| 1. |
- Craddock, Nick, et al.
(author)
-
Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
-
Journal article (peer-reviewed)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
|
|
| 2. |
- Newton-Cheh, Christopher, et al.
(author)
-
Genome-wide association study identifies eight loci associated with blood pressure
- 2009
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:6, s. 666-676
-
Journal article (peer-reviewed)abstract
- Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5 million genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N <= 71,225 European ancestry, N <= 12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N 29,136). We identified association between systolic or diastolic blood pressure and common variants in eight regions near the CYP17A1 (P = 7 x 10(-24)), CYP1A2 (P = 1 x 10(-23)), FGF5 (P = 1 x 10(-21)), SH2B3 (P = 3 x 10(-18)), MTHFR (P = 2 x 10(-13)), c10orf107 (P = 1 x 10(-9)), ZNF652 (P = 5 x 10(-9)) and PLCD3 (P = 1 x 10(-8)) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.
|
|
| 3. |
- Hudson, Thomas J., et al.
(author)
-
International network of cancer genome projects
- 2010
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7291, s. 993-998
-
Journal article (peer-reviewed)abstract
- The International Cancer Genome Consortium (ICGC) was launched to coordinate large-scale cancer genome studies in tumours from 50 different cancer types and/or subtypes that are of clinical and societal importance across the globe. Systematic studies of more than 25,000 cancer genomes at the genomic, epigenomic and transcriptomic levels will reveal the repertoire of oncogenic mutations, uncover traces of the mutagenic influences, define clinically relevant subtypes for prognosis and therapeutic management, and enable the development of new cancer therapies.
|
|
| 4. |
- Pennells, Lisa, et al.
(author)
-
Equalization of four cardiovascular risk algorithms after systematic recalibration : individual-participant meta-analysis of 86 prospective studies
- 2019
-
In: European Heart Journal. - : Oxford University Press (OUP). - 0195-668X .- 1522-9645. ; 40:7, s. 621-
-
Journal article (peer-reviewed)abstract
- Aims: There is debate about the optimum algorithm for cardiovascular disease (CVD) risk estimation. We conducted head-to-head comparisons of four algorithms recommended by primary prevention guidelines, before and after ‘recalibration’, a method that adapts risk algorithms to take account of differences in the risk characteristics of the populations being studied.Methods and results: Using individual-participant data on 360 737 participants without CVD at baseline in 86 prospective studies from 22 countries, we compared the Framingham risk score (FRS), Systematic COronary Risk Evaluation (SCORE), pooled cohort equations (PCE), and Reynolds risk score (RRS). We calculated measures of risk discrimination and calibration, and modelled clinical implications of initiating statin therapy in people judged to be at ‘high’ 10 year CVD risk. Original risk algorithms were recalibrated using the risk factor profile and CVD incidence of target populations. The four algorithms had similar risk discrimination. Before recalibration, FRS, SCORE, and PCE over-predicted CVD risk on average by 10%, 52%, and 41%, respectively, whereas RRS under-predicted by 10%. Original versions of algorithms classified 29–39% of individuals aged ≥40 years as high risk. By contrast, recalibration reduced this proportion to 22–24% for every algorithm. We estimated that to prevent one CVD event, it would be necessary to initiate statin therapy in 44–51 such individuals using original algorithms, in contrast to 37–39 individuals with recalibrated algorithms.Conclusion: Before recalibration, the clinical performance of four widely used CVD risk algorithms varied substantially. By contrast, simple recalibration nearly equalized their performance and improved modelled targeting of preventive action to clinical need.
|
|
| 5. |
- Bousquet, Jean, et al.
