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2.
  • 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.
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3.
  • Baum, Matthew L, et al. (author)
  • CSMD1 regulates brain complement activity and circuit development
  • In: Brain, Behavior, and Immunity. - 1090-2139.
  • Journal article (peer-reviewed)abstract
    • Complement proteins facilitate synaptic elimination during neurodevelopmental pruning, but neural complement regulation is not well understood. CUB and Sushi Multiple Domains 1 (CSMD1) can regulate complement activity in vitro, is expressed in the brain, and is associated with increased schizophrenia risk. Beyond this, little is known about CSMD1 including whether it regulates complement activity in the brain or otherwise plays a role in neurodevelopment. We used biochemical, immunohistochemical, and proteomic techniques to examine the regional, cellular, and subcellular distribution as well as protein interactions of CSMD1 in the brain. To evaluate whether CSMD1 is involved in complement-mediated synapse elimination, we examined Csmd1-knockout mice and CSMD1-knockout human stem cell-derived neurons. We interrogated synapse and circuit development of the mouse visual thalamus, a process that involves complement pathway activity. We also quantified complement deposition on synapses in mouse visual thalamus and on cultured human neurons. Finally, we assessed uptake of synaptosomes by cultured microglia. We found that CSMD1 is present at synapses and interacts with complement proteins in the brain. Mice lacking Csmd1 displayed increased levels of complement component C3, an increased colocalization of C3 with presynaptic terminals, fewer retinogeniculate synapses, and aberrant segregation of eye-specific retinal inputs to the visual thalamus during the critical period of complement-dependent refinement of this circuit. Loss of CSMD1 in vivo enhanced synaptosome engulfment by microglia in vitro, and this effect was dependent on activity of the microglial complement receptor, CR3. Finally, human stem cell-derived neurons lacking CSMD1 were more vulnerable to complement deposition. These data suggest that CSMD1 can function as a regulator of complement-mediated synapse elimination in the CNS during development.
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4.
  • Ji, Xuemei, et al. (author)
  • Protein-altering germline mutations implicate novel genes related to lung cancer development
  • 2020
  • In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
  • Journal article (peer-reviewed)abstract
    • Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio=8.82, P=1.18x10(-15)) and replication (adjusted OR=2.93, P=2.22x10(-3)) that is more pronounced in females (adjusted OR=6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR=2.61, P=7.98x10(-22)) and replication datasets (adjusted OR=1.55, P=0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.
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5.
  • Stamatakis, Emmanuel, et al. (author)
  • A Physical Behaviour Partnership From Heaven : The Prospective Physical Activity, Sitting, and Sleep Consortium and the International Society for the Measurement of Physical Behaviour
  • 2022
  • In: Journal for the Measurement of Physical Behaviour. - : Human Kinetics. - 2575-6605 .- 2575-6613. ; , s. 1-3
  • Journal article (other academic/artistic)abstract
    • The advancement of science demands people and organizations work together toward worthy goals, a need that is especially pronounced in nascent fields like physical behavior. Partnerships offer an ideal vehicle for long-term collaboration to build research capacity, develop new scientific endeavors, and nurture talent. In this commentary, we discuss the newly formed partnership between two key players of the field of physical behavior, the Prospective Physical Activity, Sitting, and Sleep consortium (ProPASS) and the International Society for the Measurement of Physical Behaviour (ISMPB).
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6.
  • Willer, Cristen J., et al. (author)
  • Six new loci associated with body mass index highlight a neuronal influence on body weight regulation
  • 2009
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:1, s. 25-34
  • Journal article (peer-reviewed)abstract
    • Common variants at only two loci, FTO and MC4R, have been reproducibly associated with body mass index (BMI) in humans. To identify additional loci, we conducted meta-analysis of 15 genome-wide association studies for BMI (n > 32,000) and followed up top signals in 14 additional cohorts (n > 59,000). We strongly confirm FTO and MC4R and identify six additional loci (P < 5 x 10(-8)): TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2 and NEGR1 (where a 45-kb deletion polymorphism is a candidate causal variant). Several of the likely causal genes are highly expressed or known to act in the central nervous system (CNS), emphasizing, as in rare monogenic forms of obesity, the role of the CNS in predisposition to obesity.
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7.
  • Zhu, Ying, et al. (author)
  • Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer : A Mendelian Randomization Analysis
  • 2019
  • In: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 28:5, s. 935-942
  • Journal article (peer-reviewed)abstract
    • Background: Platelets are a critical element in coagulation and inflammation, and activated platelets are linked to cancer risk through diverse mechanisms. However, a causal relationship between platelets and risk of lung cancer remains unclear. Methods: We performed single and combined multiple instrumental variable Mendelian randomization analysis by an inverse-weighted method, in addition to a series of sensitivity analyses. Summary data for associations between SNPs and platelet count are from a recent publication that included 48,666 Caucasian Europeans, and the International Lung Cancer Consortium and Transdisciplinary Research in Cancer of the Lung data consisting of 29,266 cases and 56,450 controls to analyze associations between candidate SNPs and lung cancer risk. Results: Multiple instrumental variable analysis incorporating six SNPs showed a 62% increased risk of overall nonsmall cell lung cancer [NSCLC; OR, 1.62; 95% confidence interval (CI), 1.15-2.27; P = 0.005] and a 200% increased risk for small-cell lung cancer (OR, 3.00; 95% CI, 1.27-7.06; P = 0.01). Results showed only a trending association with NSCLC histologic subtypes, which may be due to insufficient sample size and/or weak effect size. A series of sensitivity analysis retained these findings. Conclusions: Our findings suggest a causal relationship between elevated platelet count and increased risk of lung cancer and provide evidence of possible antiplatelet interventions for lung cancer prevention. Impact: These findings provide a better understanding of lung cancer etiology and potential evidence for antiplatelet interventions for lung cancer prevention.
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8.
  • Ade, Peter, et al. (author)
  • The Simons Observatory : science goals and forecasts
  • 2019
  • In: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; :2
  • Journal article (peer-reviewed)abstract
    • The Simons Observatory (SO) is a new cosmic microwave background experiment being built on Cerro Toco in Chile, due to begin observations in the early 2020s. We describe the scientific goals of the experiment, motivate the design, and forecast its performance. SO will measure the temperature and polarization anisotropy of the cosmic microwave background in six frequency bands centered at: 27, 39, 93, 145, 225 and 280 GHz. The initial con figuration of SO will have three small-aperture 0.5-m telescopes and one large-aperture 6-m telescope, with a total of 60,000 cryogenic bolometers. Our key science goals are to characterize the primordial perturbations, measure the number of relativistic species and the mass of neutrinos, test for deviations from a cosmological constant, improve our understanding of galaxy evolution, and constrain the duration of reionization. The small aperture telescopes will target the largest angular scales observable from Chile, mapping approximate to 10% of the sky to a white noise level of 2 mu K-arcmin in combined 93 and 145 GHz bands, to measure the primordial tensor-to-scalar ratio, r, at a target level of sigma(r) = 0.003. The large aperture telescope will map approximate to 40% of the sky at arcminute angular resolution to an expected white noise level of 6 mu K-arcmin in combined 93 and 145 GHz bands, overlapping with the majority of the Large Synoptic Survey Telescope sky region and partially with the Dark Energy Spectroscopic Instrument. With up to an order of magnitude lower polarization noise than maps from the Planck satellite, the high-resolution sky maps will constrain cosmological parameters derived from the damping tail, gravitational lensing of the microwave background, the primordial bispectrum, and the thermal and kinematic Sunyaev-Zel'dovich effects, and will aid in delensing the large-angle polarization signal to measure the tensor-to-scalar ratio. The survey will also provide a legacy catalog of 16,000 galaxy clusters and more than 20,000 extragalactic sources.
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9.
