| 31. |
- Bien, Stephanie A., et al.
(author)
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Genetic variant predictors of gene expression provide new insight into risk of colorectal cancer
- 2019
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In: Human Genetics. - : Springer. - 0340-6717 .- 1432-1203. ; 138:4, s. 307-326
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Journal article (peer-reviewed)abstract
- Genome-wide association studies have reported 56 independently associated colorectal cancer (CRC) risk variants, most of which are non-coding and believed to exert their effects by modulating gene expression. The computational method PrediXcan uses cis-regulatory variant predictors to impute expression and perform gene-level association tests in GWAS without directly measured transcriptomes. In this study, we used reference datasets from colon (n=169) and whole blood (n=922) transcriptomes to test CRC association with genetically determined expression levels in a genome-wide analysis of 12,186 cases and 14,718 controls. Three novel associations were discovered from colon transverse models at FDR0.2 and further evaluated in an independent replication including 32,825 cases and 39,933 controls. After adjusting for multiple comparisons, we found statistically significant associations using colon transcriptome models with TRIM4 (discovery P=2.2x10(-4), replication P=0.01), and PYGL (discovery P=2.3x10(-4), replication P=6.7x10(-4)). Interestingly, both genes encode proteins that influence redox homeostasis and are related to cellular metabolic reprogramming in tumors, implicating a novel CRC pathway linked to cell growth and proliferation. Defining CRC risk regions as one megabase up- and downstream of one of the 56 independent risk variants, we defined 44 non-overlapping CRC-risk regions. Among these risk regions, we identified genes associated with CRC (P<0.05) in 34/44 CRC-risk regions. Importantly, CRC association was found for two genes in the previously reported 2q25 locus, CXCR1 and CXCR2, which are potential cancer therapeutic targets. These findings provide strong candidate genes to prioritize for subsequent laboratory follow-up of GWAS loci. This study is the first to implement PrediXcan in a large colorectal cancer study and findings highlight the utility of integrating transcriptome data in GWAS for discovery of, and biological insight into, risk loci.
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| 32. |
- Bolin, Bryce T., et al.
(author)
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Characterization of the Nucleus, Morphology, and Activity of Interstellar Comet 2I/Borisov by Optical and Near-infrared GROWTH, Apache Point, IRTF, ZTF, and Keck Observations
- 2020
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In: Astronomical Journal. - : American Astronomical Society. - 0004-6256 .- 1538-3881. ; 160:1
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Journal article (peer-reviewed)abstract
- We present visible and near-infrared (NIR) photometric and spectroscopic observations of interstellar object (ISO) 2I/Borisov taken from 2019 September 10 to 2019 December 20 using the GROWTH, the Apache Point Observatory Astrophysical Research Consortium 3.5 m, and the NASA Infrared Telescope Facility 3.0 m combined with pre- and postdiscovery observations of 2I obtained by the Zwicky Transient Facility from 2019 March 17 to 2019 May 5. Comparison with imaging of distant solar system comets shows an object very similar to mildly active solar system comets with an outgassing rate of similar to 10(27)mol s(-1). The photometry, taken in filters spanning the visible and NIR range, shows a gradual brightening trend of similar to 0.03 mag day(-1)since 2019 September 10 UTC for a reddish object becoming neutral in the NIR. The light curve from recent and prediscovery data reveals a brightness trend suggesting the recent onset of significant H2O sublimation with the comet being active with super volatiles such as CO at heliocentric distances >6 au consistent with its extended morphology. Using the advanced capability to significantly reduce the scattered light from the coma enabled by high-resolution NIR images from Keck adaptive optics taken on 2019 October 4, we estimate a diameter for 2I's nucleus of less than or similar to 1.4 km. We use the size estimates of 1I/'Oumuamua and 2I/Borisov to roughly estimate the slope of the ISO size distribution, resulting in a slope of similar to 3.4 1.2, similar to solar system comets and bodies produced from collisional equilibrium.
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| 33. |
- Bull, Caroline J., et al.
