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Much of the variation in inherited risk of colorectal cancer (CRC) is probably due to combinations of common low risk variants. We conducted a genome-wide association study of 550,000 tag SNPs in 930 familial colorectal tumor cases and 960 controls. The most strongly associated SNP ( P = 1.72 × 10 −7 , allelic test) was rs6983267 at 8q24.21. To validate this finding, we genotyped rs6983267 in three additional CRC case-control series (4,361 affected individuals and 3,752 controls; 1,901 affected individuals and 1,079 controls; 1,072 affected individuals and 415 controls) and replicated the association, providing P = 1.27 × 10 −14 (allelic test) overall, with odds ratios (ORs) of 1.27 (95% confidence interval (c.i.): 1.16–1.39) and 1.47 (95% c.i.: 1.34–1.62) for heterozygotes and rare homozygotes, respectively. Analyses based on 1,477 individuals with colorectal adenoma and 2,136 controls suggest that susceptibility to CRC is mediated through development of adenomas (OR = 1.21, 95% c.i.: 1.10–1.34; P = 6.89 × 10 −5 ). These data show that common, low-penetrance susceptibility alleles predispose to colorectal neoplasia.

We mapped a high-penetrance gene ( CRAC1 ; also known as HMPS ) associated with colorectal cancer (CRC) in the Ashkenazi population to a 0.6-Mb region on chromosome 15 containing SCG5 (also known as SGNE1 ), GREM1 and FMN1 . We hypothesized that the CRAC1 locus harbored low-penetrance variants that increased CRC risk in the general population. In a large series of colorectal cancer cases and controls, SNPs near GREM1 and SCG5 were strongly associated with increased CRC risk (for rs4779584, P = 4.44 × 10 −14 ).

To identify risk variants for colorectal cancer (CRC), we conducted a genome-wide association study, genotyping 550,163 tag SNPs in 940 individuals with familial colorectal tumor (627 CRC, 313 advanced adenomas) and 965 controls. We evaluated selected SNPs in three replication sample sets (7,473 cases, 5,984 controls) and identified three SNPs in SMAD7 (involved in TGF-β and Wnt signaling) associated with CRC. Across the four sample sets, the association between rs4939827 and CRC was highly statistically significant ( P trend = 1.0 × 10 −12 ).

Richard Houlston and colleagues report a genome-wide association study for colorectal cancer. They report three loci newly associated with colorectal cancer, bringing the total number of common susceptibility loci to 20. We performed a meta-analysis of five genome-wide association studies to identify common variants influencing colorectal cancer (CRC) risk comprising 8,682 cases and 9,649 controls. Replication analysis was performed in case-control sets totaling 21,096 cases and 19,555 controls. We identified three new CRC risk loci at 6p21 (rs1321311, near CDKN1A ; P = 1.14 × 10 −10 ), 11q13.4 (rs3824999, intronic to POLD3 ; P = 3.65 × 10 −10 ) and Xp22.2 (rs5934683, near SHROOM2 ; P = 7.30 × 10 −10 ) This brings the number of independent loci associated with CRC risk to 20 and provides further insight into the genetic architecture of inherited susceptibility to CRC.

Richard Houlston and colleagues identify four new susceptibility loci for colorectal cancer through a meta-analysis of genome-wide association data, followed by replication testing in a large collection of independent samples. The study brings to ten the number of confirmed loci harboring low-penetrance risk alleles for this common malignancy. Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional loci with similar effect sizes, we conducted a meta-analysis of two GWA studies, comprising 13,315 individuals genotyped for 38,710 common tagging SNPs. We undertook replication testing in up to eight independent case-control series comprising 27,418 subjects. We identified four previously unreported CRC risk loci at 14q22.2 (rs4444235, BMP4 ; P = 8.1 × 10 −10 ), 16q22.1 (rs9929218, CDH1 ; P = 1.2 × 10 −8 ), 19q13.1 (rs10411210, RHPN2 ; P = 4.6 × 10 −9 ) and 20p12.3 (rs961253; P = 2.0 × 10 −10 ). These findings underscore the value of large sample series for discovery and follow-up of genetic variants contributing to the etiology of CRC.

Genome-wide association studies (GWAS) of colorectal cancer (CRC) have identified 23 susceptibility loci thus far. Analyses of previously conducted GWAS indicate additional risk loci are yet to be discovered. To identify novel CRC susceptibility loci, we conducted a new GWAS and performed a meta-analysis with five published GWAS (totalling 7,577 cases and 9,979 controls of European ancestry), imputing genotypes utilising the 1000 Genomes Project. The combined analysis identified new, significant associations with CRC at 1p36.2 marked by rs72647484 (minor allele frequency [MAF] = 0.09) near CDC42 and WNT4 ( P  = 1.21 × 10 −8 , odds ratio [OR] = 1.21 ) and at 16q24.1 marked by rs16941835 (MAF = 0.21, P  = 5.06 × 10 −8 ; OR = 1.15) within the long non-coding RNA (lncRNA) RP11-58A18.1 and ~500 kb from the nearest coding gene FOXL1 . Additionally we identified a promising association at 10p13 with rs10904849 intronic to CUBN (MAF = 0.32, P  = 7.01 × 10 -8 ; OR = 1.14). These findings provide further insights into the genetic and biological basis of inherited genetic susceptibility to CRC. Additionally, our analysis further demonstrates that imputation can be used to exploit GWAS data to identify novel disease-causing variants.