(author)
-
Allergic Rhinitis and its Impact on Asthma (ARIA) Phase 4 (2018) : Change management in allergic rhinitis and asthma multimorbidity using mobile technology
- 2019
-
In: Journal of Allergy and Clinical Immunology. - : Elsevier. - 0091-6749 .- 1097-6825. ; 143:3, s. 864-879
-
Journal article (peer-reviewed)abstract
- Allergic Rhinitis and its Impact on Asthma (ARIA) has evolved from a guideline by using the best approach to integrated care pathways using mobile technology in patients with allergic rhinitis (AR) and asthma multimorbidity. The proposed next phase of ARIA is change management, with the aim of providing an active and healthy life to patients with rhinitis and to those with asthma multimorbidity across the lifecycle irrespective of their sex or socioeconomic status to reduce health and social inequities incurred by the disease. ARIA has followed the 8-step model of Kotter to assess and implement the effect of rhinitis on asthma multimorbidity and to propose multimorbid guidelines. A second change management strategy is proposed by ARIA Phase 4 to increase self-medication and shared decision making in rhinitis and asthma multimorbidity. An innovation of ARIA has been the development and validation of information technology evidence-based tools (Mobile Airways Sentinel Network [MASK]) that can inform patient decisions on the basis of a self-care plan proposed by the health care professional.
|
|
| 6. |
- Wood, Angela M., et al.
(author)
-
Risk thresholds for alcohol consumption : combined analysis of individual-participant data for 599 912 current drinkers in 83 prospective studies
- 2018
-
In: The Lancet. - : Elsevier. - 0140-6736 .- 1474-547X. ; 391:10129, s. 1513-1523
-
Journal article (peer-reviewed)abstract
- Background: Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.Methods: We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12.5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5.6 years [5th-95th percentile 1.04-13.5]) from 71 011 participants from 37 studies.Findings: In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5.4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1.14, 95% CI, 1.10-1.17), coronary disease excluding myocardial infarction (1.06, 1.00-1.11), heart failure (1.09, 1.03-1.15), fatal hypertensive disease (1.24, 1.15-1.33); and fatal aortic aneurysm (1.15, 1.03-1.28). By contrast, increased alcohol consumption was loglinearly associated with a lower risk of myocardial infarction (HR 0.94, 0.91-0.97). In comparison to those who reported drinking >0-<= 100 g per week, those who reported drinking >100-<= 200 g per week, >200-<= 350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively.Interpretation: In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.
|
|
| 7. |
- Wormser, David, et al.
(author)
-
Adult height and the risk of cause-specific death and vascular morbidity in 1 million people : individual participant meta-analysis
- 2012
-
In: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 41:5, s. 1419-1433
-
Journal article (peer-reviewed)abstract
- BackgroundThe extent to which adult height, a biomarker of the interplay of genetic endowment and early-life experiences, is related to risk of chronic diseases in adulthood is uncertain.MethodsWe calculated hazard ratios (HRs) for height, assessed in increments of 6.5 cm, using individual-participant data on 174 374 deaths or major non-fatal vascular outcomes recorded among 1 085 949 people in 121 prospective studies.ResultsFor people born between 1900 and 1960, mean adult height increased 0.5-1 cm with each successive decade of birth. After adjustment for age, sex, smoking and year of birth, HRs per 6.5 cm greater height were 0.97 (95% confidence interval: 0.96-0.99) for death from any cause, 0.94 (0.93-0.96) for death from vascular causes, 1.04 (1.03-1.06) for death from cancer and 0.92 (0.90-0.94) for death from other causes. Height was negatively associated with death from coronary disease, stroke subtypes, heart failure, stomach and oral cancers, chronic obstructive pulmonary disease, mental disorders, liver disease and external causes. In contrast, height was positively associated with death from ruptured aortic aneurysm, pulmonary embolism, melanoma and cancers of the pancreas, endocrine and nervous systems, ovary, breast, prostate, colorectum, blood and lung. HRs per 6.5 cm greater height ranged from 1.26 (1.12-1.42) for risk of melanoma death to 0.84 (0.80-0.89) for risk of death from chronic obstructive pulmonary disease. HRs were not appreciably altered after further adjustment for adiposity, blood pressure, lipids, inflammation biomarkers, diabetes mellitus, alcohol consumption or socio-economic indicators.ConclusionAdult height has directionally opposing relationships with risk of death from several different major causes of chronic diseases.
|
|
| 8. |
- Aartsen, M. G., et al.
