C-reactive protein (CRP) is a sensitive biomarker of chronic low-grade inflammation and is associated with multiple complex diseases. The genetic determinants of chronic inflammation remain largely unknown, and the causal role of CRP in several clinical outcomes is debated. We performed two genome-wide association studies (GWASs), on HapMap and 1000 Genomes imputed data, of circulating amounts of CRP by using data from 88 studies comprising 204,402 European individuals. Additionally, we performed in silico functional analyses and Mendelian randomization analyses with several clinical outcomes. The GWAS meta-analyses of CRP revealed 58 distinct genetic loci (p < 5 3 10 À8). After adjustment for body mass index in the regression analysis, the associations at all except three loci remained. The lead variants at the distinct loci explained up to 7.0% of the variance in circulating amounts of CRP. We identified 66 gene sets that were organized in two substantially correlated clusters, one mainly composed of immune pathways and the other characterized by metabolic pathways in the liver. Mendelian randomization analyses revealed a causal protective effect of CRP on schizophrenia and a risk-increasing effect on bipolar disorder. Our findings provide further insights into the biology of inflammation and could lead to interventions for treating inflammation and its clinical consequences.

Bone mineral density (BMD) assessed by DXA is used to evaluate bone health. In children, total body (TB) measurements are commonly used; in older individuals, BMD at the lumbar spine (LS) and femoral neck (FN) is used to diagnose osteoporosis. To date, genetic variants in more than 60 loci have been identified as associated with BMD. To investigate the genetic determinants of TB-BMD variation along the life course and test for age-specific effects, we performed a meta-analysis of 30 genome-wide association studies (GWASs) of TB-BMD including 66,628 individuals overall and divided across five age strata, each spanning 15 years. We identified variants associated with TB-BMD at 80 loci, of which 36 have not been previously identified; overall, they explain approximately 10% of the TB-BMD variance when combining all age groups and influence the risk of fracture. Pathway and enrichment analysis of the association signals showed clustering within gene sets implicated in the regulation of cell growth and SMAD proteins, overexpressed in the musculoskeletal system, and enriched in enhancer and promoter regions. These findings reveal TB-BMD as a relevant trait for genetic studies of osteoporosis, enabling the identification of variants and pathways influencing different bone compartments. Only variants in ESR1 and close proximity to RANKL showed a clear effect dependency on age. This most likely indicates that the majority of genetic variants identified influence BMD early in life and that their effect can be captured throughout the life course.

Analysis of chromosomal aberrations is used to determine the prognosis of neuroblastomas (NBs) and to aid treatment decisions. MYCN amplification (MNA) alone is an incomplete poor prognostic factor, and chromosome 11q status has recently been included in risk classification. We analyzed 165 NB tumors using high-density SNP microarrays and specifically compared the high-risk groups defined by MNA ( n = 37) and 11q-deletion ( n = 21). Median patient age at diagnosis was 21 months for MNA tumors and 42 months for 11q-deletion tumors, and median survival time after diagnosis was 16 months for MNA and 40 months for 11q deletion. Overall survival (at 8 years) was ∼35% in both groups. MNA and 11q deletion were almost mutually exclusive; only one case harbored both aberrations. The numbers of segmental aberrations differed significantly; the MNA group had a median of four aberrations, whereas the 11q-deletion group had 12. The high frequency of chromosomal breaks in the 11q-deletion group is suggestive of a chromosomal instability phenotype gene located in 11q; one such gene, H2AFX , is located in 11q23.3 (within the 11q-deletion region). Furthermore, in the groups with segmental aberrations without MNA or 11q deletion, the tumors with 17q gain have worse prognosis than those with segmental aberrations without 17q gain, which have a favorable outcome. This study has implications for therapy in different risk groups and stresses that genome-wide microarray analyses should be included in clinical management to fully evaluate risk, aid diagnosis, and guide treatment.

