Kate Sullivan

Publications (14)285.94 Total impact

• Article: The colorectal cancer risk at 18q21 is caused by a novel variant altering SMAD7 expression.

  Alan M Pittman, Silvia Naranjo, Emily Webb, Peter Broderick, Esther H Lips, Tom van Wezel, Hans Morreau, Kate Sullivan, Sarah Fielding, Philip Twiss, Jayaram Vijayakrishnan, Fernando Casares, Mobshra Qureshi, José Luis Gómez-Skarmeta, Richard S Houlston
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  ABSTRACT: Recent genome-wide scans for colorectal cancer (CRC) have revealed the SMAD7 (mothers against decapentaplegic homolog 7) gene as a locus associated with a modest, but highly significant increase in CRC risk. To identify the causal basis of the association between 18q21 variation and CRC, we resequenced the 17-kb region of linkage disequilibrium and evaluated all variants in 2532 CRC cases and 2607 controls. A novel C to G single nucleotide polymorphism (SNP) at 44,703,563 bp was maximally associated with CRC risk (P = 5.98 x 10(-7); > or =1.5-fold more likely to be causal than other variants). Using transgenic assays in Xenopus laevis as a functional model, we demonstrate that the G risk allele leads to reduced reporter gene expression in the colorectum (P = 5.4 x 10(-3)). Electrophoretic mobility shift assays provided evidence for the role of Novel 1 in transcription factor binding. We propose that the novel SNP we have identified is the functional change leading to CRC predisposition through differential SMAD7 expression and, hence, aberrant TGF-beta signaling.
  Genome Research 04/2009; 19(6):987-93. · 13.61 Impact Factor
• Article: Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer.

  Richard S Houlston, Emily Webb, Peter Broderick, Alan M Pittman, Maria Chiara Di Bernardo, Steven Lubbe, Ian Chandler, Jayaram Vijayakrishnan, Kate Sullivan, Steven Penegar, [......], Henry Völzke, Jenny Chang-Claude, Michael Hoffmeister, Hermann Brenner, Brent W Zanke, Alexandre Montpetit, Thomas J Hudson, Steven Gallinger, Harry Campbell, Malcolm G Dunlop
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  ABSTRACT: 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 x 10(-10)), 16q22.1 (rs9929218, CDH1; P = 1.2 x 10(-8)), 19q13.1 (rs10411210, RHPN2; P = 4.6 x 10(-9)) and 20p12.3 (rs961253; P = 2.0 x 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.
  Nature Genetics 01/2009; 40(12):1426-35. · 35.53 Impact Factor
• Article: Deciphering the genetics of hereditary non-syndromic colorectal cancer.

  Eli Papaemmanuil, Luis Carvajal-Carmona, Gabrielle S Sellick, Zoe Kemp, Emily Webb, Sarah Spain, Kate Sullivan, Ella Barclay, Steven Lubbe, Emma Jaeger, [......], Hans K Schackert, Timm O Goecke, Elke Holinski-Feder, Peter Propping, Tom Van Wezel, Juul Wijnen, Jean-Baptiste Cazier, Huw Thomas, Richard S Houlston, Ian Tomlinson
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  ABSTRACT: Previously we have localized to chromosome 3q21-q24, a predisposition locus for colorectal cancer (CRC), through a genome-wide linkage screen (GWLS) of 69 families without familial adenomatous polyposis or hereditary non-polyposis CRC. To further investigate Mendelian susceptibility to CRC, we extended our screen to include a further GWLS of an additional 34 CRC families. We also searched for a disease gene at 3q21-q24 by linkage disequilibrium mapping in 620 familial CRC cases and 960 controls by genotyping 1676 tagging SNPs and sequencing 30 candidate genes from the region. Linkage analysis was conducted using the Affymetrix 10K SNP array. Data from both GWLSs were pooled and multipoint linkage statistics computed. The maximum NPL score (3.01; P=0.0013) across all families was at 3q22, maximal evidence for linkage coming from families segregating rectal CRC. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD=2.79; P=0.00034), with an estimated 43% of families linked. In the case-control analysis, the strongest association was obtained at rs698675 (P=0.0029), but this was not significant after adjusting for multiple testing. Analysis of candidate gene mapping to the region of maximal linkage on 3q22 failed to identify a causal mutation. There was no evidence for linkage to the previously reported 9q CRC locus (NPL=0.95, P=0.23; HLOD(dominant)=0.40, HLOD(recessive)=0.20). Our findings are consistent with the hypothesis that variation at 3q22 contributes to the risk of CRC, but this is unlikely to be mediated through a restricted set of alleles.
  European Journal of HumanGenetics 12/2008; 16(12):1477-86. · 4.40 Impact Factor
• Article: CASP8 D302H and meningioma risk: an analysis of five case-control series.

  Lara Bethke, Kate Sullivan, Emily Webb, Anne Murray, Minouk Schoemaker, Anssi Auvinen, Anne Kiuru, Tiina Salminen, Christoffer Johansen, Helle Collatz Christensen, [......], Sarah Hepworth, Polyxeni Dimitropoulou, Artitaya Lophatananon, Maria Feychting, Stefan Lönn, Anders Ahlbom, Beatrice Malmer, Roger Henriksson, Anthony Swerdlow, Richard Houlston
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  ABSTRACT: Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and hence a defence against cancer. The CASP8 polymorphism D302H has recently been shown to influence the risk of breast cancer. We tested the hypothesis that the CASP8 polymorphism D302H may influence risk of meningioma through analysis of five independent series of case patients and controls (n=631 and 637, respectively). Carrier status for 302H was not associated with a statistically significantly increased risk (OR=1.16; 95% CI: 0.87-1.53; P=0.31) making it unlikely that this variant contributes to the inherited risk of meningioma.
  Cancer letters 10/2008; 273(2):312-5. · 4.86 Impact Factor
• Article: Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer.

