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- Thomas, HS, et al.
(author)
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- 2019
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swepub:Mat__t
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- Schmit, Stephanie L, et al.
(author)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Journal article (peer-reviewed)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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- Huyghe, Jeroen R., et al.
(author)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Journal article (peer-reviewed)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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- Waldorf, Kristina M. Adams, et al.
(author)
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Congenital Zika virus infection as a silent pathology with loss of neurogenic output in the fetal brain
- 2018
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 24:3, s. 368-374
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Journal article (peer-reviewed)abstract
- Zika virus (ZIKV) is a flavivirus with teratogenic effects on fetal brain, but the spectrum of ZIKV-induced brain injury is unknown, particularly when ultrasound imaging is normal. In a pregnant pigtail macaque (Macaca nemestrina) model of ZIKV infection, we demonstrate that ZIKV-induced injury to fetal brain is substantial, even in the absence of microcephaly, and may be challenging to detect in a clinical setting. A common and subtle injury pattern was identified, including (i) periventricular T2-hyperintense foci and loss of fetal noncortical brain volume, (ii) injury to the ependymal epithelium with underlying gliosis and (iii) loss of late fetal neuronal progenitor cells in the subventricular zone (temporal cortex) and subgranular zone (dentate gyrus, hippocampus) with dysmorphic granule neuron patterning. Attenuation of fetal neurogenic output demonstrates potentially considerable teratogenic effects of congenital ZIKV infection even without microcephaly. Our findings suggest that all children exposed to ZIKV in utero should receive long-term monitoring for neurocognitive deficits, regardless of head size at birth.
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- de Blok, W.J.G., et al.
(author)
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an overview of the MHONGOOSE survey: Observing nearby galaxies with MeerKAT
- 2016
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In: Proceedings of Science. - 1824-8039.
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Conference paper (peer-reviewed)abstract
- MHONGOOSE is a deep survey of the neutral hydrogen distribution in a representative sample of 30 nearby disk and dwarf galaxies with H I masses from ∼ 106 to ∼ 1011 M, and luminosities from MR ∼ 12 to MR ∼ −22. The sample is selected to uniformly cover the available range in log(MHI). Our extremely deep observations, down to H I column density limits of well below 1018 cm−2 — or a few hundred times fainter than the typical H I disks in galaxies — will directly detect the effects of cold accretion from the intergalactic medium and the links with the cosmic web. These observations will be the first ever to probe the very low-column density neutral gas in galaxies at these high resolutions. Combination with data at other wavelengths, most of it already available, will enable accurate modeling of the properties and evolution of the mass components in these galaxies and link these with the effects of environment, dark matter distribution, and other fundamental properties such as halo mass and angular momentum. MHONGOOSE can already start addressing some of the SKA-1 science goals and will provide a comprehensive inventory of the processes driving the transformation and evolution of galaxies in the nearby universe at high resolution and over 5 orders of magnitude in column density. It will be a Nearby Galaxies Legacy Survey that will be unsurpassed until the advent of the SKA, and can serve as a highly visible, lasting statement of MeerKAT’s capabilities.
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- Watts, Eleanor L., et al.
(author)
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The associations of anthropometric, behavioural and sociodemographic factors with circulating concentrations of IGF‐I, IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 in a pooled analysis of 16,024 men from 22 studies
- 2019
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In: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 145:12, s. 3244-3256
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Journal article (peer-reviewed)abstract
- Insulin‐like growth factors (IGFs) and insulin‐like growth factor binding proteins (IGFBPs) have been implicated in the aetiology of several cancers. To better understand whether anthropometric, behavioural and sociodemographic factors may play a role in cancer risk via IGF signalling, we examined the cross‐sectional associations of these exposures with circulating concentrations of IGFs (IGF‐I and IGF‐II) and IGFBPs (IGFBP‐1, IGFBP‐2 and IGFBP‐3). The Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group dataset includes individual participant data from 16,024 male controls (i.e. without prostate cancer) aged 22–89 years from 22 prospective studies. Geometric means of protein concentrations were estimated using analysis of variance, adjusted for relevant covariates. Older age was associated with higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGF‐I, IGF‐II and IGFBP‐3. Higher body mass index was associated with lower concentrations of IGFBP‐1 and IGFBP‐2. Taller height was associated with higher concentrations of IGF‐I and IGFBP‐3 and lower concentrations of IGFBP‐1. Smokers had higher concentrations of IGFBP‐1 and IGFBP‐2 and lower concentrations of IGFBP‐3 than nonsmokers. Higher alcohol consumption was associated with higher concentrations of IGF‐II and lower concentrations of IGF‐I and IGFBP‐2. African Americans had lower concentrations of IGF‐II, IGFBP‐1, IGFBP‐2 and IGFBP‐3 and Hispanics had lower IGF‐I, IGF‐II and IGFBP‐3 than non‐Hispanic whites. These findings indicate that a range of anthropometric, behavioural and sociodemographic factors are associated with circulating concentrations of IGFs and IGFBPs in men, which will lead to a greater understanding of the mechanisms through which these factors influence cancer risk.
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