We aimed to identify genetic variants associated with cortical bone thickness (CBT) and bone mineral density (BMD) by performing two separate genome-wide association study (GWAS) meta-analyses for CBT in 3 cohorts comprising 5,878 European subjects and for BMD in 5 cohorts comprising 5,672 individuals. We then assessed selected single-nucleotide polymorphisms (SNPs) for osteoporotic fracture in 2,023 cases and 3,740 controls. Association with CBT and forearm BMD was tested for ∼2.5 million SNPs in each cohort separately, and results were meta-analyzed using fixed effect meta-analysis. We identified a missense SNP (Thr>Ile; rs2707466) located in the WNT16 gene (7q31), associated with CBT (effect size of −0.11 standard deviations [SD] per C allele, P = 6.2×10−9). This SNP, as well as another nonsynonymous SNP rs2908004 (Gly>Arg), also had genome-wide significant association with forearm BMD (−0.14 SD per C allele, P = 2.3×10−12, and −0.16 SD per G allele, P = 1.2×10−15, respectively). Four genome-wide significant SNPs arising from BMD meta-analysis were tested for association with forearm fracture. SNP rs7776725 in FAM3C, a gene adjacent to WNT16, was associated with a genome-wide significant increased risk of forearm fracture (OR = 1.33, P = 7.3×10−9), with genome-wide suggestive signals from the two missense variants in WNT16 (rs2908004: OR = 1.22, P = 4.9×10−6 and rs2707466: OR = 1.22, P = 7.2×10−6). We next generated a homozygous mouse with targeted disruption of Wnt16. Female Wnt16−/− mice had 27% (P<0.001) thinner cortical bones at the femur midshaft, and bone strength measures were reduced between 43%–61% (6.5×10−13

Background: Although dual-energy x-ray absorptiometry (DXA) assessed areal bone density (aBMD) is the clinical standard for determining fracture risk, the majority of older adults who sustain a fracture do not have osteoporosis (T-score < −2.5). Importantly, bone fragility results not only from low BMD, but also from deterioration in bone structure. We used high-resolution peripheral quantitative computed tomography (HR-pQCT) data from eight cohorts to evaluate whether HR-pQCT indices were associated with fracture risk independently of femoral neck (FN) aBMD and FRAX (Fracture Risk Assessment Tool) score. Methods: Participants included 7,254 individuals (66% women) from cohorts in the USA (Framingham, Mayo Clinic), France (QUALYOR, STRAMBO, OFELY), Switzerland (GERICO), Canada (CaMos), and Sweden (MrOS). We used Cox proportional hazards models to estimate hazards ratios (HRs) for the association between bone parameters (per standard deviation, SD, deficit) and incident fracture, adjusting for age, sex, height, weight and cohort. Findings: Mean baseline age was 69 (±9) years (range, 40 to 96). Cumulative incidence of fracture was 11% (n=765) over a mean follow-up time of 4.6 (± 2.4) years. The majority of participants (92%) had a femoral neck T-score >−2.5, and thus did not meet diagnostic criteria for osteoporosis. Failure load was the bone measure most strongly associated with risk of fracture: tibia HR=2.40 (1.98-2.91), radius HR=2.13 (1.77-2.56), per SD decrease in failure load. HRs for other bone indices ranged from HR=1.12 (1.03-1.23) per SD increase in tibia cortical porosity to HR=1.58 (1.45-1.72) per SD decrease in radius trabecular volumetric bone density (vBMD). After further adjustment for FN aBMD or FRAX, HRs were attenuated, but most bone parameters remained significantly associated with fracture. Cortical density, trabecular number, and trabecular thickness at the distal radius were the best set of predictors of fracture; while the same indices plus cortical area were identified for the tibia. These HR-pQCT indices and failure load improved prediction of fracture, beyond FN aBMD alone or FRAX. Interpretation: Results from this large international cohort of women and men confirm prior studies showing that deficits in trabecular and cortical bone density and structure contribute to fracture risk independently of aBMD and FRAX. Measurements of cortical and trabecular bone density and morphology at the peripheral skeleton may improve identification of those at highest risk for fracture. Funding: National Institutes of Health, National Institute of Arthritis Musculoskeletal and Skin Diseases, R01AR061445

