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Sökning: WFRF:(Ntzani Evangelia E.)

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1.
  • Medina-Gomez, C., et al. (författare)
  • Life-Course Genome-wide Association Study Meta-analysis of Total Body BMD and Assessment of Age-Specific Effects
  • 2018
  • Ingår i: American Journal of Human Genetics. - : Cell Press. - 0002-9297. ; 102:1, s. 88-102
  • Tidskriftsartikel (refereegranskat)abstract
    • 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. © 2017 American Society of Human Genetics
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2.
  • Zheng, Hou-Feng, et al. (författare)
  • Whole-genome sequencing identifies EN1 as a determinant of bone density and fracture.
  • 2015
  • Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; 526:7571, s. 112-117
  • Tidskriftsartikel (refereegranskat)abstract
    • 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 mainly unknown. Bone mineral density (BMD) is highly heritable, a major predictor of osteoporotic fractures, and has been previously associated with common genetic variants, as well as rare, population-specific, coding variants. 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 (ref. 10); a population-based genome sequencing consortium), whole-exome sequencing (n = 3,549), deep imputation of genotyped samples using a combined UK10K/1000 Genomes 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 fourfold larger than the mean of previously reported common variants for lumbar spine BMD (rs11692564(T), MAF = 1.6%, replication effect size = +0.20 s.d., Pmeta = 2 × 10(-14)), which was also associated with a decreased risk of fracture (odds ratio = 0.85; P = 2 × 10(-11); ncases = 98,742 and ncontrols = 409,511). Using an En1(cre/flox) mouse model, we observed that conditional loss of En1 results in low bone mass, probably as a consequence of high bone turnover. We also identified a novel low-frequency non-coding variant with large effects on BMD near WNT16 (rs148771817(T), MAF = 1.2%, replication effect size = +0.41 s.d., 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.
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3.
  • Estrada, Karol, et al. (författare)
  • Genome-wide meta-analysis identifies 56 bone mineral density loci and reveals 14 loci associated with risk of fracture.
  • 2012
  • Ingår i: Nature genetics. - : Nature Publishing Group. - 1546-1718 .- 1061-4036. ; 44:5, s. 491-501
  • Tidskriftsartikel (refereegranskat)abstract
    • 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.
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4.
  • Oei, L., et al. (författare)
  • Genome-wide association study for radiographic vertebral fractures: A potential role for the 16q24 BMD locus
  • 2014
  • Ingår i: Bone. - : Elsevier. - 8756-3282 .- 1873-2763. ; 59, s. 20-27
  • Tidskriftsartikel (refereegranskat)abstract
    • Vertebral fracture risk is a heritable complex trait. The aim of this study was to identify genetic susceptibility factors for osteoporotic vertebral fracture applying a genome-wide association study (GWAS) approach. The GWAS discovery was based on the Rotterdam Study, a population-based study of elderly Dutch individuals aged >55 years; and comprising 329 cases and 2666 controls with radiographic scoring (McCloskey-Kanis) and genetic data. Replication of one top-associated SNP was pursued by de-novo genotyping of 15 independent studies across Europe, the United States, and Australia and one Asian study. Radiographic vertebral fracture assessment was performed using McCloskey-Kanis or Genant semi-quantitative definitions. SNPs were analyzed in relation to vertebral fracture using logistic regression models corrected for age and sex. Fixed effects inverse variance and Han-Eskin alternative random effects meta-analyses were applied. Genome-wide significance was set at p<5 x 10(-8). In the discovery, a SNP (rs11645938) on chromosome 16q24 was associated with the risk for vertebral fractures at p = 4.6 x 10(-8). However, the association was not significant across 5720 cases and 21,791 controls from 14 studies. Fixed-effects meta-analysis summary estimate was 1.06 (95% Cl: 0.98-1.14; p = 0.17), displaying high degree of heterogeneity (I-2= 57%; Q(het)p = 0.0006). Under Han-Eskin alternative random effects model the summary effect was significant (p = 0.0005). The SNP maps to a region previously found associated with lumbar spine bone mineral density (LS-BMD) in two large meta-analyses from the GEFOS consortium. A false positive association in the GWAS discovery cannot be excluded, yet, the low-powered setting of the discovery and replication settings (appropriate to identify risk effect size >1.25) may still be consistent with an effect size <1.10, more of the type expected in complex traits. Larger effort in studies with standardized phenotype definitions is needed to confirm or reject the involvement of this locus on the risk for vertebral fractures. (C) 2013 Elsevier Inc. All rights reserved.