  • Bendall, Matthew L, et al. (author)
  • Genome-wide selective sweeps and gene-specific sweeps in natural bacterial populations
  • 2016
  • In: The ISME Journal. - : Springer Science and Business Media LLC. - 1751-7362 .- 1751-7370. ; 10:7, s. 1589-1601
  • Journal article (peer-reviewed)abstract
    • Multiple models describe the formation and evolution of distinct microbial phylogenetic groups. These evolutionary models make different predictions regarding how adaptive alleles spread through populations and how genetic diversity is maintained. Processes predicted by competing evolutionary models, for example, genome-wide selective sweeps vs gene-specific sweeps, could be captured in natural populations using time-series metagenomics if the approach were applied over a sufficiently long time frame. Direct observations of either process would help resolve how distinct microbial groups evolve. Here, from a 9-year metagenomic study of a freshwater lake (2005-2013), we explore changes in single-nucleotide polymorphism (SNP) frequencies and patterns of gene gain and loss in 30 bacterial populations. SNP analyses revealed substantial genetic heterogeneity within these populations, although the degree of heterogeneity varied by >1000-fold among populations. SNP allele frequencies also changed dramatically over time within some populations. Interestingly, nearly all SNP variants were slowly purged over several years from one population of green sulfur bacteria, while at the same time multiple genes either swept through or were lost from this population. These patterns were consistent with a genome-wide selective sweep in progress, a process predicted by the /`ecotype model/' of speciation but not previously observed in nature. In contrast, other populations contained large, SNP-free genomic regions that appear to have swept independently through the populations prior to the study without purging diversity elsewhere in the genome. Evidence for both genome-wide and gene-specific sweeps suggests that different models of bacterial speciation may apply to different populations coexisting in the same environment.
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10.
  • Bosse, Yohan, et al. (author)
  • Transcriptome-wide association study reveals candidate causal genes for lung cancer
  • 2020
  • In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 146:7, s. 1862-1878
  • Journal article (peer-reviewed)abstract
    • We have recently completed the largest GWAS on lung cancer including 29,266 cases and 56,450 controls of European descent. The goal of our study has been to integrate the complete GWAS results with a large‐scale expression quantitative trait loci (eQTL) mapping study in human lung tissues (n = 1,038) to identify candidate causal genes for lung cancer. We performed transcriptome‐wide association study (TWAS) for lung cancer overall, by histology (adenocarcinoma, squamous cell carcinoma and small cell lung cancer) and smoking subgroups (never‐ and ever‐smokers). We performed replication analysis using lung data from the Genotype‐Tissue Expression (GTEx) project. DNA damage assays were performed in human lung fibroblasts for selected TWAS genes. As expected, the main TWAS signal for all histological subtypes and ever‐smokers was on chromosome 15q25. The gene most strongly associated with lung cancer at this locus using the TWAS approach was IREB2 (pTWAS = 1.09E−99), where lower predicted expression increased lung cancer risk. A new lung adenocarcinoma susceptibility locus was revealed on 9p13.3 and associated with higher predicted expression of AQP3 (pTWAS = 3.72E−6). Among the 45 previously described lung cancer GWAS loci, we mapped candidate target gene for 17 of them. The association AQP3‐adenocarcinoma on 9p13.3 was replicated using GTEx (pTWAS = 6.55E−5). Consistent with the effect of risk alleles on gene expression levels, IREB2 knockdown and AQP3 overproduction promote endogenous DNA damage. These findings indicate genes whose expression in lung tissue directly influences lung cancer risk.
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11.
  • Conti, David, V, et al. (author)
  • Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction
  • 2021
  • In: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 53:1, s. 65-75
  • Journal article (peer-reviewed)abstract
    • Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction. A meta-analysis of genome-wide association studies across different populations highlights new risk loci and provides a genetic risk score that can stratify prostate cancer risk across ancestries.
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12.
  • Dai, Juncheng, et al. (author)
  • Genome-wide association study of INDELs identified four novel susceptibility loci associated with lung cancer risk
  • 2020
  • In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 146:10, s. 2855-2864
  • Journal article (peer-reviewed)abstract
    • Genome-wide association studies (GWAS) have identified 45 susceptibility loci associated with lung ncer. Only less than SNPs, small insertions and deletions (INDELs) are the second most abundant netic polymorphisms in the human genome. INDELs are highly associated with multiple human seases, including lung cancer. However, limited studies with large-scale samples have been available to stematically evaluate the effects of INDELs on lung cancer risk. Here, we performed a large-scale meta- alysis to evaluate INDELs and their risk for lung cancer in 23,202 cases and 19,048 controls. Functional notations were performed to further explore the potential function of lung cancer risk INDELs. nditional analysis was used to clarify the relationship between INDELs and SNPs. Four new risk loci re identified in genome-wide INDEL analysis (1p13.2: rs5777156, Insertion, OR = 0.92, p = 9.10 x 10(- ; 4q28.2: rs58404727, Deletion, OR = 1.19, p = 5.25 x 10(-7); 12p13.31: rs71450133, Deletion, OR = 09, p = 8.83 x 10(-7); and 14q22.3: rs34057993, Deletion, OR = 0.90, p = 7.64 x 10(-8)). The eQTL alysis and functional annotation suggested that INDELs might affect lung cancer susceptibility by gulating the expression of target genes. After conducting conditional analysis on potential causal SNPs, e INDELs in the new loci were still nominally significant. Our findings indicate that INDELs could be tentially functional genetic variants for lung cancer risk. Further functional experiments are needed to tter understand INDEL mechanisms in carcinogenesis.
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13.
  • Ferroni, Luis, et al. (author)
  • Hilbert–Poincaré series of matroid Chow rings and intersection cohomology
  • 2023
  • In: Seminaire Lotharingien de Combinatoire. - : Universitat Wien, Fakultat fur Mathematik. - 1286-4889. ; :89
  • Journal article (peer-reviewed)abstract
    • We study the Hilbert–Poincaré series of three algebraic objects arising in the Chow-theoretic and Kazhdan–Lusztig framework of matroids. These are, respectively, the Hilbert–Poincaré series of the Chow ring, the augmented Chow ring, and the intersection cohomology module. We develop and highlight an explicit parallelism between the Kazhdan–Lusztig polynomial of a matroid and the Hilbert–Poincaré series of its Chow ring that extends naturally to the Hilbert–Poincaré series of both the intersection cohomology module and the augmented Chow ring.
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14.
  • Ferroni, Luis, et al. (author)
  • Hilbert–Poincaré series of matroid Chow rings and intersection cohomology
  • 2024
  • In: Advances in Mathematics. - : Elsevier BV. - 0001-8708 .- 1090-2082. ; 449
  • Journal article (peer-reviewed)abstract
    • We study the Hilbert series of four objects arising in the Chow-theoretic and Kazhdan–Lusztig framework of matroids. These are, respectively, the Hilbert series of the Chow ring, the augmented Chow ring, the intersection cohomology module, and its stalk at the empty flat. (The last two are known as the Z-polynomial and the Kazhdan–Lusztig polynomial, respectively.) We develop an explicit parallelism between the Kazhdan–Lusztig polynomial of a matroid and the Hilbert–Poincaré series of its Chow ring. This extends to a parallelism between the Z-polynomial of a matroid and the Hilbert–Poincaré series of its augmented Chow ring. This suggests to bring ideas from one framework to the other. Our two main motivations are the real-rootedness conjecture for all of these polynomials, and the problem of computing them. We provide several intrinsic definitions of these invariants via recursions they satisfy. Uniform matroids are a case of combinatorial interest; we link the resulting polynomials with certain real-rooted families appearing in combinatorics such as the Eulerian and the binomial Eulerian polynomials, and we settle a conjecture of Hameister, Rao, and Simpson. Furthermore, we prove the real-rootedness of the Hilbert series of the augmented Chow rings of uniform matroids via a technique introduced by Haglund and Zhang; and in addition, we prove a version of a conjecture of Gedeon in the Chow setting: uniform matroids maximize coefficient-wise these polynomials for matroids with fixed rank and cardinality. By relying on the nonnegativity of the coefficients of the Kazhdan–Lusztig polynomials and the semi-small decompositions of Braden, Huh, Matherne, Proudfoot, and Wang, we strengthen the unimodality of the Hilbert series of Chow rings, augmented Chow rings, and intersection cohomologies to γ-positivity, a property for palindromic polynomials that lies between unimodality and real-rootedness; this also settles a conjecture of Ferroni, Nasr, and Vecchi.
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15.
  • Field, Dawn, et al. (author)
  • The minimum information about a genome sequence (MIGS) specification.