Common single-nucleotide polymorphisms (SNPs) are predicted to collectively explain 40–50% of phenotypic variation in human height, but identifying the specific variants and associated regions requires huge sample sizes1. Here, using data from a genome-wide association study of 5.4 million individuals of diverse ancestries, we show that 12,111 independent SNPs that are significantly associated with height account for nearly all of the common SNP-based heritability. These SNPs are clustered within 7,209 non-overlapping genomic segments with a mean size of around 90 kb, covering about 21% of the genome. The density of independent associations varies across the genome and the regions of increased density are enriched for biologically relevant genes. In out-of-sample estimation and prediction, the 12,111 SNPs (or all SNPs in the HapMap 3 panel2) account for 40% (45%) of phenotypic variance in populations of European ancestry but only around 10–20% (14–24%) in populations of other ancestries. Effect sizes, associated regions and gene prioritization are similar across ancestries, indicating that reduced prediction accuracy is likely to be explained by linkage disequilibrium and differences in allele frequency within associated regions. Finally, we show that the relevant biological pathways are detectable with smaller sample sizes than are needed to implicate causal genes and variants. Overall, this study provides a comprehensive map of specific genomic regions that contain the vast majority of common height-associated variants. Although this map is saturated for populations of European ancestry, further research is needed to achieve equivalent saturation in other ancestries.

Objective There is no curative treatment for osteoarthritis (OA), which is the most common form of arthritis. This study was undertaken to identify causal risk factors of knee, hip, and hand OA. Methods Individual‐level data from 384,838 unrelated participants in the UK Biobank study were analyzed. Mendelian randomization (MR) analyses were performed to test for causality for body mass index (BMI), bone mineral density (BMD), serum high‐density lipoprotein cholesterol, low‐density lipoprotein cholesterol, and triglyceride levels, type 2 diabetes, systolic blood pressure (BP), and C‐reactive protein (CRP) levels. The primary outcome measure was OA determined using hospital diagnoses (all sites, n = 48,431; knee, n = 19,727; hip, n = 11,875; hand, n = 2,330). Odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. Results MR analyses demonstrated a robust causal association of genetically determined BMI with all OA (OR per SD increase 1.57 [95% CI 1.44–1.71]), and with knee OA and hip OA, but not with hand OA. Increased genetically determined femoral neck BMD was causally associated with all OA (OR per SD increase 1.14 [95% CI 1.06–1.22]), knee OA, and hip OA. Low systolic BP was causally associated with all OA (OR per SD decrease 1.55 [95% CI 1.29–1.87]), knee OA, and hip OA. There was no evidence of causality for the other tested metabolic factors or CRP level. Conclusion Our findings indicate that BMI exerts a major causal effect on the risk of OA at weight‐bearing joints, but not at the hand. Evidence of causality of all OA, knee OA, and hip OA was also observed for high femoral neck BMD and low systolic BP. However, we found no evidence of causality for other metabolic factors or CRP level.

Most previous genetic epidemiology studies within the field of osteoporosis have focused on the genetics of the complex trait areal bone mineral density (aBMD), not being able to differentiate genetic determinants of cortical volumetric BMD (vBMD), trabecular vBMD, and bone microstructural traits. The objective of this study was to separately identify genetic determinants of these bone traits as analysed by peripheral quantitative computed tomography (pQCT). Separate GWA meta-analyses for cortical and trabecular vBMDs were performed. The cortical vBMD GWA meta-analysis (n = 5,878) followed by replication (n = 1,052) identified genetic variants in four separate loci reaching genome-wide significance (RANKL, rs1021188, p = 3.6×10−14; LOC285735, rs271170, p = 2.7×10−12; OPG, rs7839059, p = 1.2×10−10; and ESR1/C6orf97, rs6909279, p = 1.1×10−9). The trabecular vBMD GWA meta-analysis (n = 2,500) followed by replication (n = 1,022) identified one locus reaching genome-wide significance (FMN2/GREM2, rs9287237, p = 1.9×10−9). High-resolution pQCT analyses, giving information about bone microstructure, were available in a subset of the GOOD cohort (n = 729). rs1021188 was significantly associated with cortical porosity while rs9287237 was significantly associated with trabecular bone fraction. The genetic variant in the FMN2/GREM2 locus was associated with fracture risk in the MrOS Sweden cohort (HR per extra T allele 0.75, 95% confidence interval 0.60–0.93) and GREM2 expression in human osteoblasts. In conclusion, five genetic loci associated with trabecular or cortical vBMD were identified. Two of these (FMN2/GREM2 and LOC285735) are novel bone-related loci, while the other three have previously been reported to be associated with aBMD. The genetic variants associated with cortical and trabecular bone parameters differed, underscoring the complexity of the genetics of bone parameters. We propose that a genetic variant in the RANKL locus influences cortical vBMD, at least partly, via effects on cortical porosity, and that a genetic variant in the FMN2/GREM2 locus influences GREM2 expression in osteoblasts and thereby trabecular number and thickness as well as fracture risk.