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5.
  • Papadimitriou, Nikos, et al. (författare)
  • Burden of hip fracture using disability-adjusted life-years: : a pooled analysis of prospective cohorts in the CHANCES consortium
  • 2017
  • Ingår i: ; 2:5, s. e239-e246
  • Tidskriftsartikel (refereegranskat)abstract
    • BACKGROUND: No studies have estimated disability-adjusted life-years (DALYs) lost due to hip fractures using real-life follow-up cohort data. We aimed to quantify the burden of disease due to incident hip fracture using DALYs in prospective cohorts in the CHANCES consortium, and to calculate population attributable fractions based on DALYs for specific risk factors.METHODS: We used data from six cohorts of participants aged 50 years or older at recruitment to calculate DALYs. We applied disability weights proposed by the National Osteoporosis Foundation and did a series of sensitivity analyses to examine the robustness of DALY estimates. We calculated population attributable fractions for smoking, body-mass index (BMI), physical activity, alcohol intake, type 2 diabetes and parity, use of hormone replacement therapy, and oral contraceptives in women. We calculated summary risk estimates across cohorts with pooled analysis and random-effects meta-analysis methods.FINDINGS: 223 880 men and women were followed up for a mean of 13 years (SD 6). 7724 (3·5%) participants developed an incident hip fracture, of whom 413 (5·3%) died as a result. 5964 DALYs (27 per 1000 individuals) were lost due to hip fractures, 1230 (20·6%) of which were in the group aged 75-79 years. 4150 (69·6%) DALYs were attributed to disability. Current smoking was the risk factor responsible for the greatest hip fracture burden (7·5%, 95% CI 5·2-9·7) followed by physical inactivity (5·5%, 2·1-8·5), history of diabetes (2·8%, 2·1-4·0), and low to average BMI (2·0%, 1·4-2·7), whereas low alcohol consumption (0·01-2·5 g per day) and high BMI had a protective effect.INTERPRETATION: Hip fracture can lead to a substantial loss of healthy life-years in elderly people. National public health policies should be strengthened to reduce hip fracture incidence and mortality. Primary prevention measures should be strengthened to prevent falls, and reduce smoking and a sedentary lifestyle.FUNDING: European Community's Seventh Framework Programme.
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6.
  • Evangelou, Evangelos, et al. (författare)
  • A meta-analysis of genome-wide association studies identifies novel variants associated with osteoarthritis of the hip
  • 2014
  • Ingår i: Annals of the Rheumatic Diseases. - : British Medical Association. - 1468-2060. ; 73:12, s. 2130-2136
  • Tidskriftsartikel (refereegranskat)abstract
    • Objectives Osteoarthritis (OA) is the most common form of arthritis with a clear genetic component. To identify novel loci associated with hip OA we performed a meta-analysis of genome-wide association studies (GWAS) on European subjects. Methods We performed a two-stage meta-analysis on more than 78 000 participants. In stage 1, we synthesised data from eight GWAS whereas data from 10 centres were used for 'in silico' or 'de novo' replication. Besides the main analysis, a stratified by sex analysis was performed to detect possible sex-specific signals. Meta-analysis was performed using inverse-variance fixed effects models. A random effects approach was also used. Results We accumulated 11 277 cases of radiographic and symptomatic hip OA. We prioritised eight single nucleotide polymorphism (SNPs) for follow-up in the discovery stage (4349 OA cases); five from the combined analysis, two male specific and one female specific. One locus, at 20q13, represented by rs6094710 (minor allele frequency (MAF) 4%) near the NCOA3 (nuclear receptor coactivator 3) gene, reached genome-wide significance level with p=7.9x10(-9) and OR=1.28 (95% CI 1.18 to 1.39) in the combined analysis of discovery (p= 5.6x10(-8)) and follow-up studies (p=7.3x10(-4)). We showed that this gene is expressed in articular cartilage and its expression was significantly reduced in OA-affected cartilage. Moreover, two loci remained suggestive associated; rs5009270 at 7q31 (MAF 30%, p=9.9x10(-7), OR=1.10) and rs3757837 at 7p13 (MAF 6%, p=2.2x10(-6), OR=1.27 in male specific analysis). Conclusions Novel genetic loci for hip OA were found in this meta-analysis of GWAS.
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7.
