×10−11; ncases = 98,742 and ncontrols = 409,511). Using an En1Cre/flox mouse model, we observed that conditional loss of En1 results in low bone mass, likely as a consequence of high bone turn-over. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817[T], MAF = 1.1%, replication effect size = +0.39 SD, Pmeta = 1×10−11). In general, there was an excess of association signals arising from deleterious coding and conserved non-coding variants. These findings provide evidence that low-frequency non-coding variants have large effects on BMD and fracture, thereby providing rationale for whole-genome sequencing and improved imputation reference panels to study the genetic architecture of complex traits and disease in the general population.

Background and purposeFractures are most common in youth and in the elderly, with differences in incidence over time and between regions. We present the fracture pattern in a population of youths ≤ 19 years of age, who were seen at Umeå University Hospital, Sweden.Material and methodsAll injuries seen at the hospital have been recorded in a database since 1993. The data include variables such as age, sex, date, type of injury, mechanism of injury, and treatment. For the period 1993–2007, there were 10,203 injury events that had resulted in at least 1 fracture.ResultsThe incidence for the whole period was 201/104 person years. The incidence increased by 13% during the period 1998–2007, when we were able to control for registration errors. The most common fracture site was the distal forearm. The most common type of injury mechanism was falling. The peak incidence occurred at 11–12 years in girls and at 13–14 years in boys, with a male-to-female incidence ratio of 1.5. We found variations in mechanisms and activities at injury with age, and over time.InterpretationFractures are caused by a combination of intrinsic and extrinsic factors that vary with age. We believe the increase in incidence is partly explained by changes in children's activity patterns over time. Further research may help to identify preventive measures to reduce the number of fractures, in particular those involving hospital care, surgical treatment, and—most importantly—long-term impairment.

Patients with postoperative delirium can be successfully treated, resulting in fewer days of delirium, fewer other complications, and shorter length of hospitalization.

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Identification of genes associated with pain insensitivity syndromes can increase the understanding of the pathways involved in pain and contribute to the understanding of how sensory pathways relate to other neurological functions. In this report we describe the mapping and identification of the gene responsible for loss of deep pain perception in a large family from northern Sweden. The loss of pain perception in this family is characterized by impairment in the sensing of deep pain and temperature but with normal mental abilities and with most other neurological responses intact. A severe reduction of unmyelinated nerve fibers and a moderate loss of thin myelinated nerve fibers are observed in the patients. Thus the cases in this study fall into the class of patients with loss of pain perception with underlying peripheral neuropathy. Clinically they best fit into HSAN V. Using a model of recessive inheritance we identified an 8.3 Mb region on chromosome 1p11.2-p13.2 shared by the affected individuals in the family. Analysis of functional candidate genes in the disease critical region revealed a mutation in the coding region of the nerve growth-factor beta (NGFB) gene specific for the disease haplotype. This NGF mutation seems to separate the effects of NGF involved in development of central nervous system functions such as mental abilities, from those involved in peripheral pain pathways. This mutation could therefore potentially provide an important tool to study different roles of NGF, and of pain control.

This prospective observational data collection study assessed the cost and quality of life related to hip, vertebral and wrist fracture 1 year after the fracture, based on a patient sample consisting of 635 male and female patients surviving a year after fracture. Data regarding resource use and quality of life related to fractures was collected by questionnaires at baseline, 4 months and 12 months. Information was collected by the use of patients' records, register sources and by asking the patient. Quality of life was estimated with the EQ-5D questionnaire. Costs were estimated from a societal perspective, including direct and indirect costs. The mean fracture-related cost the year after a hip, vertebral and wrist fracture were estimated, in euros (), at 14,221, 12,544 and 2,147, respectively [converted from Swedish krona (SEK) at an exchange rate of 9.1268 SEK/]. The mean reduction in quality of life was estimated at 0.17, 0.26 and 0.06 for hip, vertebral and wrist fracture, respectively. Based on the results, the yearly burden of osteoporosis in Sweden could be estimated at 0.5 billion (SEK 4.6 billion). The patient sample for vertebral fracture was fairly small and included a high proportion of fractures leading to hospitalization, but they indicate a higher cost and loss of quality of life related to vertebral fracture than previously perceived.

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