  • 2008
  • In: Nature biotechnology. - : Springer Science and Business Media LLC. - 1546-1696 .- 1087-0156. ; 26:5, s. 541-7
  • Journal article (peer-reviewed)abstract
    • With the quantity of genomic data increasing at an exponential rate, it is imperative that these data be captured electronically, in a standard format. Standardization activities must proceed within the auspices of open-access and international working bodies. To tackle the issues surrounding the development of better descriptions of genomic investigations, we have formed the Genomic Standards Consortium (GSC). Here, we introduce the minimum information about a genome sequence (MIGS) specification with the intent of promoting participation in its development and discussing the resources that will be required to develop improved mechanisms of metadata capture and exchange. As part of its wider goals, the GSC also supports improving the 'transparency' of the information contained in existing genomic databases.
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16.
  • Henrion, Marc Y R, et al. (author)
  • Common variation at 1q24.1 (ALDH9A1) is a potential risk factor for renal cancer
  • 2015
  • In: PLOS ONE. - : Public library science. - 1932-6203. ; 10:3
  • Journal article (peer-reviewed)abstract
    • So far six susceptibility loci for renal cell carcinoma (RCC) have been discovered by genome-wide association studies (GWAS). To identify additional RCC common risk loci, we performed a meta-analysis of published GWAS (totalling 2,215 cases and 8,566 controls of Western-European background) with imputation using 1000 Genomes Project and UK10K Project data as reference panels and followed up the most significant association signals [22 single nucleotide polymorphisms (SNPs) and 3 indels in eight genomic regions] in 383 cases and 2,189 controls from The Cancer Genome Atlas (TCGA). A combined analysis identified a promising susceptibility locus mapping to 1q24.1 marked by the imputed SNP rs3845536 (Pcombined =2.30x10-8). Specifically, the signal maps to intron 4 of the ALDH9A1 gene (aldehyde dehydrogenase 9 family, member A1). We further evaluated this potential signal in 2,461 cases and 5,081 controls from the International Agency for Research on Cancer (IARC) GWAS of RCC cases and controls from multiple European regions. In contrast to earlier findings no association was shown in the IARC series (P=0.94; Pcombined =2.73x10-5). While variation at 1q24.1 represents a potential risk locus for RCC, future replication analyses are required to substantiate our observation.
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17.
  • James, Stefan K., et al. (author)
  • Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management : substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial
  • 2011
  • In: The BMJ. - : BMJ. - 1756-1833. ; 342, s. d3527-
  • Journal article (peer-reviewed)abstract
    • Objective To evaluate efficacy and safety outcomes in patients in the PLATelet inhibition and patient Outcomes (PLATO) trial who at randomisation were planned for a non-invasive treatment strategy. Design Pre-specified analysis of pre-randomisation defined subgroup of prospective randomised clinical trial. Setting 862 centres in 43 countries. Participants 5216 (28%) of 18 624 patients admitted to hospital for acute coronary syndrome who were specified as planned for non-invasive management. Interventions Randomised treatment with ticagrelor (n=2601) versus clopidogrel (2615). Main outcome measurements Primary composite end point of cardiovascular death, myocardial infarction, and stroke; their individual components; and PLATO defined major bleeding during one year. Results 2183 (41.9%) patients had coronary angiography during their initial hospital admission, 1065 (20.4%) had percutaneous coronary intervention, and 208 (4.0%) had coronary artery bypass surgery. Cumulatively, 3143 (60.3%) patients had been managed non-invasively by the end of follow-up. The incidence of the primary end point was lower with ticagrelor than with clopidogrel (12.0% (n=295) v 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P=0.04). Overall mortality was also lower (6.1% (147) v 8.2% (195); 0.75, 0.61 to 0.93; P=0.01). The incidence of total major bleeding (11.9% (272) v 10.3% (238); 1.17, 0.98 to 1.39; P=0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) v 3.1% (71); 1.30, 0.95 to 1.77; P=0.10) was numerically higher with ticagrelor than with clopidogrel. Conclusions In patients with acute coronary syndrome initially intended for non-invasive management, the benefits of ticagrelor over clopidogrel were consistent with those from the overall PLATO results, indicating the broad benefits of P2Y12 inhibition with ticagrelor regardless of intended management strategy.
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18.
  • Januario, Leticia, 1990-, et al. (author)
  • Are resident handlings in eldercare wards associated with musculoskeletal pain and sickness absence among the workers? A prospective study based on onsite observations
  • 2021
  • In: Scandinavian Journal of Work, Environment and Health. - : NOROSH. - 0355-3140 .- 1795-990X. ; 47:8, s. 609-618
  • Journal article (peer-reviewed)abstract
    • Objectives We aimed to identify eldercare wards with different types of resident handling characteristics (‘phenotypes’) and determine the prospective association between these characteristics and musculoskeletal pain and sickness absence among workers during a one-year follow-up.Methods Our study was based on the DOSES cohort, including 467 workers at 103 eldercare wards. At baseline, resident handlings were assessed using onsite observations. Workers’ self-reported musculoskeletal pain and sickness absence were assessed during the following year using text messages. Observations of the frequency of handlings per shift, use of assistive devices, assistance from others, and barriers (interruptions and impediments) were estimated for each worker, aggregated at ward level, and entered into a latent profile analysis, identifying ward phenotypes. We then used generalized estimating equations to determine associations between ward phenotypes, musculoskeletal pain and sickness absence.Results We identified four ward phenotypes: ‘turbulent’ (many handlings with devices and assistance, many barriers), ‘strained’ (many handlings without devices or assistance, some barriers), ‘unpressured’ (few handlings, yet without devices or assistance, few barriers) and ‘balanced’ (some handlings with devices and assistance, some barriers). Compared to workers in balanced wards, workers in turbulent wards had more days with neck-shoulder and low-back pain (LBP); and those working in strained wards had more days with LBP and higher pain intensities.Conclusion We found that ward phenotypes based on resident handling characteristics were predictive of musculoskeletal pain and sickness absence over one year. This shows that organizational factors related to resident handling are important determinants of musculoskeletal health among eldercare workers.
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19.
  • Januario, Leticia, 1990-, et al. (author)
  • Combined effects of physical behavior compositions and psychosocial resources on perceived exertion among eldercare workers
  • 2020
  • In: Annals of Work Exposures and Health. - : Oxford Academic. - 2398-7308 .- 2398-7316. ; 64:9, s. 923-935
  • Journal article (peer-reviewed)abstract
    • High perceived physical exertion is common in eldercare workers and a strong predictor for impaired health. However, little is known on how physical behaviors at work associate with physical exertion in this group. The aim of this study was to determine the extent to which the composition of physical behaviors at work is associated with perceived physical exertion in nursing home eldercare workers, and the extent to which these associations are modified by psychosocial resources.MethodsOur population consisted of 399 female eldercare workers from 126 wards in 20 different nursing homes. We evaluated time spent in physical behaviors at work [sitting, standing still, light activities (LAs), and moderate to vigorous activities (MVAs)] using triaxial accelerometers worn, on average, for three working days. We accounted for inherent codependency between the behaviors using compositional data analysis. We used multilevel linear mixed regression models to determine associations between the behaviors and perceived exertion, measured on a numeric rating scale (0–10), and included interactions between each behavior and psychosocial resources (influence at work, social support, and quality of leadership) to determine a possible moderating effect of resources. Regression results were illustrated using isotemporal substitution.ResultsSitting was negatively (β: −0.64; P < 0.01) while MVA was positively (β: 0.95; P = 0.02) associated with perceived exertion. According to isotemporal substitution, replacing 30 min of MVA by sitting would, for an average worker, be associated with a decrease in physical exertion by −0.14 on the 0–10 scale. Job resources marginally moderated the association between LA and exertion. Thus, among workers with low influence and low social support, we found a positive association between LA and exertion, while that was not found for workers with medium or high influence and support (interactions for influence and support: P = 0.08 and P = 0.10).ConclusionsOur findings suggest that reallocating time from MVA to sitting can mitigate perceived physical exertion in eldercare workers. More time in LA increased physical exertion only for workers with low psychosocial resources, supporting a positive effect of a better psychosocial work environment in elderly care.
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21.
  • Januario, Leticia, 1990-, et al. (author)
  • Ward-level leadership quality and prospective low-back pain of eldercare workers – do resident handlings mediate the association?