To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10 −4 in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 ( P = 2.5 × 10 −13 overall; P = 6.9 × 10 −12 replication), and rs16892766, at 8q23.3 ( P = 3.3 × 10 −18 overall; P = 9.6 × 10 −17 replication), which tags a plausible causative gene, EIF3H . These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.

This research abstracts a history of human-machine interaction to map the look, feel and sounds of a networked environment and what it is to exist within it. To do this, a cross-disciplinary examination of systems theory, art history, computational design and contemporary philosophy has been employed to chart the aesthetics of the network and to critically understand deterministic forces in the architectures of connection.With so much discussion about networked technologies predicated upon its future, it is vital to turn our heads back to historical examples of both technological innovation and how artists have engaged with it. This thesis examines key events in network culture, such as the implementation of the telegraph, the advent of the database, cybernetics, the Macy conferences and the world wide web alongside contextual responses from historical and contemporary art.What cultural influences are at work in the construction of the digital architectures set to shape this century? What is the aesthetic language used to explore and communicate these ideas? What is the form that information takes? This thesis explores the ways in which art making practices can help us understand the connected condition and the politics of a lived experience that is fundamentally embedded. It comprises a written thesis with documentation of an accompanying body of work, contextualised with historical and contemporary contributions to the fields of art, computational history and philosophy.I argue that knowledge pertaining to the semantics of innovation, the nature of information storage and the aesthetics of new systems in cryptography and transmission are being revealed in current art making practices and bring important, valuable insight to understanding the connected condition. This research determines that key characteristics of network aesthetics draw upon the cybernetic ideas of self-reflexivity, dissonance, poetic technicity, dynamic behaviour, the telematic and metaphor, but also stresses the importance of understanding less visible relationships between gender, labour and ethnicity in technological innovation.

Background: Observational studies have associated adiposity with an increased risk of colorectal cancer (CRC). However, such studies do not establish a causal relationship. To minimise bias from confounding we performed a Mendelian randomisation (MR) analysis to examine the relationship between adiposity and CRC. Methods: We used SNPs associated with adult body mass index (BMI), waist-hip ratio (WHR), childhood obesity and birth weight as instrumental variables in a MR analysis of 9254 CRC cases and 18 386 controls. Results: In the MR analysis, the odds ratios (ORs) of CRC risk per unit increase in BMI, WHR and childhood obesity were 1.23 (95% CI: 1.02–1.49, P =0.033), 1.59 (95% CI: 1.08–2.34, P =0.019) and 1.07 (95% CI: 1.03–1.13, P =0.018), respectively. There was no evidence for association between birth weight and CRC (OR=1.22, 95% CI: 0.89–1.67, P =0.22). Combining these data with a concurrent MR-based analysis for BMI and WHR with CRC risk (totalling to 18 190 cases, 27 617 controls) provided increased support, ORs for BMI and WHR were 1.26 (95% CI: 1.10–1.44, P =7.7 × 10 −4 ) and 1.40 (95% CI: 1.14–1.72, P =1.2 × 10 −3 ), respectively. Conclusions: These data provide further evidence for a strong causal relationship between adiposity and the risk of developing CRC highlighting the urgent need for prevention and treatment of adiposity.

Objective Colorectal cancer (CRC) has a substantial heritable component. Common genetic variation has been shown to contribute to CRC risk. A study was conducted in a large multi-population study to assess the feasibility of CRC risk prediction using common genetic variant data combined with other risk factors. A risk prediction model was built and applied to the Scottish population using available data. Design Nine populations of European descent were studied to develop and validate CRC risk prediction models. Binary logistic regression was used to assess the combined effect of age, gender, family history (FH) and genotypes at 10 susceptibility loci that individually only modestly influence CRC risk. Risk models were generated from case-control data incorporating genotypes alone (n=39 266) and in combination with gender, age and FH (n=11 324). Model discriminatory performance was assessed using 10-fold internal cross-validation and externally using 4187 independent samples. The 10-year absolute risk was estimated by modelling genotype and FH with age- and gender-specific population risks. Results The median number of risk alleles was greater in cases than controls (10 vs 9, p<2.2×10−16), confirmed in external validation sets (Sweden p=1.2×10−6, Finland p=2×10−5). The mean per-allele increase in risk was 9% (OR 1.09; 95% CI 1.05 to 1.13). Discriminative performance was poor across the risk spectrum (area under curve for genotypes alone 0.57; area under curve for genotype/age/gender/FH 0.59). However, modelling genotype data, FH, age and gender with Scottish population data shows the practicalities of identifying a subgroup with >5% predicted 10-year absolute risk. Conclusion Genotype data provide additional information that complements age, gender and FH as risk factors, but individualised genetic risk prediction is not currently feasible. Nonetheless, the modelling exercise suggests public health potential since it is possible to stratify the population into CRC risk categories, thereby informing targeted prevention and surveillance.