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- Lu, Yingchang, et al.
(author)
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New loci for body fat percentage reveal link between adiposity and cardiometabolic disease risk
- 2016
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Journal article (peer-reviewed)abstract
- To increase our understanding of the genetic basis of adiposity and its links to cardiometabolic disease risk, we conducted a genome-wide association meta-analysis of body fat percentage (BF%) in up to 100,716 individuals. Twelve loci reached genome-wide significance (P<5 × 10(-8)), of which eight were previously associated with increased overall adiposity (BMI, BF%) and four (in or near COBLL1/GRB14, IGF2BP1, PLA2G6, CRTC1) were novel associations with BF%. Seven loci showed a larger effect on BF% than on BMI, suggestive of a primary association with adiposity, while five loci showed larger effects on BMI than on BF%, suggesting association with both fat and lean mass. In particular, the loci more strongly associated with BF% showed distinct cross-phenotype association signatures with a range of cardiometabolic traits revealing new insights in the link between adiposity and disease risk.
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- Freitag, Daniel F., et al.
(author)
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Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomisation analysis
- 2015
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In: The Lancet Diabetes & Endocrinology. - 2213-8595. ; 3:4, s. 243-253
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Journal article (peer-reviewed)abstract
- Background To investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, we studied genetic variants that produce inhibition of IL-1, a master regulator of inflammation. Methods We created a genetic score combining the effects of alleles of two common variants (rs6743376 and rs1542176) that are located upstream of IL1RN, the gene encoding the IL-1 receptor antagonist (IL-1Ra; an endogenous inhibitor of both IL-1 alpha and IL-1 beta); both alleles increase soluble IL-1Ra protein concentration. We compared effects on inflammation biomarkers of this genetic score with those of anakinra, the recombinant form of IL-1Ra, which has previously been studied in randomised trials of rheumatoid arthritis and other inflammatory disorders. In primary analyses, we investigated the score in relation to rheumatoid arthritis and four cardiometabolic diseases (type 2 diabetes, coronary heart disease, ischaemic stroke, and abdominal aortic aneurysm; 453 411 total participants). In exploratory analyses, we studied the relation of the score to many disease traits and to 24 other disorders of proposed relevance to IL-1 signalling (746 171 total participants). Findings For each IL1RN minor allele inherited, serum concentrations of IL-1Ra increased by 0.22 SD (95% CI 0.18-0.25; 12.5%; p=9.3 x 10(-33)), concentrations of interleukin 6 decreased by 0.02 SD (-0.04 to -0.01; -1,7%; p=3.5 x 10(-3)), and concentrations of C-reactive protein decreased by 0.03 SD (-0.04 to -0.02; -3.4%; p=7.7 x 10(-14)). We noted the effects of the genetic score on these inflammation biomarkers to be directionally concordant with those of anakinra. The allele count of the genetic score had roughly log-linear, dose-dependent associations with both IL-1Ra concentration and risk of coronary heart disease. For people who carried four IL-1Ra-raising alleles, the odds ratio for coronary heart disease was 1.15 (1.08-1.22; p=1.8 x 10(-6)) compared with people who carried no IL-1Ra-raising alleles; the per-allele odds ratio for coronary heart disease was 1.03 (1.02-1.04; p=3.9 x 10(-10)). Perallele odds ratios were 0.97 (0.95-0.99; p=9.9 x 10(-4)) for rheumatoid arthritis, 0.99 (0.97-1.01; p=0.47) for type 2 diabetes, 1.00 (0.98-1.02; p=0.92) for ischaemic stroke, and 1.08 (1.04-1.12; p=1.8 x 10(-5)) for abdominal aortic aneurysm. In exploratory analyses, we observed per-allele increases in concentrations of proatherogenic lipids, including LDL-cholesterol, but no clear evidence of association for blood pressure, glycaemic traits, or any of the 24 other disorders studied. Modelling suggested that the observed increase in LDL-cholesterol could account for about a third of the association observed between the genetic score and increased coronary risk. Interpretation Human genetic data suggest that long-term dual IL-1 alpha/beta inhibition could increase cardiovascular risk and, conversely, reduce the risk of development of rheumatoid arthritis. The cardiovascular risk might, in part, be mediated through an increase in proatherogenic lipid concentrations. Copyright (C) The Interleukin 1 Genetics Consortium. Open Access article distributed under the terms of CC-BY-NC-ND.
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- Huyghe, Jeroen R., et al.
(author)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Journal article (peer-reviewed)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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- Figueroa, Jonine D., et al.