  • 2023
  • In: International Archives of Occupational and Environmental Health. - : Springer. - 0340-0131 .- 1432-1246. ; 96, s. 1049-1059
  • Journal article (peer-reviewed)abstract
    • Objective: We investigated the extent to which ward-level leadership quality was associated with prospective low-back pain among eldercare workers, and how this association was mediated by observed resident handlings.Methods: 530 Danish eldercare workers, employed in 121 wards, distributed across 20 nursing homes were evaluated. At baseline, leadership quality was measured using the Copenhagen Psychosocial Questionnaire, and resident handlings [handlings per shift, handlings not using assistive devices, handlings done alone, interruptions to handlings, impediments to handlings] were assessed using observations. Frequency and intensity of low-back pain was assessed monthly during the following year. All variables were averaged for each ward. We used ordinary least squares regressions to examine direct effects of leadership on low-back pain and indirect effects through handlings, using PROCESS-macro for SPSS. Results: After adjustments for low-back pain at baseline, type of ward, staff ratio (i.e., number of workers divided by number of residents) and proportion of devices not in place, leadership quality showed no effect on prospective low-back pain frequency (β=0.01 [-0.05:0.07]) and a small beneficial effect on pain intensity (β=-0.02 [-0.04:0.00]). Resident handlings did not mediate the association between leadership quality and frequency or intensity of low-back pain. Conclusions: Good leadership quality was associated with a small decrease in prospective low-back pain intensity, but resident handlings did not seem to play a mediating role, although better ward-level leadership quality contributed to fewer workplace-observed resident handlings without assistance. Potentially, organizational factors such as type of ward and staff ratio, may have a greater influence on handlings and low-back pain than leadership quality per se among eldercare workers.
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22.
  • Ji, Xuemei, et al. (author)
  • Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk
  • 2018
  • In: Nature Communications. - : NATURE PUBLISHING GROUP. - 2041-1723. ; 9, s. 1-15
  • Journal article (peer-reviewed)abstract
    • Genome-wide association studies (GWAS) identified the chromosome 15q25.1 locus as a leading susceptibility region for lung cancer. However, the pathogenic pathways, through which susceptibility SNPs within chromosome 15q25.1 affects lung cancer risk, have not been explored. We analyzed three cohorts with GWAS data consisting 42,901 individuals and lung expression quantitative trait loci (eQTL) data on 409 individuals to identify and validate the underlying pathways and to investigate the combined effect of genes from the identified susceptibility pathways. The KEGG neuroactive ligand receptor interaction pathway, two Reactome pathways, and 22 Gene Ontology terms were identified and replicated to be significantly associated with lung cancer risk, with P values less than 0.05 and FDR less than 0.1. Functional annotation of eQTL analysis results showed that the neuroactive ligand receptor interaction pathway and gated channel activity were involved in lung cancer risk. These pathways provide important insights for the etiology of lung cancer.
  •  
23.
  • Johansson, Mattias, et al. (author)
  • The influence of obesity-related factors in the etiology of renal cell carcinoma—A mendelian randomization study
  • 2019
  • In: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1277 .- 1549-1676. ; 16:1
  • Journal article (peer-reviewed)abstract
    • Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation.Methods and findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44–1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40–1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44–1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30–2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11–1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84–1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose.Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk.
  •  
24.
  • Jones, Benedict C, et al. (author)
  • To which world regions does the valence-dominance model of social perception apply?
  • 2021
  • In: Nature Human Behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 5:1, s. 159-169
  • Journal article (peer-reviewed)abstract
    • Over the past 10 years, Oosterhof and Todorov's valence-dominance model has emerged as the most prominent account of how people evaluate faces on social dimensions. In this model, two dimensions (valence and dominance) underpin social judgements of faces. Because this model has primarily been developed and tested in Western regions, it is unclear whether these findings apply to other regions. We addressed this question by replicating Oosterhof and Todorov's methodology across 11 world regions, 41 countries and 11,570 participants. When we used Oosterhof and Todorov's original analysis strategy, the valence-dominance model generalized across regions. When we used an alternative methodology to allow for correlated dimensions, we observed much less generalization. Collectively, these results suggest that, while the valence-dominance model generalizes very well across regions when dimensions are forced to be orthogonal, regional differences are revealed when we use different extraction methods and correlate and rotate the dimension reduction solution. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 5 November 2018. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.7611443.v1 .
  •  
25.
  • Kirby, Andrew, et al. (author)
  • Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel sequencing
  • 2013
  • In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:3, s. 299-303
  • Journal article (peer-reviewed)abstract
    • Although genetic lesions responsible for some mendelian disorders can be rapidly discovered through massively parallel sequencing of whole genomes or exomes, not all diseases readily yield to such efforts. We describe the illustrative case of the simple mendelian disorder medullary cystic kidney disease type 1 (MCKD1), mapped more than a decade ago to a 2-Mb region on chromosome 1. Ultimately, only by cloning, capillary sequencing and de novo assembly did we find that each of six families with MCKD1 harbors an equivalent but apparently independently arising mutation in sequence markedly under-represented in massively parallel sequencing data: the insertion of a single cytosine in one copy (but a different copy in each family) of the repeat unit comprising the extremely long (similar to 1.5-5 kb), GC-rich (>80%) coding variable-number tandem repeat (VNTR) sequence in the MUC1 gene encoding mucin 1. These results provide a cautionary tale about the challenges in identifying the genes responsible for mendelian, let alone more complex, disorders through massively parallel sequencing.
  •  
26.
  • Kottyan, Leah C., et al. (author)
  • The IRF5-TNPO3 association with systemic lupus erythematosus has two components that other autoimmune disorders variably share.
  • 2015
  • In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 24:2, s. 582-596
  • Journal article (peer-reviewed)abstract
    • Exploiting genotyping, DNA sequencing, imputation and trans-ancestral mapping, we used Bayesian and frequentist approaches to model the IRF5-TNPO3 locus association, now implicated in two immunotherapies and seven autoimmune diseases. Specifically, in systemic lupus erythematosus (SLE), we resolved separate associations in the IRF5 promoter (all ancestries) and with an extended European haplotype. We captured 3230 IRF5-TNPO3 high-quality, common variants across 5 ethnicities in 8395 SLE cases and 7367 controls. The genetic effect from the IRF5 promoter can be explained by any one of four variants in 5.7 kb (P-valuemeta = 6 × 10(-49); OR = 1.38-1.97). The second genetic effect spanned an 85.5-kb, 24-variant haplotype that included the genes IRF5 and TNPO3 (P-valuesEU = 10(-27)-10(-32), OR = 1.7-1.81). Many variants at the IRF5 locus with previously assigned biological function are not members of either final credible set of potential causal variants identified herein. In addition to the known biologically functional variants, we demonstrated that the risk allele of rs4728142, a variant in the promoter among the lowest frequentist probability and highest Bayesian posterior probability, was correlated with IRF5 expression and differentially binds the transcription factor ZBTB3. Our analytical strategy provides a novel framework for future studies aimed at dissecting etiological genetic effects. Finally, both SLE elements of the statistical model appear to operate in Sjögrens syndrome and systemic sclerosis whereas only the IRF5-TNPO3 gene-spanning haplotype is associated with primary biliary cirrhosis, demonstrating the nuance of similarity and difference in autoimmune disease risk mechanisms at IRF5-TNPO3.
  •  
27.
  • Machiela, Mitchell J, et al. (author)
  • Genetic Variants Related to Longer Telomere Length are Associated with Increased Risk of Renal Cell Carcinoma.
  • 2017
  • In: European Urology. - : Elsevier BV. - 0302-2838 .- 1873-7560. ; 72:5, s. 747-754
  • Journal article (peer-reviewed)abstract
    • BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings.OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length.OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis.RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p<0.0001). As a sensitivity analysis, we excluded two telomere length variants in linkage disequilibrium (R2>0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p<0.0001). Exploratory analyses for individual histologic subtypes suggested comparable associations with the telomere length GRS for clear cell (N=5573, OR=1.93, 95% CI=1.50-2.49, p<0.0001), papillary (N=573, OR=1.96, 95% CI=1.01-3.81, p=0.046), and chromophobe RCC (N=203, OR=2.37, 95% CI=0.78-7.17, p=0.13).CONCLUSIONS: Our investigation adds to the growing body of evidence indicating some aspect of longer telomere length is important for RCC risk.PATIENT SUMMARY: Telomeres are segments of DNA at chromosome ends that maintain chromosomal stability. Our study investigated the relationship between genetic variants associated with telomere length and renal cell carcinoma risk. We found evidence suggesting individuals with inherited predisposition to longer telomere length are at increased risk of developing renal cell carcinoma.