(author)
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Adiposity, metabolites, and colorectal cancer risk : Mendelian randomization study
- 2020
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In: BMC Medicine. - : BMC. - 1741-7015. ; 18:1
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Journal article (peer-reviewed)abstract
- Background Higher adiposity increases the risk of colorectal cancer (CRC), but whether this relationship varies by anatomical sub-site or by sex is unclear. Further, the metabolic alterations mediating the effects of adiposity on CRC are not fully understood. Methods We examined sex- and site-specific associations of adiposity with CRC risk and whether adiposity-associated metabolites explain the associations of adiposity with CRC. Genetic variants from genome-wide association studies of body mass index (BMI) and waist-to-hip ratio (WHR, unadjusted for BMI; N = 806,810), and 123 metabolites from targeted nuclear magnetic resonance metabolomics (N = 24,925), were used as instruments. Sex-combined and sex-specific Mendelian randomization (MR) was conducted for BMI and WHR with CRC risk (58,221 cases and 67,694 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium, Colorectal Cancer Transdisciplinary Study, and Colon Cancer Family Registry). Sex-combined MR was conducted for BMI and WHR with metabolites, for metabolites with CRC, and for BMI and WHR with CRC adjusted for metabolite classes in multivariable models. Results In sex-specific MR analyses, higher BMI (per 4.2 kg/m(2)) was associated with 1.23 (95% confidence interval (CI) = 1.08, 1.38) times higher CRC odds among men (inverse-variance-weighted (IVW) model); among women, higher BMI (per 5.2 kg/m(2)) was associated with 1.09 (95% CI = 0.97, 1.22) times higher CRC odds. WHR (per 0.07 higher) was more strongly associated with CRC risk among women (IVW OR = 1.25, 95% CI = 1.08, 1.43) than men (IVW OR = 1.05, 95% CI = 0.81, 1.36). BMI or WHR was associated with 104/123 metabolites at false discovery rate-corrected P <= 0.05; several metabolites were associated with CRC, but not in directions that were consistent with the mediation of positive adiposity-CRC relations. In multivariable MR analyses, associations of BMI and WHR with CRC were not attenuated following adjustment for representative metabolite classes, e.g., the univariable IVW OR for BMI with CRC was 1.12 (95% CI = 1.00, 1.26), and this became 1.11 (95% CI = 0.99, 1.26) when adjusting for cholesterol in low-density lipoprotein particles. Conclusions Our results suggest that higher BMI more greatly raises CRC risk among men, whereas higher WHR more greatly raises CRC risk among women. Adiposity was associated with numerous metabolic alterations, but none of these explained associations between adiposity and CRC. More detailed metabolomic measures are likely needed to clarify the mechanistic pathways.
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| 34. |
- Cowie, A. L., et al.
(author)
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Applying a science-based systems perspective to dispel misconceptions about climate effects of forest bioenergy
- 2021
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In: Global Change Biology Bioenergy. - : John Wiley and Sons Inc. - 1757-1693 .- 1757-1707. ; 13:8, s. 1210-1231
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Journal article (peer-reviewed)abstract
- The scientific literature contains contrasting findings about the climate effects of forest bioenergy, partly due to the wide diversity of bioenergy systems and associated contexts, but also due to differences in assessment methods. The climate effects of bioenergy must be accurately assessed to inform policy-making, but the complexity of bioenergy systems and associated land, industry and energy systems raises challenges for assessment. We examine misconceptions about climate effects of forest bioenergy and discuss important considerations in assessing these effects and devising measures to incentivize sustainable bioenergy as a component of climate policy. The temporal and spatial system boundary and the reference (counterfactual) scenarios are key methodology choices that strongly influence results. Focussing on carbon balances of individual forest stands and comparing emissions at the point of combustion neglect system-level interactions that influence the climate effects of forest bioenergy. We highlight the need for a systems approach, in assessing options and developing policy for forest bioenergy that: (1) considers the whole life cycle of bioenergy systems, including effects of the associated forest management and harvesting on landscape carbon balances; (2) identifies how forest bioenergy can best be deployed to support energy system transformation required to achieve climate goals; and (3) incentivizes those forest bioenergy systems that augment the mitigation value of the forest sector as a whole. Emphasis on short-term emissions reduction targets can lead to decisions that make medium- to long-term climate goals more difficult to achieve. The most important climate change mitigation measure is the transformation of energy, industry and transport systems so that fossil carbon remains underground. Narrow perspectives obscure the significant role that bioenergy can play by displacing fossil fuels now, and supporting energy system transition. Greater transparency and consistency is needed in greenhouse gas reporting and accounting related to bioenergy.
