| 1. |
- Fernandez-Rozadilla, Ceres, et al.
(författare)
-
Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
- 2023
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
-
Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
|
|
| 2. |
- Agertz, Oscar, et al.
(författare)
-
EDGE : The mass-metallicity relation as a critical test of galaxy formation physics
- 2020
-
Ingår i: Monthly Notices of the Royal Astronomical Society. - : Oxford University Press (OUP). - 0035-8711 .- 1365-2966. ; 491:2, s. 1656-1672
-
Tidskriftsartikel (refereegranskat)abstract
- We introduce the 'Engineering Dwarfs at Galaxy Formation's Edge' (EDGE) project to study the cosmological formation and evolution of the smallest galaxies in the Universe. In this first paper, we explore the effects of resolution and sub-grid physics on a single low-mass halo (Mhalo = 109M⊙), simulated to redshift z = 0 at amass and spatial resolution of ∼ 20 M⊙ and ∼3 pc. We consider different star formation prescriptions, supernova feedback strengths, and on-the-fly radiative transfer (RT). We show that RT changes the mode of galactic self-regulation at this halo mass, suppressing star formation by causing the interstellar and circumgalactic gas to remain predominantly warm (∼104K) even before cosmic reionization. By contrast, without RT, star formation regulation occurs only through starbursts and their associated vigorous galactic outflows. In spite of this difference, the entire simulation suite (with the exception of models without any feedback) matches observed dwarf galaxy sizes, velocity dispersions, V-band magnitudes, and dynamical mass-to-light-ratios. This is because such structural scaling relations are predominantly set by the host dark matter halo, with the remaining model-to-model variation being smaller than the observational scatter. We find that only the stellar mass-metallicity relation differentiates the galaxy formation models. Explosive feedback ejects more metals from the dwarf, leading to a lower metallicity at a fixed stellar mass. We conclude that the stellar mass-metallicity relation of the very smallest galaxies provides a unique constraint on galaxy formation physics.
|
|
| 3. |
- Huyghe, Jeroen R., et al.
(författare)
-
Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
-
Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
-
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.
|
|
| 4. |
- Kim, Ji Hoon, et al.
(författare)
-
THE AGORA HIGH-RESOLUTION GALAXY SIMULATIONS COMPARISON PROJECT. II. ISOLATED DISK TEST
- 2016
-
Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 833:2
-
Tidskriftsartikel (refereegranskat)abstract
- Using an isolated Milky Way-mass galaxy simulation, we compare results from nine state-of-the-art gravito-hydrodynamics codes widely used in the numerical community. We utilize the infrastructure we have built for the AGORA High-resolution Galaxy Simulations Comparison Project. This includes the common disk initial conditions, common physics models (e.g., radiative cooling and UV background by the standardized package Grackle) and common analysis toolkit yt, all of which are publicly available. Subgrid physics models such as Jeans pressure floor, star formation, supernova feedback energy, and metal production are carefully constrained across code platforms. With numerical accuracy that resolves the disk scale height, we find that the codes overall agree well with one another in many dimensions including: gas and stellar surface densities, rotation curves, velocity dispersions, density and temperature distribution functions, disk vertical heights, stellar clumps, star formation rates, and Kennicutt-Schmidt relations. Quantities such as velocity dispersions are very robust (agreement within a few tens of percent at all radii) while measures like newly formed stellar clump mass functions show more significant variation (difference by up to a factor of ∼3). Systematic differences exist, for example, between mesh-based and particle-based codes in the low-density region, and between more diffusive and less diffusive schemes in the high-density tail of the density distribution. Yet intrinsic code differences are generally small compared to the variations in numerical implementations of the common subgrid physics such as supernova feedback. Our experiment reassures that, if adequately designed in accordance with our proposed common parameters, results of a modern high-resolution galaxy formation simulation are more sensitive to input physics than to intrinsic differences in numerical schemes.
|
|