  •  
28.
  • McKay, James D., et al. (author)
  • Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes
  • 2017
  • In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 49:7, s. 1126-1132
  • Journal article (peer-reviewed)abstract
    • Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genomewide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.
  •  
29.
  • Naghavi, Mohsen, et al. (author)
  • Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013
  • 2015
  • In: The Lancet. - 1474-547X .- 0140-6736. ; 385:9963, s. 117-171
  • Journal article (peer-reviewed)abstract
    • Background Up-to-date evidence on levels and trends for age-sex-specifi c all-cause and cause-specifi c mortality is essential for the formation of global, regional, and national health policies. In the Global Burden of Disease Study 2013 (GBD 2013) we estimated yearly deaths for 188 countries between 1990, and 2013. We used the results to assess whether there is epidemiological convergence across countries. Methods We estimated age-sex-specifi c all-cause mortality using the GBD 2010 methods with some refinements to improve accuracy applied to an updated database of vital registration, survey, and census data. We generally estimated cause of death as in the GBD 2010. Key improvements included the addition of more recent vital registration data for 72 countries, an updated verbal autopsy literature review, two new and detailed data systems for China, and more detail for Mexico, UK, Turkey, and Russia. We improved statistical models for garbage code redistribution. We used six different modelling strategies across the 240 causes; cause of death ensemble modelling (CODEm) was the dominant strategy for causes with sufficient information. Trends for Alzheimer's disease and other dementias were informed by meta-regression of prevalence studies. For pathogen-specifi c causes of diarrhoea and lower respiratory infections we used a counterfactual approach. We computed two measures of convergence (inequality) across countries: the average relative difference across all pairs of countries (Gini coefficient) and the average absolute difference across countries. To summarise broad findings, we used multiple decrement life-tables to decompose probabilities of death from birth to exact age 15 years, from exact age 15 years to exact age 50 years, and from exact age 50 years to exact age 75 years, and life expectancy at birth into major causes. For all quantities reported, we computed 95% uncertainty intervals (UIs). We constrained cause-specific fractions within each age-sex-country-year group to sum to all-cause mortality based on draws from the uncertainty distributions. Findings Global life expectancy for both sexes increased from 65.3 years (UI 65.0-65.6) in 1990, to 71.5 years (UI 71.0-71.9) in 2013, while the number of deaths increased from 47.5 million (UI 46.8-48.2) to 54.9 million (UI 53.6-56.3) over the same interval. Global progress masked variation by age and sex: for children, average absolute diff erences between countries decreased but relative diff erences increased. For women aged 25-39 years and older than 75 years and for men aged 20-49 years and 65 years and older, both absolute and relative diff erences increased. Decomposition of global and regional life expectancy showed the prominent role of reductions in age-standardised death rates for cardiovascular diseases and cancers in high-income regions, and reductions in child deaths from diarrhoea, lower respiratory infections, and neonatal causes in low-income regions. HIV/AIDS reduced life expectancy in southern sub-Saharan Africa. For most communicable causes of death both numbers of deaths and age-standardised death rates fell whereas for most non-communicable causes, demographic shifts have increased numbers of deaths but decreased age-standardised death rates. Global deaths from injury increased by 10.7%, from 4.3 million deaths in 1990 to 4.8 million in 2013; but age-standardised rates declined over the same period by 21%. For some causes of more than 100 000 deaths per year in 2013, age-standardised death rates increased between 1990 and 2013, including HIV/AIDS, pancreatic cancer, atrial fibrillation and flutter, drug use disorders, diabetes, chronic kidney disease, and sickle-cell anaemias. Diarrhoeal diseases, lower respiratory infections, neonatal causes, and malaria are still in the top five causes of death in children younger than 5 years. The most important pathogens are rotavirus for diarrhoea and pneumococcus for lower respiratory infections. Country-specific probabilities of death over three phases of life were substantially varied between and within regions. Interpretation For most countries, the general pattern of reductions in age-sex specifi c mortality has been associated with a progressive shift towards a larger share of the remaining deaths caused by non-communicable disease and injuries. Assessing epidemiological convergence across countries depends on whether an absolute or relative measure of inequality is used. Nevertheless, age-standardised death rates for seven substantial causes are increasing, suggesting the potential for reversals in some countries. Important gaps exist in the empirical data for cause of death estimates for some countries; for example, no national data for India are available for the past decade.
  •  
30.
  • Oakman, Jodi, et al. (author)
  • Do organisational and ward-level factors explain the variance in multi-site musculoskeletal pain in eldercare workers? A multi-level cross-sectional study
  • 2020
  • In: International Archives of Occupational and Environmental Health. - : Springer. - 0340-0131 .- 1432-1246. ; 93:7, s. 891-898
  • Journal article (peer-reviewed)abstract
    • PurposeMulti-site musculoskeletal pain (MSP) is highly prevalent among eldercare workers, leading to increased incidence of sickness absence and early retirement. Most research on MSP in eldercare workers has focused on individual-level factors reported by the employees, with limited focus at the organisation and ward level. To address this gap, the aim of this study was to investigate whether organisation and ward-level factors explain the variance in MSP among Danish eldercare workers.MethodsA multi-level cross-sectional study was conducted among 20 Danish nursing homes, containing 126 wards, and 418 workers who participated in measurements of organisational factors, working environment factors, and MSP (classified as reporting pain in 2 or more body regions). Data were collected at the level of the organisation, ward, and individual. The proportion of variance in MSP explained by each level was estimated using variance components analysis. The association between factors at each level of the organisation and MSP was investigated using generalised linear mixed-effects regression.ResultsSixty seven percent of participants reported having MSP. The organisational and ward-level factors explained 0% of the variance in MSP, while the individual-level factors explained 100% of the variance in MSP. Moreover, no factors at the organisational and ward levels showed statistically significant associations with MSP. Individual-level perceived physical exertion and quantitative demands had a statistically significant association with a higher prevalence of MSP.ConclusionsThe organisation and ward levels did not contribute to explaining any of the variance in MSP. All variance in MSP was explained at the individual level.
  •  
31.
  • Osmanski, Austin B., et al. (author)
  • Insights into mammalian TE diversity through the curation of 248 genome assemblies
  • 2023
  • In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 380:6643, s. 371-
  • Journal article (peer-reviewed)abstract
    • We examined transposable element (TE) content of 248 placental mammal genome assemblies, the largest de novo TE curation effort in eukaryotes to date. We found that although mammals resemble one another in total TE content and diversity, they show substantial differences with regard to recent TE accumulation. This includes multiple recent expansion and quiescence events across the mammalian tree. Young TEs, particularly long interspersed elements, drive increases in genome size, whereas DNA transposons are associated with smaller genomes. Mammals tend to accumulate only a few types of TEs at any given time, with one TE type dominating. We also found association between dietary habit and the presence of DNA transposon invasions. These detailed annotations will serve as a benchmark for future comparative TE analyses among placental mammals.
  •  
32.
  • Qin, Na, et al. (author)
  • Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma
  • 2021
  • In: Frontiers of Medicine. - : Springer-Verlag New York. - 2095-0217 .- 2095-0225. ; 15:2, s. 275-291
  • Journal article (peer-reviewed)abstract
    • Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95,P= 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.
  •  
33.
  • Rajaraman, Preetha, et al. (author)
  • Genome-wide association study of glioma and meta-analysis
  • 2012
  • In: Human Genetics. - : SPRINGER. - 0340-6717 .- 1432-1203. ; 131:12, s. 1877-1888
  • Journal article (peer-reviewed)abstract
    • Gliomas account for approximately 80 % of all primary malignant brain tumors and, despite improvements in clinical care over the last 20 years, remain among the most lethal tumors, underscoring the need for gaining new insights that could translate into clinical advances. Recent genome-wide association studies (GWAS) have identified seven new susceptibility regions. We conducted a new independent GWAS of glioma using 1,856 cases and 4,955 controls (from 14 cohort studies, 3 case-control studies, and 1 population-based case-only study) and found evidence of strong replication for three of the seven previously reported associations at 20q13.33 (RTEL), 5p15.33 (TERT), and 9p21.3 (CDKN2BAS), and consistent association signals for the remaining four at 7p11.2 (EGFR both loci), 8q24.21 (CCDC26) and 11q23.3 (PHLDB1). The direction and magnitude of the signal were consistent for samples from cohort and case-control studies, but the strength of the association was more pronounced for loci rs6010620 (20q,13.33; RTEL) and rs2736100 (5p15.33, TERT) in cohort studies despite the smaller number of cases in this group, likely due to relatively more higher grade tumors being captured in the cohort studies. We further examined the 85 most promising single nucleotide polymorphism (SNP) markers identified in our study in three replication sets (5,015 cases and 11,601 controls), but no new markers reached genome-wide significance. Our findings suggest that larger studies focusing on novel approaches as well as specific tumor subtypes or subgroups will be required to identify additional common susceptibility loci for glioma risk.