(author)
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Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry
- 2016
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In: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 25:6, s. 1203-1214
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Journal article (peer-reviewed)abstract
- Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10−6), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10−11) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10−10). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region—the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r2 = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case–case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.
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- D'Orangeville, Loic, et al.
(author)
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Drought timing and local climate determine the sensitivity of eastern temperate forests to drought
- 2018
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In: Global Change Biology. - : Wiley. - 1354-1013 .- 1365-2486. ; 24:6, s. 2339-2351
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Journal article (peer-reviewed)abstract
- Projected changes in temperature and drought regime are likely to reduce carbon (C) storage in forests, thereby amplifying rates of climate change. While such reductions are often presumed to be greatest in semi-arid forests that experience widespread tree mortality, the consequences of drought may also be important in temperate mesic forests of Eastern North America (ENA) if tree growth is significantly curtailed by drought. Investigations of the environmental conditions that determine drought sensitivity are critically needed to accurately predict ecosystem feedbacks to climate change. We matched site factors with the growth responses to drought of 10,753 trees across mesic forests of ENA, representing 24 species and 346 stands, to determine the broad-scale drivers of drought sensitivity for the dominant trees in ENA. Here we show that two factors-the timing of drought, and the atmospheric demand for water (i.e., local potential evapotranspiration; PET)-are stronger drivers of drought sensitivity than soil and stand characteristics. Droughtinduced reductions in tree growth were greatest when the droughts occurred during early-season peaks in radial growth, especially for trees growing in the warmest, driest regions (i.e., highest PET). Further, mean species trait values (rooting depth and psi(50)) were poor predictors of drought sensitivity, as intraspecific variation in sensitivity was equal to or greater than interspecific variation in 17 of 24 species. From a general circulation model ensemble, we find that future increases in earlyseason PET may exacerbate these effects, and potentially offset gains in C uptake and storage in ENA owing to other global change factors.
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- Broadbent, David P., et al.
(author)
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The impact of contextual priors and anxiety on performance effectiveness and processing efficiency in anticipation
- 2019
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In: Cognition & Emotion. - Abingdon : Routledge. - 0269-9931 .- 1464-0600. ; 33:3, s. 589-596
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Journal article (peer-reviewed)abstract
- It is proposed that experts are able to integrate prior contextual knowledge with emergent visual information to make complex predictive judgments about the world around them, often under heightened levels of uncertainty and extreme time constraints. However, limited knowledge exists about the impact of anxiety on the use of such contextual priors when forming our decisions. We provide a novel insight into the combined impact of contextual priors and anxiety on anticipation in soccer. Altogether, 12 expert soccer players were required to predict the actions of an oncoming opponent while viewing life-sized video simulations of 2-versus-2 defensive scenarios. Performance effectiveness and processing efficiency were measured under four conditions: no contextual priors (CP) about the action tendencies of the opponent and low anxiety (LA); no CP and high anxiety (HA); CP and LA; CP and HA. The provision of contextual priors did not affect processing efficiency, but it improved performance effectiveness on congruent trials. Anxiety negatively affected processing efficiency, but this did not affect the use of contextual priors or influence performance effectiveness. It appears that anxiety and prior contextual information impact attentional resources independent of each other. Findings are discussed with reference to current models of anticipation and anxiety. © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group.
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| 10. |
- Gredin, Viktor, 1986-, et al.
(author)
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Experts integrate explicit contextual priors and environmental information to improve anticipation efficiency
- 2018
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In: Journal of experimental psychology. Applied. - Washington : American Psychological Association (APA). - 1076-898X .- 1939-2192. ; 24:4, s. 509-520
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Journal article (peer-reviewed)abstract
- The understanding of how experts integrate prior situation-specific information (i.e., contextual priors) with emergent visual information when performing dynamic and temporally constrained tasks is limited. We used a soccer-based anticipation task to examine the ability of expert and novice players to integrate prior information about an opponent's action tendencies with unfolding environmental information such as opponent kinematics. We recorded gaze behaviors and ongoing expectations during task performance. Moreover, we assessed their final anticipatory judgments and perceived levels of cognitive effort invested. Explicit contextual priors biased the allocation of visual attention and shaped ongoing expectations in experts but not in novices. When the final action was congruent with the most likely action given the opponent's action tendencies, the contextual priors enhanced the final judgments for both groups. For incongruent trials, the explicit priors had a negative impact on the final judgments of novices but not experts. We interpreted the data using a Bayesian framework to provide novel insights into how contextual priors and dynamic environmental information are combined when making decisions under time pressure. Moreover, we provide evidence that this integration is governed by the temporal relevance of the information at hand as well as the ability to infer this relevance. © 2018 American Psychological Association.
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