| 1. |
- Jiang, X., et al.
(författare)
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Shared heritability and functional enrichment across six solid cancers
- 2019
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
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| 4. |
- Huyghe, Jeroen R., et al.
(författare)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Tidskriftsartikel (refereegranskat)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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| 5. |
- Huyghe, Jeroen R, et al.
(författare)
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Genetic architectures of proximal and distal colorectal cancer are partly distinct
- 2021
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Ingår i: Gut. - : BMJ Publishing Group Ltd. - 0017-5749 .- 1468-3288. ; 70:7, s. 1325-1334
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Tidskriftsartikel (refereegranskat)abstract
- Objective: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined.Design: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling.Results: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer.Conclusion: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
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| 6. |
- Schmit, Stephanie L, et al.
(författare)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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| 7. |
- Dehaes, S., et al.
(författare)
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SED for 7 stellar calibrators (Dehaes+, 2011)
- 2011
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Ingår i: VizieR Online Data Catalog. ; 353
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Tidskriftsartikel (refereegranskat)abstract
- This catalogue presents the theoretical spectral energy distributions for 7 stellar calibrators of the ESA Herschel satellite in the wavelength range from 2 to 200 micron. The stellar atmosphere model and theoretical spectrum are generated using the MARCS theoretical stellar atmosphere code (Gustafsson et al., 1975A\ampA....42..407G and further updates; Gustafsson et al. 2003A\ampA...400..709D) and the TURBOSPECTRUM synthetic spectrum code (Plez et al., 1992A\ampA...256..551P). Stellar parameters (and uncertainties thereon) have been derived by Decin et al. (2003A\ampA...400..709D) and are described in the text files added to this catalogue. The line lists used in the spectrum calculation are discussed in Decin (2000, PhD Thesis, Leuven University) and Decin and Eriksson (2007A\ampA...472.1041D). The outermost depth point of the theoretical atmosphere model was taken at log(tau$_lambda$)=-7.2 with lambda being 2.2 micron. The atmosphere model was calculated with a spherically symmetric (parallel for Sirius) geometry, under the assumption of radiative and hydrostatic equilibrium, local thermodynamic equilibrium (LTE) and homogeneous layers. The original theoretical spectrum was calculated at a resolution of Δλ=0.5Å, and then degraded to a resolution of λ/Δλ=5000 applying a gaussian convolution. The wavelength coverage is from 2 to 200 micron. Uncertainties on the theoretical spectrum predictions are discussed in depth in Decin \amp Eriksson (2007A\ampA...472.1041D). Absolute flux calibration is based on Selby (1988A\ampAS...74..127S) K-band (TCS for Sirius) photometry Zero-point is determined on the basis of an ideal ’Vega’, i.e. the K-band photometry of Vega is corrected for a flux excess of 1.29% (cf. Absil et al. 2006A\ampA...452..237A). The determined Selby K-band zeropoint is 4.0517E-10 W/m2/um. The determined TCS K-band zeropoint is 4.4506E-10W/m2/um (for Sirius) The estimated absolute flux uncertainty is 1% These theoretical spectra should be referenced as Decin \amp Eriksson (2007A\ampA...472.1041D). (3 data files).
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| 8. |
- Dehaes, S., et al.
(författare)
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Structure of the outer layers of cool standard stars
- 2011
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Ingår i: Astronomy and Astrophysics. - : EDP Sciences. - 0004-6361 .- 1432-0746. ; 533, s. A107-
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Tidskriftsartikel (refereegranskat)abstract
- Context. Among late-type red giants, an interesting change occurs in the structure of the outer atmospheric layers as one moves to later spectral types in the Hertzsprung-Russell diagram: a chromosphere is always present, but the coronal emission diminishes and a cool massive wind steps in. Aims. Where most studies have focussed on short-wavelength observations, this article explores the influence of the chromosphere and the wind on long-wavelength photometric measurements. The goal of this study is to assess wether a set of standard near-infrared calibration sources are fiducial calibrators in the far-infrared, beyond 50 mu m. Methods. The observational spectral energy distributions were compared with the theoretical model predictions for a sample of nine K- and M-giants. The discrepancies found are explained using basic models for flux emission originating in a chromosphere or an ionised wind. Results. For seven out of nine sample stars, a clear flux excess is detected at (sub)millimetre and/or centimetre wavelengths, while only observational upper limits are obtained for the other two. The precise start of the excess depends upon the star under consideration. For six sources the flux excess starts beyond 210 mu m and they can be considered as fiducial calibrators for Herschel/PACS (60-210 mu m). Out of this sample, four sources show no flux excess in the Herschel/SPIRE wavelength range (200-670 mu m) and are good calibration sources for this instrument as well. The flux at wavelengths shorter than similar to 1 mm is most likely dominated by an optically thick chromosphere, where an optically thick ionised wind is the main flux contributor at longer wavelengths. Conclusions. Although the optical to mid-infrared spectrum of the studied K- and M-type infrared standard stars is represented well by a radiative equilibrium atmospheric model, a chromosphere and/or ionised stellar wind at higher altitudes dominates the spectrum in the (sub)millimetre and centimetre wavelength ranges. The presence of a flux excess has implications on the role of the stars as fiducial spectrophotometric calibrators in these wavelength ranges.
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| 9. |
- Hrudkova, M., et al.
(författare)
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The discovery of a planetary candidate around the evolved low-mass Kepler giant star HD 175370
- 2017
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Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 464:1, s. 1018-1028
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Tidskriftsartikel (refereegranskat)abstract
- We report on the discovery of a planetary companion candidate with a minimum mass M sin i = 4.6 +/- 1.0 M-Jupiter orbiting the K2 III giant star HD 175370 (KIC 007940959). This star was a target in our programme to search for planets around a sample of 95 giant stars observed with Kepler. This detection was made possible using precise stellar radial velocity measurements of HD 175370 taken over five years and four months using the coude echelle spectrograph of the 2-m Alfred Jensch Telescope and the fibre-fed echelle spectrograph High Efficiency and Resolution Mercator Echelle Spectrograph of the 1.2-m Mercator Telescope. Our radial velocity measurements reveal a periodic (349.5 +/- 4.5 d) variation with a semi-amplitude K = 133 +/- 25 ms(-1), superimposed on a long-term trend. A low-mass stellar companion with an orbital period of similar to 88 yr in a highly eccentric orbit and a planet in a Keplerian orbit with an eccentricity e = 0.22 are the most plausible explanation of the radial velocity variations. However, we cannot exclude the existence of stellar envelope pulsations as a cause for the low-amplitude radial velocity variations and only future continued monitoring of this system may answer this uncertainty. From Kepler photometry, we find that HD 175370 is most likely a low-mass red giant branch or asymptotic giant branch star.
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