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| 35. |
- Klein, Alison P., et al.
(author)
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Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer
- 2018
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In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 9
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Journal article (peer-reviewed)abstract
- In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 x 10(-8)). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PAN-DoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 x 10(-14)), rs2941471 at 8q21.11 (HNF4G, P = 6.60 x 10(-10)), rs4795218 at 17q12 (HNF1B, P = 1.32 x 10(-8)), and rs1517037 at 18q21.32 (GRP, P = 3.28 x 10(-8)). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.
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| 36. |
- Purdum, Josiah N., et al.
(author)
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Time-series and Phase-curve Photometry of the Episodically Active Asteroid (6478) Gault in a Quiescent State Using APO, GROWTH, P200, and ZTF
- 2021
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In: Astrophysical Journal Letters. - : American Astronomical Society. - 2041-8205 .- 2041-8213. ; 911:2
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Journal article (peer-reviewed)abstract
- We observed the episodically active asteroid (6478) Gault in 2020 with multiple telescopes in Asia and North America and found that it is no longer active after its recent outbursts at the end of 2018 and the start of 2019. The inactivity during this apparition allowed us to measure the absolute magnitude of Gault of H ( r ) = 14.63 +/- 0.02, G ( r ) = 0.21 +/- 0.02 from our secular phase-curve observations. In addition, we were able to constrain Gault's rotation period using time-series photometric lightcurves taken over 17 hr on multiple days in 2020 August, September, and October. The photometric lightcurves have a repeating less than or similar to 0.05 mag feature suggesting that (6478) Gault has a rotation period of similar to 2.5 hr and may have a semispherical or top-like shape, much like the near-Earth asteroids Ryugu and Bennu. The rotation period of similar to 2.5 hr is near the expected critical rotation period for an asteroid with the physical properties of (6478) Gault, suggesting that its activity observed over multiple epochs is due to surface mass shedding from its fast rotation spin-up by the Yarkovsky-O'Keefe-Radzievskii-Paddack effect.
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| 37. |
- Wang, Sophia S., et al.
(author)
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HLA Class I and II Diversity Contributes to the Etiologic Heterogeneity of Non-Hodgkin Lymphoma Subtypes
- 2018
-
In: Cancer Research. - 0008-5472 .- 1538-7445. ; 78:14, s. 4086-4096
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Journal article (peer-reviewed)abstract
- A growing number of loci within the human leukocyte antigen (HLA) region have been implicated in non-Hodgkin lymphoma (NHL) etiology. Here, we test a complementary hypothesis of "heterozygote advantage" regarding the role of HLA and NHL, whereby HLA diversity is beneficial and homozygous HLA loci are associated with increased disease risk. HLA alleles at class I and II loci were imputed from genome-wide association studies (GWAS) using SNP2HLA for 3,617 diffuse large B-cell lymphomas (DLBCL), 2,686 follicular lymphomas (FL), 2,878 chronic lymphocytic leukemia/small lymphocytic lymphomas (CLL/SLL), 741 marginal zone lymphomas (MZL), and 8,753 controls of European descent. Both DLBCL and MZL risk were elevated with homozygosity at class I HLA-B and -C loci (OR DLBCL = 1.31, 95% CI = 1.06-1.60; OR MZL = 1.45, 95% CI = 1.12-1.89) and class II HLA-DRB1 locus (OR DLBCL = 2.10, 95% CI = 1.24-3.55; OR MZL = 2.10, 95% CI = 0.99-4.45). Increased FL risk was observed with the overall increase in number of homozygous HLA class II loci (P trend < 0.0001, FDR = 0.0005). These results support a role for HLA zygosity in NHL etiology and suggests that distinct immune pathways may underly the etiology of the different NHL subtypes. Significance: HLA gene diversity reduces risk for non-Hodgkin lymphoma.
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| 38. |
- Aharonian, Felix, et al.