(author)
-
A Combined Maximum-Likelihood Analysis Of The High-Energy Astrophysical Neutrino Flux Measured With Icecube
- 2015
-
In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 809:1
-
Journal article (peer-reviewed)abstract
- Evidence for an extraterrestrial flux of high-energy neutrinos has now been found in multiple searches with the IceCube detector. The first solid evidence was provided by a search for neutrino events with deposited energies greater than or similar to 30 TeV and interaction vertices inside the instrumented volume. Recent analyses suggest that the extraterrestrial flux extends to lower energies and is also visible with throughgoing, nu(mu)-induced tracks from the Northern Hemisphere. Here, we combine the results from six different IceCube searches for astrophysical neutrinos in a maximum-likelihood analysis. The combined event sample features high-statistics samples of shower-like and track-like events. The data are fit in up to three observables: energy, zenith angle, and event topology. Assuming the astrophysical neutrino flux to be isotropic and to consist of equal flavors at Earth, the all-flavor spectrum with neutrino energies between 25 TeV and 2.8 PeV is well described by an unbroken power law with best-fit spectral index -2.50 +/- 0.09 and a flux at 100 TeV of (6.7(-1.2)(+1.1)) x 10(-18) GeV-1 s(-1) sr(-1) cm(-2). Under the same assumptions, an unbroken power law with index -2 is disfavored with a significance of 3.8 sigma (p = 0.0066%) with respect to the best fit. This significance is reduced to 2.1 sigma (p = 1.7%) if instead we compare the best fit to a spectrum with index -2 that has an exponential cut-off at high energies. Allowing the electron-neutrino flux to deviate from the other two flavors, we find a nu(e) fraction of 0.18 +/- 0.11 at Earth. The sole production of electron neutrinos, which would be characteristic of neutron-decay-dominated sources, is rejected with a significance of 3.6 sigma ( p = 0.014%).
|
|
| 9. |
- Aartsen, M. G., et al.
(author)
-
An All-Sky Search For Three Flavors Of Neutrinos From Gamma-Ray Bursts With The Icecube Neutrino Observatory
- 2016
-
In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 824:2
-
Journal article (peer-reviewed)abstract
- We present the results and methodology of a search for neutrinos produced in the decay of charged pions created in interactions between protons and gamma-rays during the prompt emission of 807 gamma-ray bursts (GRBs) over the entire sky. This three-year search is the first in IceCube for shower-like Cherenkov light patterns from electron, muon, and tau neutrinos correlated with GRBs. We detect five low-significance events correlated with five GRBs. These events are consistent with the background expectation from atmospheric muons and neutrinos. The results of this search in combination with those of IceCube's four years of searches for track-like Cherenkov light patterns from muon neutrinos correlated with Northern-Hemisphere GRBs produce limits that tightly constrain current models of neutrino and ultra high energy cosmic ray production in GRB fireballs.
|
|
| 10. |
- Aartsen, M. G., et al.
(author)
-
Anisotropy In Cosmic-Ray Arrival Directions In The Southern Hemisphere Based On Six Years Of Data From The Icecube Detector
- 2016
-
In: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 826:2
-
Journal article (peer-reviewed)abstract
- The IceCube Neutrino Observatory accumulated a total of 318 billion cosmic-ray-induced muon events between 2009 May and 2015 May. This data set was used for a detailed analysis of the sidereal anisotropy in the arrival directions of cosmic rays in the TeV to PeV energy range. The observed global sidereal anisotropy features large regions of relative excess and deficit, with amplitudes of the order of 10(-3) up to about 100 TeV. A decomposition of the arrival direction distribution into spherical harmonics shows that most of the power is contained in the low-multipole (l <= 4) moments. However, higher multipole components are found to be statistically significant down to an angular scale of less than 10 degrees, approaching the angular resolution of the detector. Above 100 TeV, a change in the morphology of the arrival direction distribution is observed, and the anisotropy is characterized by a wide relative deficit whose amplitude increases with primary energy up to at least 5 PeV, the highest energies currently accessible to IceCube. No time dependence of the large-and small-scale structures is observed in the period of six years covered by this analysis. The high-statistics data set reveals more details of the properties of the anisotropy and is potentially able to shed light on the various physical processes that are responsible for the complex angular structure and energy evolution.
|
|
