Principles for the post-GWAS functional characterisation of risk loci

Several challenges lie ahead in assigning functionality to susceptibility SNPs. For example, most effect sizes are small relative to effects seen in monogenic diseases, with per allele odds ratios usually ranging from 1.15 to 1.3. It is unclear whether current molecular biology methods have enough resolution to differentiate such small effects. Our objective here is therefore to provide a set of recommendations to optimize the allocation of effort and resources in order maximize the chances of elucidating the functional contribution of specific loci to the disease phenotype. It has been estimated that 88% of currently identified disease-associated SNP are intronic or intergenic. Thus, in this paper we will focus our attention on the analysis of non-coding variants and outline a hierarchical approach for post-GWAS functional studies

Cholecystectomy and the risk of colorectal cancer by tumor mismatch repair deficiency status

Gallbladder diseases and cholecystectomy may play a role in the development of colorectal cancer (CRC). Our aim was to investigate the association between cholecystectomy and CRC risk overall and by sex, family history, anatomical location, and tumor mismatch repair (MMR) status

Infrared Luminous Lyman Break Galaxies: A Population that Bridges LBGs and SCUBA Galaxies

This is the publisher's version, also available electronically from http://iopscience.iop.org/0004-637X/634/1/137/.A deep mid- and far-infrared survey in the extended Groth strip (EGS) area gives 3.6 to 8 μm flux densities or upper limits for 253 Lyman break galaxies (LBGs). The LBGs are a diverse population but with properties correlated with luminosity. The LBGs show a factor of 30 range in indicated stellar mass and a factor of 10 range in apparent dust content relative to stellar mass. About 5% of LBGs are luminous at all wavelengths, with powerful emission at rest 6 μm. In the rest 0.9 to 2 μm spectral range these galaxies have stellar spectral slopes with no sign of an AGN power-law component, suggesting that their emission is mainly powered by intensive star formation. Galaxies in this luminous population share the infrared properties of cold Submillimeter Common-User Bolometric Array (SCUBA) sources: both are massive and dusty starburst galaxies at 2 < z < 3; their stellar mass is larger than 1011 M☉. We suggest that these galaxies are the progenitors of present-day giant elliptical galaxies, with a substantial fraction of their stars already formed at z ≈ 3

Colorectal cancer linkage on chromosomes 4q21, 8q13, 12q24, and 15q22

A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no loss of tumor expression of MMR proteins, no microsatellite instability (MSI)-high tumors, or no evidence of linkage to MMR genes). Families were ascertained via the Colon Cancer Family Registry multi-site NCI-supported consortium (Colon CFR), the City of Hope Comprehensive Cancer Center, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family including 2.2 affected) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed assuming heterogeneity. The greatest were among families with mean age of diagnosis less than 50 years at 4q21.1 (dominant HLOD = 4.51, α = 0.84, 145.40 cM, rs10518142) and among all families at 12q24.32 (dominant HLOD = 3.60, α = 0.48, 285.15 cM, rs952093). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD = 3.07, α = 0.29; dominant HLOD = 3.03, α = 0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD = 3.02, α = 0.51, 132.52 cM, rs1319036). These previously unreported linkage peaks demonstrate the continued utility of family-based data in complex traits and suggest that new CRC risk alleles remain to be elucidated. © 2012 Cicek et al

Patterns of place:an integrated approach for the design and evaluation of real and virtual environments

This chapter describes an approach to the development of virtual representations of real places. The work was funded under the European Union’s €20 m Future and Emerging Technologies theme of the 5th Framework Programme, “Presence”. The aim of the project, called BENOGO, was to develop a novel technology based on real-time image-based rendering (IBR) for representing places in virtual environments. The specific focus of the work presented here concerned how to capture the essential features of real places, and how to represent that knowledge, so that the team developing the IBR-based virtual environments could produce an environment that was as realistic as possible. This involved the development and evaluation of a number of virtual environments and the evolution of two complementary techniques; the Place Probe and Patterns of place

Infrared Array Camera (IRAC) Imaging of the Lockman Hole

This is the published version, also available here: http://dx.doi.org/10.1086/422882.IRAC imaging of a 4farcm7 × 4farcm7 area in the Lockman Hole detected over 400 galaxies in the IRAC 3.6 and 4.5 μm bands, 120 in the 5.8 μm band, and 80 in the 8.0 μm band in 30 minutes of observing time. Color-color diagrams suggest that about half of these galaxies are at redshifts 0.6 1.3). We also detect IRAC counterparts for six of the seven SCUBA sources and all nine XMM-Newton sources in this area. The detection of the counterparts of the SCUBA sources and galaxies at z > 1.3 demonstrates the ability of IRAC to probe the universe at very high redshifts

Meta-analysis of 8q24 for seven cancers reveals a locus between NOV and ENPP2 associated with cancer development.