(author)
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Atmospheric gas dynamics in the Perseus cluster observed with Hitomi
- 2018
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In: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:2
-
Journal article (peer-reviewed)abstract
- Extending the earlier measurements reported in Hitomi collaboration (2016, Nature, 535, 117), we examine the atmospheric gas motions within the central 100 kpc of the Perseus cluster using observations obtained with the Hitomi satellite. After correcting for the point spread function of the telescope and using optically thin emission lines, we find that the line-of-sight velocity dispersion of the hot gas is remarkably low and mostly uniform. The velocity dispersion reaches a maxima of approximately 200 km s(-1) toward the central active galactic nucleus (AGN) and toward the AGN inflated northwestern ghost bubble. Elsewhere within the observed region, the velocity dispersion appears constant around 100 km s(-1). We also detect a velocity gradient with a 100 km s(-1) amplitude across the cluster core, consistent with large-scale sloshing of the core gas. If the observed gas motions are isotropic, the kinetic pressure support is less than 10% of the thermal pressure support in the cluster core. The well-resolved, optically thin emission lines have Gaussian shapes, indicating that the turbulent driving scale is likely below 100 kpc, which is consistent with the size of the AGN jet inflated bubbles. We also report the first measurement of the ion temperature in the intracluster medium, which we find to be consistent with the electron temperature. In addition, we present a new measurement of the redshift of the brightest cluster galaxy NGC 1275.
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| 39. |
- Aharonian, Felix, et al.
(author)
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Atomic data and spectral modeling constraints from high-resolution X-ray observations of the Perseus cluster with Hitomi
- 2018
-
In: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:2
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Journal article (peer-reviewed)abstract
- The Hitomi Soft X-ray Spectrometer spectrum of the Perseus cluster, with similar to 5 eV resolution in the 2-9 keV band, offers an unprecedented benchmark of the atomic modeling and database for hot collisional plasmas. It reveals both successes and challenges of the current atomic data and models. The latest versions of AtomDB/APEC (3.0.8), SPEX (3.03.00), and CHIANTI (8.0) all provide reasonable fits to the broad-band spectrum, and are in close agreement on best-fit temperature, emission measure, and abundances of a few elements such as Ni. For the Fe abundance, the APEC and SPEX measurements differ by 16%, which is 17 times higher than the statistical uncertainty. This is mostly attributed to the differences in adopted collisional excitation and dielectronic recombination rates of the strongest emission lines. We further investigate and compare the sensitivity of the derived physical parameters to the astrophysical source modeling and instrumental effects. The Hitomi results show that accurate atomic data and models are as important as the astrophysical modeling and instrumental calibration aspects. Substantial updates of atomic databases and targeted laboratory measurements are needed to get the current data and models ready for the data from the next Hitomi-level mission.
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| 40. |
- Aharonian, Felix, et al.
(author)
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Detection of polarized gamma-ray emission from the Crab nebula with the Hitomi Soft Gamma-ray Detector
- 2018
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In: Publications of the Astronomical Society of Japan. - : Oxford University Press (OUP). - 0004-6264 .- 2053-051X. ; 70:6
-
Journal article (peer-reviewed)abstract
- We present the results from the Hitomi Soft Gamma-ray Detector (SGD) observation of the Crab nebula. The main part of SGD is a Compton camera, which in addition to being a spectrometer, is capable of measuring polarization of gamma-ray photons. The Crab nebula is one of the brightest X-ray / gamma-ray sources on the sky, and, the only source from which polarized X-ray photons have been detected. SGD observed the Crab nebula during the initial test observation phase of Hitomi. We performed the data analysis of the SGD observation, the SGD background estimation and the SGD Monte Carlo simulations, and, successfully detected polarized gamma-ray emission from the Crab nebula with only about 5 ks exposure time. The obtained polarization fraction of the phase-integrated Crab emission (sum of pulsar and nebula emissions) is (22.1% +/- 10.6%), and, the polarization angle is 110.degrees 7 + 13.degrees 2 /-13.degrees 0 in the energy range of 60-160 keV (The errors correspond to the 1 sigma deviation). The confidence level of the polarization detection was 99.3%. The polarization angle measured by SGD is about one sigma deviation with the projected spin axis of the pulsar, 124.degrees 0 +/- 0.degrees 1.
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