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Sökning: WFRF:(Mason Amy M.)

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1.
  • Beecham, Ashley H, et al. (författare)
  • Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis.
  • 2013
  • Ingår i: Nature genetics. - : NATURE PUBLISHING GROUP, 75 VARICK ST, 9TH FLR, NEW YORK, NY 10013-1917 USA. - 1546-1718 .- 1061-4036. ; 45:11, s. 1353-60
  • Tidskriftsartikel (refereegranskat)abstract
    • Using the ImmunoChip custom genotyping array, we analyzed 14,498 subjects with multiple sclerosis and 24,091 healthy controls for 161,311 autosomal variants and identified 135 potentially associated regions (P < 1.0 × 10(-4)). In a replication phase, we combined these data with previous genome-wide association study (GWAS) data from an independent 14,802 subjects with multiple sclerosis and 26,703 healthy controls. In these 80,094 individuals of European ancestry, we identified 48 new susceptibility variants (P < 5.0 × 10(-8)), 3 of which we found after conditioning on previously identified variants. Thus, there are now 110 established multiple sclerosis risk variants at 103 discrete loci outside of the major histocompatibility complex. With high-resolution Bayesian fine mapping, we identified five regions where one variant accounted for more than 50% of the posterior probability of association. This study enhances the catalog of multiple sclerosis risk variants and illustrates the value of fine mapping in the resolution of GWAS signals.
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2.
  • Sawcer, Stephen, et al. (författare)
  • Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
  • 2011
  • Ingår i: Nature. - 0028-0836 .- 1476-4687. ; 476:7359, s. 214-219
  • Tidskriftsartikel (refereegranskat)abstract
    • Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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3.
  • Kattge, Jens, et al. (författare)
  • TRY plant trait database - enhanced coverage and open access
  • 2020
  • Ingår i: Global Change Biology. - : Wiley-Blackwell. - 1354-1013 .- 1365-2486. ; 26:1, s. 119-188
  • Tidskriftsartikel (refereegranskat)abstract
    • Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives.
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4.
  • Gill, Dipender, et al. (författare)
  • ACE inhibition and cardiometabolic risk factors, lung ACE2 and TMPRSS2 gene expression, and plasma ACE2 levels : a Mendelian randomization study
  • 2020
  • Ingår i: Royal Society Open Science. - : ROYAL SOC. - 2054-5703. ; 7:11
  • Tidskriftsartikel (refereegranskat)abstract
    • Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). The expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19. We use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to investigate whether these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. We observed no consistent evidence of an association of genetically predicted serum ACE levels with any of our outcomes. There was weak evidence for an association of genetically predicted serum ACE levels with ACE2 gene expression in the Lung eQTL Consortium (p = 0.014), but this finding did not replicate. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in the Gene-Tissue Expression (GTEx) study (p = 4 x 10(-4)) and with circulating plasma ACE2 levels in the INTERVAL study (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations of genetically proxied liability to the other cardiometabolic traits with any outcome. This study does not provide consistent evidence to support an effect of serum ACE levels (as a proxy for ACE inhibitors) or cardiometabolic risk factors on lung ACE2 and TMPRSS2 expression or plasma ACE2 levels.
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5.
  • Larsson, Susanna C., et al. (författare)
  • Body mass index and body composition in relation to 14 cardiovascular conditions in UK Biobank : a Mendelian randomization study
  • 2020
  • Ingår i: European Heart Journal. - : OXFORD UNIV PRESS. - 0195-668X .- 1522-9645. ; 41:2, s. 221-226
  • Tidskriftsartikel (refereegranskat)abstract
    • Aims: The causal role of adiposity for several cardiovascular diseases (CVDs) is unclear. Our primary aim was to apply the Mendelian randomization design to investigate the associations of body mass index (BMI) with 13 CVDs and arterial hypertension. We also assessed the roles of fat mass and fat-free mass on the same outcomes.Methods and results: Single-nucleotide polymorphisms associated with BMI and fat mass and fat-free mass indices were used as instru- and results mental variables to estimate the associations with the cardiovascular conditions among 367 703 UK Biobank participants. After correcting for multiple testing, genetically predicted BMI was significantly positively associated with eight outcomes, including and with decreasing magnitude of association: aortic valve stenosis, heart failure, deep vein thrombosis, arterial hypertension, peripheral artery disease, coronary artery disease, atrial fibrillation, and pulmonary embolism. The odds ratio (OR) per 1 kg/m(2) increase in BMI ranged from 1.06 [95% confidence interval (CI) 1.02-1.11; P=2.6 x 10(-3)] for pulmonary embolism to 1.13 (95% CI 1.05-1.21; P=1.2 x 10(-3)) for aortic valve stenosis. There was suggestive evidence of positive associations of genetically predicted fat mass index with nine outcomes (P < 0.05). The strongest magnitude of association was with aortic valve stenosis (OR per 1 kg/m(2) increase in fat mass index 1.46, 95% CI 1.13-1.88; P=3.9 x 10(-3)). There was suggestive evidence of inverse associations of fat-free mass index with atrial fibrillation, ischaemic stroke, and abdominal aortic aneurysm.Conclusion: This study provides evidence that higher BMI and particularly fat mass index are associated with increased risk of aortic valve stenosis and most other cardiovascular conditions.