  •  
34.
  • Robbins, Hilary A., et al. (author)
  • Design and methodological considerations for biomarker discovery and validation in the Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) Program
  • 2023
  • In: Annals of Epidemiology. - : Elsevier. - 1047-2797 .- 1873-2585. ; 77, s. 1-12
  • Journal article (peer-reviewed)abstract
    • The Integrative Analysis of Lung Cancer Etiology and Risk (INTEGRAL) program is an NCI-funded initiative with an objective to develop tools to optimize low-dose CT (LDCT) lung cancer screening. Here, we describe the rationale and design for the Risk Biomarker and Nodule Malignancy projects within INTEGRAL. The overarching goal of these projects is to systematically investigate circulating protein markers to include on a panel for use (i) pre-LDCT, to identify people likely to benefit from screening, and (ii) post-LDCT, to differentiate benign versus malignant nodules. To identify informative proteins, the Risk Biomarker project measured 1161 proteins in a nested-case control study within 2 prospective cohorts (n = 252 lung cancer cases and 252 controls) and replicated associations for a subset of proteins in 4 cohorts (n = 479 cases and 479 controls). Eligible participants had a current or former history of smoking and cases were diagnosed up to 3 years following blood draw. The Nodule Malignancy project measured 1078 proteins among participants with a heavy smoking history within four LDCT screening studies (n = 425 cases diagnosed up to 5 years following blood draw, 430 benign-nodule controls, and 398 nodule-free controls). The INTEGRAL panel will enable absolute quantification of 21 proteins. We will evaluate its performance in the Risk Biomarker project using a case-cohort study including 14 cohorts (n = 1696 cases and 2926 subcohort representatives), and in the Nodule Malignancy project within five LDCT screening studies (n = 675 cases, 680 benign-nodule controls, and 648 nodule-free controls). Future progress to advance lung cancer early detection biomarkers will require carefully designed validation, translational, and comparative studies.
  •  
35.
  • Satizabal, Claudia L., et al. (author)
  • Genetic architecture of subcortical brain structures in 38,851 individuals
  • 2019
  • In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
  • Journal article (peer-reviewed)abstract
    • Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
  •  
36.
  • Scelo, Ghislaine, et al. (author)
  • Genome-wide association study identifies multiple risk loci for renal cell carcinoma.
  • 2017
  • In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 8
  • Journal article (peer-reviewed)abstract
    • Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10-10), 3p22.1 (rs67311347, P=2.5 × 10-8), 3q26.2 (rs10936602, P=8.8 × 10-9), 8p21.3 (rs2241261, P=5.8 × 10-9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10-8), 11q22.3 (rs74911261, P=2.1 × 10-10) and 14q24.2 (rs4903064, P=2.2 × 10-24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.
  •  
37.
  • Stamatakis, Emmanuel, et al. (author)
  • Emerging collaborative research platforms for the next generation of physical activity, sleep and exercise medicine guidelines : the Prospective Physical Activity, Sitting, and Sleep consortium (ProPASS)
  • 2020
  • In: British Journal of Sports Medicine. - : BMJ. - 0306-3674 .- 1473-0480. ; 54:8, s. 435-437
  • Journal article (other academic/artistic)abstract
    • Galileo Galilei’s quote ‘measure what is measurable, and make measurable what is not so’ has particular relevance to health behaviours, such as physical activity (PA), sitting and sleep, whose measurement during free living is notoriously difficult. To date, much of what we know about how these behaviours affect our health is based on self-report by questionnaires which have limited validity, are prone to bias and inquire about selective aspects of these behaviours. Although self-reported evidence has made great contributions to shaping public health and exercise medicine policy and guidelines until now,1 the ongoing advancements of accelerometry-based measurement and evidence synthesis methods are set to change the landscape. The aim of this editorial is to outline new directions in PA and sleep-related epidemiology that open new horizons for guideline development and improvement; and to describe a new research collaboration platform: the Prospective Physical Activity, Sitting, and Sleep consortium (ProPASS).
  •  
38.
  • Stevens, H. C., et al. (author)
  • Regulation and function of miR-214 in pulmonary arterial hypertension
  • 2016
  • In: Pulmonary Circulation. - : Wiley. - 2045-8932 .- 2045-8940. ; 6:1, s. 109-117
  • Journal article (peer-reviewed)abstract
    • Dysregulation of microRNAs (miRNAs) can contribute to the etiology of diseases, including pulmonary arterial hypertension (PAH). Here we investigated a potential role for the miR-214 stem loop miRNA and the closely linked miR-199a miRNAs in PAH. All 4 miRNAs were upregulated in the lung and right ventricle (RV) in mice and rats exposed to the Sugen (SU) 5416 hypoxia model of PAH. Further, expression of the miRNAs was increased in pulmonary artery smooth muscle cells exposed to transforming growth factor β 1 but not BMP4. We then examined miR-214-/- mice exposed to the SU 5416 hypoxia model of PAH or normoxic conditions and littermate controls. There were no changes in RV systolic pressure or remodeling observed between the miR-214-/- and wild-type hypoxic groups. However, we observed a significant increase in RV hypertrophy (RVH) in hypoxic miR-214-/- male mice compared with controls. Further, we identified that the validated miR-214 target phosphatase and tensin homolog was upregulated in miR-214-/- mice. Thus, miR-214 stem loop loss leads to elevated RVH and may contribute to the heart failure associated with PAH. © 2016 by the Pulmonary Vascular Research Institute. All rights reserved.
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39.
  • Stevens, Kristen N, et al. (author)
  • 19p13.1 is a triple negative-specific breast cancer susceptibility locus
  • 2012
  • In: Cancer Research. - 0008-5472 .- 1538-7445. ; 72, s. 1795-
  • Journal article (peer-reviewed)abstract
    • The 19p13.1 breast cancer susceptibility locus is a modifier of breast cancer risk in BRCA1 mutation carriers and is also associated with risk of ovarian cancer. Here we investigated 19p13.1 variation and risk of breast cancer subtypes, defined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2) status, using 48,869 breast cancer cases and 49,787 controls from the Breast Cancer Association Consortium (BCAC). Variants from 19p13.1 were not associated with breast cancer overall or with ER-positive breast cancer but were significantly associated with ER-negative breast cancer risk [rs8170 Odds Ratio (OR)=1.10, 95% Confidence Interval (CI) 1.05 - 1.15, p=3.49 x 10-5] and triple negative (TN) (ER, PR and HER2 negative) breast cancer [rs8170 OR=1.22, 95% CI 1.13 - 1.31, p=2.22 x 10-7]. However, rs8170 was no longer associated with ER-negative breast cancer risk when TN cases were excluded [OR=0.98, 95% CI 0.89 - 1.07, p=0.62]. In addition, a combined analysis of TN cases from BCAC and the Triple Negative Breast Cancer Consortium (TNBCC) (n=3,566) identified a genome-wide significant association between rs8170 and TN breast cancer risk [OR=1.25, 95% CI 1.18 - 1.33, p=3.31 x 10-13]. Thus, 19p13.1 is the first triple negative-specific breast cancer risk locus and the first locus specific to a histological subtype defined by ER, PR, and HER2 to be identified. These findings provide convincing evidence that genetic susceptibility to breast cancer varies by tumor subtype and that triple negative tumors and other subtypes likely arise through distinct etiologic pathways.
  •  
40.