  • Windhaber, Thomas, et al. (författare)
  • Educational strategies to train health care professionals across the education continuum on the process of frailty prevention and frailty management : a systematic review
  • 2018
  • Ingår i: Aging Clinical and Experimental Research. - 1594-0667 .- 1720-8319. ; 30:12, s. 1409-1415
  • Forskningsöversikt (refereegranskat)abstract
    • Background In addition to the normal process of ageing, frailty, defined as a geriatric syndrome, is becoming more prevalent. Around 10% of people over 65years and 25-50% of those aged over 85years are frail. Frail elderly are more vulnerable to external stressors and have an increased risk of adverse health outcomes. To tackle these challenges, European Union (EU) member states need to develop a health work force capable of the right skills mix. A goal-centred education and training of professionals is crucial for effective and efficient health care delivery for Europe's greying population.Aims The aim of this study was to systematically collect, review and critically appraise studies carried out to investigate the efficacy and effectiveness of comprehensive educational programmes for health professionals related to frailty prevention and/or frailty management.Methods A systematic review was carried out searching the databases PubMed, CINAHL, Cochrane CENTRAL, Medline, Up to date and Embase. Additionally, a manual search of the reference lists and searches via Google Scholar and greylit.org was done.Results No relevant publications addressing the evidence and sustainability of educational/training programmes for frailty prevention and/or frailty management were identified.Discussion The result of an empty review is surprising because several educational programmes in different countries are currently run.Conclusions A significant knowledge gap exists in the scientific literature regarding education and training of health care workers regarding prevention and management of frailty. Further research is needed to identify effective educational strategies for health professionals to prevent and manage frailty.
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8.
  • Morris, John A, et al. (författare)
  • An atlas of genetic influences on osteoporosis in humans and mice.
  • 2019
  • Ingår i: Nature genetics. - 1546-1718. ; 51, s. 258-266
  • Tidskriftsartikel (refereegranskat)abstract
    • Osteoporosis is a common aging-related disease diagnosed primarily using bone mineral density (BMD). We assessed genetic determinants of BMD as estimated by heel quantitative ultrasound in 426,824 individuals, identifying 518 genome-wide significant loci (301 novel), explaining 20% of its variance. We identified 13 bone fracture loci, all associated with estimated BMD (eBMD), in ~1.2 million individuals. We then identified target genes enriched for genes known to influence bone density and strength (maximum odds ratio (OR) = 58, P = 1 × 10-75) from cell-specific features, including chromatin conformation and accessible chromatin sites. We next performed rapid-throughput skeletal phenotyping of 126 knockout mice with disruptions in predicted target genes and found an increased abnormal skeletal phenotype frequency compared to 526 unselected lines (P < 0.0001). In-depth analysis of one gene, DAAM2, showed a disproportionate decrease in bone strength relative to mineralization. This genetic atlas provides evidence linking associated SNPs to causal genes, offers new insight into osteoporosis pathophysiology, and highlights opportunities for drug development.
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9.
  • Panagopoulou, Paraskevi, et al. (författare)
  • Parental age and the risk of childhood acute myeloid leukemia : results from the Childhood Leukemia International Consortium
  • 2019
  • Ingår i: Cancer Epidemiology. - 1877-7821 .- 1877-783X. ; 59, s. 158-165
  • Tidskriftsartikel (refereegranskat)abstract
    • Background:Parental age has been associated with several childhood cancers, albeit the evidence is still inconsistent.Aim:To examine the associations of parental age at birth with acute myeloid leukemia (AML) among children aged 0-14 years using individual-level data from the Childhood Leukemia International Consortium (CLIC) and non-CLIC studies.Material/methods: We analyzed data of 3182 incident AML cases and 8377 controls from 17 studies [seven registry-based case-control (RCC) studies and ten questionnaire-based case-control (QCC) studies]. AML risk in association with parental age was calculated using multiple logistic regression, meta-analyses, and pooled-effect estimates. Models were stratified by age at diagnosis (infants < 1 year-old vs. children 1-14 years-old) and by study design, using five-year parental age increments and controlling for sex, ethnicity, birthweight, prematurity, multiple gestation, birth order, maternal smoking and education, age at diagnosis (cases aged 1-14 years), and recruitment time period.Results:Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) derived from RCC, but not from the QCC, studies showed a higher AML risk for infants of mothers >= 40-year-old (OR = 6.87; 95% CI: 2.12-22.25). There were no associations observed between any other maternal or paternal age group and AML risk for children older than one year.Conclusions:An increased risk of infant AML with advanced maternal age was found using data from RCC, but not from QCC studies; no parental age-AML associations were observed for older children.
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