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6.
  • Larsson, Susanna C., et al. (författare)
  • Genetic predisposition to smoking in relation to 14 cardiovascular diseases
  • 2020
  • Ingår i: European Heart Journal. - 0195-668X .- 1522-9645. ; 41:35, s. 3304-3310
  • Tidskriftsartikel (refereegranskat)abstract
    • AIMS: The aim of this study was to use Mendelian randomization (MR) to determine the causality of the association between smoking and 14 different cardiovascular diseases (CVDs).METHODS AND RESULTS: Our primary genetic instrument comprised 361 single-nucleotide polymorphisms (SNPs) associated with smoking initiation (ever smoked regularly) at genome-wide significance. Data on the associations between the SNPs and 14 CVDs were obtained from the UK Biobank study (N = 367 643 individuals), CARDIoGRAMplusC4D consortium (N = 184 305 individuals), Atrial Fibrillation Consortium (2017 dataset; N = 154 432 individuals), and Million Veteran Program (MVP; N = 190 266 individuals). The main analyses were conducted using the random-effects inverse-variance weighted method and complemented with multivariable MR analyses and the weighted median and MR-Egger approaches. Genetic predisposition to smoking initiation was most strongly and consistently associated with higher odds of coronary artery disease, heart failure, abdominal aortic aneurysm, ischaemic stroke, transient ischaemic attack, peripheral arterial disease, and arterial hypertension. Genetic predisposition to smoking initiation was additionally associated with higher odds of deep vein thrombosis and pulmonary embolism in the UK Biobank but not with venous thromboembolism in the MVP. There was limited evidence of causal associations of smoking initiation with atrial fibrillation, aortic valve stenosis, thoracic aortic aneurysm, and intracerebral and subarachnoid haemorrhage.CONCLUSION: This MR study supports a causal association between smoking and a broad range of CVDs, in particular, coronary artery disease, heart failure, abdominal aortic aneurysm, ischaemic stroke, transient ischaemic attack, peripheral arterial disease, and arterial hypertension.
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7.
  • Yuan, Shuai, et al. (författare)
  • Effects of tumour necrosis factor on cardiovascular disease and cancer : A two-sample Mendelian randomization study
  • 2020
  • Ingår i: EBioMedicine. - : ELSEVIER. - 2352-3964. ; 59
  • Tidskriftsartikel (refereegranskat)abstract
    • Background: Tumour necrosis factor (TNF) inhibitors are used in the treatment of certain autoimmune diseases but given the role of TNF in tumour biology and atherosclerosis, such therapies may influence the risk of cancer and cardiovascular disease. We conducted a Mendelian randomization study to explore whether TNF levels are causally related to cardiovascular disease and cancer.Methods: Single-nucleotide polymorphisms associated with TNF levels at genome-wide significance were identified from a genome-wide association study of 30 912 European-ancestry individuals. Three TNF-associated single-nucleotide polymorphisms associated with higher risk of autoimmune diseases were used as instrumental variables. Summary-level data for 14 cardiovascular diseases, overall cancer and 14 site-specific cancers were obtained from UK Biobank and consortia.Findings: Genetically-predicted TNF levels were positively associated with coronary artery disease (odds ratio (OR) 2.25; 95% confidence interval (CI) 1.50, 3.37) and ischaemic stroke (OR 2.27; 95% CI 1.50, 3.43), and inversely associated with overall cancer (OR 0.54; 95% CI 0.42, 0.69), breast cancer (OR 0.51; 95% CI 0.39, 0.67), and colorectal cancer (OR 0.20; 95% CI 0.09, 0.45). There were suggestive associations of TNF with venous thromboembolism (OR 2.18; 95% CI 1.32, 3.59), endometrial cancer (OR 0.25; 95% CI 0.07, 0.94), and lung cancer (OR 0.45; 95% CI 0.21, 0.94).Interpretation: This study found evidence of causal associations of increased TNF levels with higher risk of common cardiovascular diseases and lower risk of overall and certain cancers.
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8.