  • Stevens, Lesley A., et al. (author)
  • Development and validation of GFR-estimating equations using diabetes, transplant and weight
  • 2010
  • In: Nephrology Dialysis Transplantation. - : Oxford University Press (OUP). - 1460-2385 .- 0931-0509. ; 25:2, s. 449-457
  • Journal article (peer-reviewed)abstract
    • Methods. Linear regression was used to relate log-measured GFR (mGFR) to sex, race, diabetes, transplant, weight, various transformations of creatinine and age with and without interactions. Equations were developed in a pooled database of 10 studies [2/3 (N = 5504) for development and 1/3 (N = 2750) for internal validation], and final model selection occurred in 16 additional studies [external validation (N = 3896)]. Results. The mean mGFR was 68, 67 and 68 ml/min/ 1.73 m(2) in the development, internal validation and external validation datasets, respectively. In external validation, an equation that included a linear age term and spline terms in creatinine to account for a reduction in the magnitude of the slope at low serum creatinine values exhibited the best performance (bias = 2.5, RMSE = 0.250) among models using the four basic predictor variables. Addition of terms for diabetes and transplant did not improve performance. Equations with weight showed a small improvement in the subgroup with BMI < 20 kg/m(2). Conclusions. The CKD-EPI equation, based on creatinine, age, sex and race, has been validated and is more accurate than the MDRD study equation. The addition of weight, diabetes and transplant does not significantly improve equation performance.
  •  
41.
  • Stevens, Matthew, et al. (author)
  • Accelerometer-measured physical activity at work and need for recovery: A compositional analysis of cross-sectional data
  • 2020
  • In: Annals of Work Exposures and Health. - : Oxford University Press. - 2398-7308 .- 2398-7316. ; 64:2, s. 138-151
  • Journal article (peer-reviewed)abstract
    • ObjectivesPrevious research has shown strong associations between occupational physical activity (OPA) and need for recovery (NFR). However this research has only utilized self-reported measures of OPA which may be biased. Thus, there is a need for investigating if the previously documented association between self-reported OPA and NFR can be found when using technical measures of OPA. There is also the need to investigate whether older workers are particularly susceptible to increased NFR, since age-related declines in physical capacity mean that it is likely these workers will have a higher NFR for a given physical activity. The aim of this study was to investigate the association between technically measured OPA and NFR, and whether this relationship is modified by age.MethodsThis study utilized data from the Danish Physical Activity Cohort with Objective Measurements cohort—comprising Danish workers (n = 840) from the cleaning, manufacturing, and transportation sectors. OPA was measured by accelerometers attached to the thigh and upper back for at least one work day and classified into four physical behaviour categories (sedentary, standing, light, or moderate/vigorous). NFR was measured using a shortened version of the Danish NFR scale. Analysis was conducted using linear regression and isotemporal substitution analyses for compositional data.ResultsThe overall association between OPA and NFR was statistically significant in the unadjusted model (P < 0.001), but not when adjusted for age, sex, occupation, and shift work (P = 0.166). Isotemporal substitution showed small but significant reductions in NFR when increasing sedentary time relative to other behaviours (adjusted: ΔNFR = −0.010 [−0.019; −0.001]). There were no significant interactions between age and OPA (P = 0.409).ConclusionsThis study found significant associations between OPA and NFR, but the effect sizes were small. Reallocating 30 min to sedentary behaviours from other behaviours was associated with a reduced NFR, but the effect size may not be practically relevant. Moreover, no clear modifying effects of age were identified.
  •  
42.
  • Stevens, Matthew, et al. (author)
  • Associations between perceived quantitative work demands at different organisational levels and pain and sickness absence in eldercare workers: A multilevel longitudinal analysis
  • 2022
  • In: International Archives of Occupational and Environmental Health. - : Springer. - 0340-0131 .- 1432-1246. ; 95, s. 993-1001
  • Journal article (peer-reviewed)abstract
    • PurposeEldercare work is characterised by high quantitative work demands and high occurrence of musculoskeletal pain and sickness absence. Our aim was to investigate the association between quantitative demands aggregated at the different organizational levels of eldercare and low back pain (LBP) and sickness absence due to pain among workers.MethodsThis study was conducted in 527 eldercare workers from 105 wards across 20 nursing homes in Denmark. We collected workers’ perceived quantitative demands at baseline and workers’ LBP and sickness absence repeatedly over the following year. We aggregated worker-level quantitative demands to the ward and nursing home-levels, and used mixed-effects regression models to investigate the associations between quantitative demands at different organizational levels and LBP and sickness absence over 1 year.ResultsAcross all models, increased quantitative demands (0-100 scale) at the worker-level was associated with an increased likelihood (OR = 1.02) and intensity of LBP (β = 0.01). We did not identify any associations between quantitative demands at the wardlevel and either of our outcomes. Across all models, increased quantitative demands at the nursing home-level was associated with increased days with sickness absence due to pain (β = 0.03 to 0.06).ConclusionIn eldercare, workers’ perceived quantitative demands are associated with the presence and intensity of LBP. Further, quantitative demands across the overall nursing home-level are associated with sickness absence due to pain among eldercare workers. These results are of relevance to developing organisational interventions targeting quantitative demands to reduce sickness absence in eldercare. 
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43.
  • Stevens, Matthew, et al. (author)
  • Nursing home, ward and worker level determinants of perceived quantitative work demands: a multi-level cross-sectional analysis in elderly care
  • 2022
  • In: Annals of Work Exposures and Health. - : Oxford University Press. - 2398-7308 .- 2398-7316. ; 66:8, s. 1033-1043
  • Journal article (peer-reviewed)abstract
    • Introduction Perceived quantitative demands at work have been associated with poor mental and physical health, long-term sickness absence and subsequent early retirement. Identifying modifiable predictors of perceived quantitative demands at different levels of the organization is key to developing effective interventions. The aim of the study was to identify predictors of perceived quantitative demands at work and examine the extent to which they occur at different levels of the eldercare organisation (i.e., the worker, ward and nursing home levels).Methods We collected data on 383 eldercare workers in 95 wards at 20 nursing homes in Denmark using workplace observations and questionnaires to workers and their managers. Perceived quantitative work demands were assessed using two items from the Copenhagen Psychosocial Questionnaire, II (COPSOQ-II). We identified contributions to overall variability from the three organisational levels using variance components analysis, and examined associations between predictors at these three levels and quantitative demands.Results Almost all (90.9%) the variability in perceived quantitative demands occurred between eldercare workers (within wards). Predictors significantly associated with lower quantitative demands were: having a job as a care helper, working fixed evening shifts, being born outside Denmark, having lower influence at work, higher quality of leadership and lower emotional demands. None of the investigated physical factors (e.g. resident handlings, push/pull tasks, step-count) were associated with perceived quantitative demands.Conclusion We found that the variability in perceived quantitative demands occurred primarily between eldercare workers within wards. Our study indicates that psychosocial work environment factors are the strongest modifiable predictors of perceived quantitative demands in eldercare, while organisational factors related to job position, shift, and resident-staff ratio also play a role. Interventions should test if changes in these predictors can reduce perceived quantitative demands at work in eldercare.  
  •  
44.
  • Stevens, Matthew, et al. (author)
  • What determines step-rate at work? An investigation of factors at the shift, worker, ward and nursing home levels in eldercare
  • 2021
  • In: Annals of Work Exposures and Health. - : Oxford Academic. - 2398-7308 .- 2398-7316. ; 65:8, s. 919-927
  • Journal article (peer-reviewed)abstract
    • Objectives. Current knowledge on the determinants of step-rate at different organisational levels is limited. Thus, our aim was to identify, in eldercare, at what workplace level differences in step-rate occur and to identify determinants of workers’ step-rate at these levels.Methods. Participants were 420 eldercare workers from 17 nursing homes (126 wards) in Denmark. Accelerometry was used to assess step-rate (steps/hour) of workers over multiple shifts. We assessed various determinants at different levels of the workplace, i.e., at the 1) shift, 2) worker, 3) ward and 4) nursing home levels. Variance components analysis identified the percentage contribution to total variance in step-rate from each respective level. Multi-level linear regression modelling was used to investigate the association between candidate determinants at each level and step-rate.Results. Differences in eldercare workers’ step-rate occurred primarily between shifts (within workers; 44.9%) and between workers (within wards; 49.1%). A higher step-rate was associated with: 1) weekend and evening shifts (vs. weekday/day); 2) job as a care helper (vs. care aide) and an increased proportion of time spent on direct care tasks; 3) working in a somatic ward (vs. dementia), an increased resident-staff ratio and permission to take unscheduled breaks; and 4) lack of elevators.Conclusion. We found that nearly all variability in step-rate in eldercare work occurs between shifts (within workers) and between workers (within wards). The main determinants of step-rate were related to the type of shift, type of work tasks, staffing ratio, break policy and availability of elevators. 