BACKGROUND: Human chromosomal region 8q24 contains several genes which could be functionally related to cancer, including the proto-oncogene c-MYC. However, the abundance of associations around 128 Mb on chromosome 8 could mask the appearance of a weaker, but important, association elsewhere on 8q24. METHODS: In this study, we completed a meta-analysis of results from nine genome-wide association studies for seven types of solid-tumor cancers (breast, prostate, pancreatic, lung, ovarian, colon, and glioma) to identify additional associations that were not apparent in any individual study. RESULTS: Fifteen SNPs in the 8q24 region had meta-analysis p-values < 1E-04. In particular, the region consisting of 120,576,000-120,627,000 bp contained 7 SNPs with p-values < 1.0E-4, including rs6993464 (p = 1.25E-07). This association lies in the region between two genes, NOV and ENPP2, which have been shown to play a role in tumor development and motility. An additional region consisting of 5 markers from 128,478,000 bp - 128,524,000 (around gene POU5F1B) had p-values < 1E-04, including rs6983267, which had the smallest p-value (p = 6.34E-08). This result replicates previous reports of association between rs6983267 and prostate and colon cancer. CONCLUSIONS: Further research in this area is warranted as these results demonstrate that the chromosomal region 8q24 may contain a locus that influences general cancer susceptibility between 120,576 and 120,630 kb.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Lack of an association between gallstone disease and bilirubin levels with risk of colorectal cancer : a Mendelian randomisation analysis

BACKGROUND: Epidemiological studies of the relationship between gallstone disease and circulating levels of bilirubin with risk of developing colorectal cancer (CRC) have been inconsistent. To address possible confounding and reverse causation, we examine the relationship between these potential risk factors and CRC using Mendelian randomisation (MR). METHODS: We used two-sample MR to examine the relationship between genetic liability to gallstone disease and circulating levels of bilirubin with CRC in 26,397 patients and 41,481 controls. We calculated the odds ratio per genetically predicted SD unit increase in log bilirubin levels (ORSD) for CRC and tested for a non-zero causal effect of gallstones on CRC. Sensitivity analysis was applied to identify violations of estimator assumptions. RESULTS: No association between either gallstone disease (P value = 0.60) or circulating levels of bilirubin (ORSD = 1.00, 95% confidence interval (CI) = 0.96-1.03, P value = 0.90) with CRC was shown. CONCLUSIONS: Despite the large scale of this study, we found no evidence for a causal relationship between either circulating levels of bilirubin or gallstone disease with risk of developing CRC. While the magnitude of effect suggested by some observational studies can confidently be excluded, we cannot exclude the possibility of smaller effect sizes and non-linear relationships.Peer reviewe

Extremely Red Objects in the Lockman Hole

This is the published version, also available here: http://dx.doi.org/10.1086/422716.We investigate extremely red objects (EROs) using near- and mid-infrared observations in five passbands (3.6 to 24 μm) obtained from the Spitzer Space Telescope, and deep ground-based R and K imaging. The great sensitivity of the Infrared Array Camera (IRAC) camera allows us to detect 64 EROs (a surface density of 2.90 ± 0.36 arcmin-2; [3.6]AB 1.3 EROs. We find ~17% of all galaxies detected by IRAC at 3.6 or 4.5 μm to be EROs. These percentages rise to about 40% at 5.8 μm, and about 60% at 8.0 μm. We utilize the spectral bump at 1.6 μm to divide the EROs into broad redshift slices using only near-infrared colors (2.2/3.6/4.5 μm). We conclude that two-thirds of all EROs lie at redshift z > 1.3. Detections at 24 μm imply that at least 11% of 0.6 1.3 EROs are dusty star-forming galaxies