  • Yuan, Shuai, et al. (författare)
  • Genetically Proxied Inhibition of Coagulation Factors and Risk of Cardiovascular Disease : A Mendelian Randomization Study
  • 2021
  • Ingår i: Journal of the American Heart Association. - : Ovid Technologies (Wolters Kluwer Health). - 2047-9980 .- 2047-9980. ; 10:8
  • Tidskriftsartikel (refereegranskat)abstract
    • Background We conducted Mendelian randomization analyses investigating the linear associations of genetically proxied inhibition of different coagulation factors with risk of common cardiovascular diseases. Methods and Results Genetic instruments proxying coagulation factor inhibition were identified from genome-wide association studies for activated partial thromboplastin time and prothrombin time in BioBank Japan (up to 58 110 participants). Instruments were identified for 9 coagulation factors (fibrinogen alpha, beta, and gamma chain; and factors II, V, VII, X, XI, and XII). Age- and sex-adjusted estimates for associations of the instruments with the outcomes were derived from UK Biobank and the FinnGen, CARDIoGRAMplusC4D (Coronary Artery Disease Genome-wide Replication and Meta-analysis), and MEGASTROKE consortia with numbers of incident and prevalent cases of 820 to 60 810. Genetically proxied inhibition of fibrinogen alpha, beta, and gamma chain, factor II, and factor XI were associated with reduced risk of venous thromboembolism (P<0.001). With the exception of fibrinogen beta and factor II, inhibition of these factors was also associated with reduced risk of any ischemic stroke and cardioembolic stroke (P <= 0.002). Genetically proxied inhibition of fibrinogen beta and gamma were associated with reduced large-artery stroke risk (P=0.001). There were suggestive protective associations of genetically proxied inhibition of factors V, VII, and X with ischemic stroke (P<0.05), and suggestive adverse associations of genetically proxied inhibition of factors II and XII with subarachnoid hemorrhage.Conclusions This study supports targeting fibrinogen and factor XI for reducing venous thromboembolism and ischemic stroke risk, and showed suggestive evidence that inhibition of factors V, VII, and X might reduce ischemic stroke risk.
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9.
  • Yuan, Shuai, et al. (författare)
  • Plasma Phospholipid Fatty Acids, FADS1 and Risk of 15 Cardiovascular Diseases : A Mendelian Randomisation Study
  • 2019
  • Ingår i: Nutrients. - : MDPI. - 2072-6643 .- 2072-6643. ; 11:12
  • Tidskriftsartikel (refereegranskat)abstract
    • Whether circulating fatty acids (FAs) play a causal role in the development of cardiovascular disease (CVD) remains unclear. We conducted a Mendelian randomisation study to explore the associations between plasma phospholipid FA levels and 15 CVDs. Summary-level data from the CARDIoGRAMp1usC4D, MEGASTROKE, and Atrial Fibrillation consortia and UK Biobank were used. Sixteen single-nucleotide polymorphisms (SNPs) associated with ten plasma FAs were used as instrumental variables. SNPs in or close to the FADS1 gene were associated with most FAs. We performed a secondary analysis of the association between a functional variant (rs174547) in FADS1, which encodes Delta 5-desaturase (a key enzyme in the endogenous FA synthesis), and CVD. Genetic predisposition to higher plasma alpha-linolenic, linoleic, and oleic acid levels was associated with lower odds of large-artery stroke and venous thromboembolism, whereas higher arachidonic and stearic acid levels were associated with higher odds of these two CVDs. The associations were driven by SNPs in or close to FADS1. In the secondary analysis, the minor allele of rs174547 in FADS1 was associated with significantly lower odds of any ischemic stroke, large-artery stroke, and venous thromboembolism and showed suggestive evidence of inverse association with coronary artery disease, abdominal aortic aneurysm and aortic valve stenosis. Genetically higher plasma alpha-linolenic, linoleic, and oleic acid levels are inversely associated with large-artery stroke and venous thromboembolism, whereas arachidonic and stearic acid levels are positively associated with these CVDs. The associations were driven by FADS1, which was also associated with other CVDs.
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10.
  • Carter, Paul, et al. (författare)
  • Predicting the effect of statins on cancer risk using genetic variants from a Mendelian randomization study in the UK Biobank
  • 2020
  • Ingår i: eLIFE. - 2050-084X. ; 9
  • Tidskriftsartikel (refereegranskat)abstract
    • Laboratory studies have suggested oncogenic roles of lipids, as well as anticarcinogenic effects of statins. Here we assess the potential effect of statin therapy on cancer risk using evidence from human genetics. We obtained associations of lipid-related genetic variants with the risk of overall and 22 site-specific cancers for 367,703 individuals in the UK Biobank. In total, 75,037 individuals had a cancer event. Variants in the HMGCR gene region, which represent proxies for statin treatment, were associated with overall cancer risk (odds ratio [OR] per one standard deviation decrease in low-density lipoprotein [LDL] cholesterol 0.76, 95% confidence interval [CI] 0.65-0.88, p=0.0003) but variants in gene regions representing alternative lipid-lowering treatment targets (PCSK9, LDLR, NPC1L1, APOC3, LPL) were not. Genetically predicted LDL-cholesterol was not associated with overall cancer risk (OR per standard deviation increase 1.01, 95% CI 0.98-1.05, p=0.50). Our results predict that statins reduce cancer risk but other lipidlowering treatments do not. This suggests that statins reduce cancer risk through a cholesterol independent pathway.
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