  •  
45.
  • Stevens, Thomas, et al. (author)
  • Eustatic control of late Quaternary sea-level change in the Arabian/Persian Gulf
  • 2014
  • In: Quaternary Research. - : Cambridge University Press (CUP). - 0033-5894 .- 1096-0287. ; 82:1, s. 175-184
  • Journal article (peer-reviewed)abstract
    • Accurate sea-level reconstruction is critical in understanding the drivers of coastal evolution. Inliers of shallow marine limestone and aeolianite are exposed as zeugen (carbonate-capped erosional remnants) on the southern coast of the Arabian/Persian Gulf. These have generally been accepted as evidence of a eustatically driven, last-interglacial relative sea-level highstand preceded by a penultimate glacial-age lowstand. Instead, recent optically stimulated luminescence (OSL) dating suggests a last glacial age for these deposits, requiring >100 m of uplift since the last glacial maximum in order to keep pace with eustatic sea-level rise and implying the need for a wholesale revision of tectonic, stratigraphic and sea-level histories of the Gulf. These two hypotheses have radically different implications for regional neotectonics and land–sea distribution histories. Here we test these hypotheses using OSL dating of the zeugen formations. These new ages are remarkably consistent with earlier interpretations of the formations being last interglacial or older in age, showing that tectonic movements are negligible and eustatic sea-level variations are responsible for local sea-level changes in the Gulf. The cause of the large age differences between recent studies is unclear, although it appears related to large differences in the measured accumulated dose in different OSL samples.
  •  
46.
  • Thomas, Matthew D., et al. (author)
  • Spatial and Temporal Scales of Sverdrup Balance
  • 2014
  • In: Journal of Physical Oceanography. - 0022-3670 .- 1520-0485. ; 44:10, s. 2644-2660
  • Journal article (peer-reviewed)abstract
    • Sverdrup balance underlies much of the theory of ocean circulation and provides a potential tool for describing the interior ocean transport from only the wind stress. Using both a model state estimate and an eddy-permitting coupled climate model, this study assesses to what extent and over what spatial and temporal scales Sverdrup balance describes the meridional transport. The authors find that Sverdrup balance holds to first order in the interior subtropical ocean when considered at spatial scales greater than approximately 5 degrees. Outside the subtropics, in western boundary currents and at short spatial scales, significant departures occur due to failures in both the assumptions that there is a level of no motion at some depth and that thevorticity equation is linear. Despite the ocean transport adjustment occurring on time scales consistent with the basin-crossing times for Rossby waves, as predicted by theory, Sverdrup balance gives a useful measure of the subtropical circulation after only a few years. This is because the interannual transport variability is small compared to the mean transports. The vorticity input to the deep ocean by the interaction between deep currents and topography is found to be very large in both models. These deep transports, however, are separated from upper-layer transports that are in Sverdrup balance when considered over large scales.
  •  
47.
  • Wang, Kanix, et al. (author)
  • NERO: a biomedical named-entity (recognition) ontology with a large, annotated corpus reveals meaningful associations through text embedding
  • 2021
  • In: npj Systems Biology and Applications. - : Springer Science and Business Media LLC. - 2056-7189. ; 7:1
  • Journal article (peer-reviewed)abstract
    • Machine reading (MR) is essential for unlocking valuable knowledge contained in millions of existing biomedical documents. Over the last two decades1,2, the most dramatic advances in MR have followed in the wake of critical corpus development3. Large, well-annotated corpora have been associated with punctuated advances in MR methodology and automated knowledge extraction systems in the same way that ImageNet4 was fundamental for developing machine vision techniques. This study contributes six components to an advanced, named entity analysis tool for biomedicine: (a) a new, Named Entity Recognition Ontology (NERO) developed specifically for describing textual entities in biomedical texts, which accounts for diverse levels of ambiguity, bridging the scientific sublanguages of molecular biology, genetics, biochemistry, and medicine; (b) detailed guidelines for human experts annotating hundreds of named entity classes; (c) pictographs for all named entities, to simplify the burden of annotation for curators; (d) an original, annotated corpus comprising 35,865 sentences, which encapsulate 190,679 named entities and 43,438 events connecting two or more entities; (e) validated, off-the-shelf, named entity recognition (NER) automated extraction, and; (f) embedding models that demonstrate the promise of biomedical associations embedded within this corpus.
  •  
48.
  • Wang, Yuzhuo, et al. (author)
  • Association Analysis of Driver Gene-Related Genetic Variants Identified Novel Lung Cancer Susceptibility Loci with 20,871 Lung Cancer Cases and 15,971 Controls
  • 2020
  • In: Cancer Epidemiology, Biomarkers and Prevention. - : American Association for Cancer Research. - 1055-9965 .- 1538-7755. ; 29:7, s. 1423-1429
  • Journal article (peer-reviewed)abstract
    • Background: A substantial proportion of cancer driver genes (CDG) are also cancer predisposition genes. However, the associations between genetic variants in lung CDGs and the susceptibility to lung cancer have rarely been investigated.Methods: We selected expression-related single-nucleotide polymorphisms (eSNP) and nonsynonymous variants of lung CDGs, and tested their associations with lung cancer risk in two large-scale genome-wide association studies (20,871 cases and 15,971 controls of European descent). Conditional and joint association analysis was performed to identify independent risk variants. The associations of independent risk variants with somatic alterations in lung CDGs or recurrently altered pathways were investigated using data from The Cancer Genome Atlas (TCGA) project.Results: We identified seven independent SNPs in five lung CDGs that were consistently associated with lung cancer risk in discovery (P < 0.001) and validation (P < 0.05) stages. Among these loci, rs78062588 in TPM3 (1q21.3) was a new lung cancer susceptibility locus (OR = 0.86, P = 1.65 x 10(-6)). Subgroup analysis by histologic types further identified nine lung CDGs. Analysis of somatic alterations found that in lung adenocarcinomas, rs78062588[C] allele (TPM3 in 1q21.3) was associated with elevated somatic copy number of TPM3 (OR = 1.16, P = 0.02). In lung adenocarcinomas, rs1611182 (HLA-A in 6p22.1) was associated with truncation mutations of the transcriptional misregulation in cancer pathway (OR = 0.66, P = 1.76 x 10(-3)).Conclusions: Genetic variants can regulate functions of lung CDGs and influence lung cancer susceptibility. Impact: Our findings might help unravel biological mechanisms underlying lung cancer susceptibility.
  •  
49.
  • 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.
  •  
50.
  • Wu, Lang, et al. (author)
  • Identification of Novel Susceptibility Loci and Genes for Prostate Cancer Risk : A Transcriptome-Wide Association Study in over 140,000 European Descendants
  • 2019
  • In: Cancer Research. - : AMER ASSOC CANCER RESEARCH. - 0008-5472 .- 1538-7445. ; 79:13, s. 3192-3204
  • Journal article (peer-reviewed)abstract
    • Genome-wide association study-identified prostate cancer risk variants explain only a relatively small fraction of its familial relative risk, and the genes responsible for many of these identified associations remain unknown. To discover novel prostate cancer genetic loci and possible causal genes at previously identified risk loci, we performed a transcriptome-wide association study in 79,194 cases and 61,112 controls of European ancestry. Using data from the Genotype-Tissue Expression Project, we established genetic models to predict gene expression across the transcriptome for both prostate models and cross-tissue models and evaluated model performance using two independent datasets. We identified significant associations for 137 genes at P < 2.61 x 10(-6), a Bonferroni-corrected threshold, including nine genes that remained significant at P < 2.61 x 10(-6) after adjusting for all known prostate cancer risk variants in nearby regions. Of the 128 remaining associated genes, 94 have not yet been reported as potential target genes at known loci. We silenced 14 genes and many showed a consistent effect on viability and colony-forming efficiency in three cell lines. Our study provides substantial new information to advance our understanding of prostate cancer genetics and biology. Significance: This study identifies novel prostate cancer genetic loci and possible causal genes, advancing our understanding of the molecular mechanisms that drive prostate cancer.
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