  Alan M Pittman, Emily Webb, Luis Carvajal-Carmona, Kimberley Howarth, Maria Chiara Di Bernardo, Peter Broderick, Sarah Spain, Axel Walther, Amy Price, Kate Sullivan, [......], Jose M Ladero, Miguel de la Hoya, Trinidad Caldés, Iina Niittymäki, Sari Tuupanen, Auli Karhu, Lauri A Aaltonen, Jean-Baptiste Cazier, Ian P M Tomlinson, Richard S Houlston
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  ABSTRACT: The common single-nucleotide polymorphism (SNP) rs3802842 at 11q23.1 has recently been reported to be associated with risk of colorectal cancer (CRC). To examine this association in detail we genotyped rs3802842 in eight independent case-control series comprising a total of 10 638 cases and 10 457 healthy individuals. A significant association between the C allele of rs3802842 and CRC risk was found (per allele OR = 1.17; 95% confidence interval [CI]: 1.12-1.22; P = 1.08 x 10(-12)) with the risk allele more frequent in rectal than colonic disease (P = 0.02). In combination with 8q21, 8q24, 10p14, 11q, 15q13.3 and 18q21 variants, the risk of CRC increases with an increasing numbers of variant alleles for the six loci (OR(per allele) = 1.19; 95% CI: 1.15-1.23; P(trend) = 7.4 x 10(-24)). Using the data from our genome-wide association study of CRC, LD mapping and imputation, we were able to refine the location of the causal locus to a 60 kb region and screened for coding changes. The absence of exonic mutations in any of the transcripts (FLJ45803, LOC120376, C11orf53 and POU2AF1) mapping to this region makes the association likely to be a consequence of non-coding effects on gene expression.
  Human Molecular Genetics 09/2008; 17(23):3720-7. · 7.64 Impact Factor
• Article: A genome-wide association study identifies six susceptibility loci for chronic lymphocytic leukemia.

  Maria Chiara Di Bernardo, Dalemari Crowther-Swanepoel, Peter Broderick, Emily Webb, Gabrielle Sellick, Ruth Wild, Kate Sullivan, Jayaram Vijayakrishnan, Yufei Wang, Alan M Pittman, [......], Andrew R Pettitt, Peter Hillmen, David J Allsup, James R Bailey, Guy Pratt, Chris Pepper, Chris Fegan, James M Allan, Daniel Catovsky, Richard S Houlston
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  ABSTRACT: We conducted a genome-wide association study of 299,983 tagging SNPs for chronic lymphocytic leukemia (CLL) and performed validation in two additional series totaling 1,529 cases and 3,115 controls. We identified six previously unreported CLL risk loci at 2q13 (rs17483466; P = 2.36 x 10(-10)), 2q37.1 (rs13397985, SP140; P = 5.40 x 10(-10)), 6p25.3 (rs872071, IRF4; P = 1.91 x 10(-20)), 11q24.1 (rs735665; P = 3.78 x 10(-12)), 15q23 (rs7176508; P = 4.54 x 10(-12)) and 19q13.32 (rs11083846, PRKD2; P = 3.96 x 10(-9)). These data provide the first evidence for the existence of common, low-penetrance susceptibility to a hematological malignancy and new insights into disease causation in CLL.
  Nature Genetics 09/2008; 40(10):1204-10. · 35.53 Impact Factor
• Source

  Available from: Qiong Dong

  Article: Genome-wide association scan of tag SNPs identifies a susceptibility locus for lung cancer at 15q25.1.

  Christopher I Amos, Xifeng Wu, Peter Broderick, Ivan P Gorlov, Jian Gu, Timothy Eisen, Qiong Dong, Qing Zhang, Xiangjun Gu, Jayaram Vijayakrishnan, Kate Sullivan, Athena Matakidou, Yufei Wang, Gordon Mills, Kimberly Doheny, Ya-Yu Tsai, Wei Vivien Chen, Sanjay Shete, Margaret R Spitz, Richard S Houlston
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  ABSTRACT: To identify risk variants for lung cancer, we conducted a multistage genome-wide association study. In the discovery phase, we analyzed 315,450 tagging SNPs in 1,154 current and former (ever) smoking cases of European ancestry and 1,137 frequency-matched, ever-smoking controls from Houston, Texas. For replication, we evaluated the ten SNPs most significantly associated with lung cancer in an additional 711 cases and 632 controls from Texas and 2,013 cases and 3,062 controls from the UK. Two SNPs, rs1051730 and rs8034191, mapping to a region of strong linkage disequilibrium within 15q25.1 containing PSMA4 and the nicotinic acetylcholine receptor subunit genes CHRNA3 and CHRNA5, were significantly associated with risk in both replication sets. Combined analysis yielded odds ratios of 1.32 (P < 1 x 10(-17)) for both SNPs. Haplotype analysis was consistent with there being a single risk variant in this region. We conclude that variation in a region of 15q25.1 containing nicotinic acetylcholine receptors genes contributes to lung cancer risk.
  Nature Genetics 06/2008; 40(5):616-22. · 35.53 Impact Factor
• Article: A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3.

  Ian P M Tomlinson, Emily Webb, Luis Carvajal-Carmona, Peter Broderick, Kimberley Howarth, Alan M Pittman, Sarah Spain, Steven Lubbe, Axel Walther, Kate Sullivan, [......], Miguel de la Hoya, Trinidad Caldés, Iina Niittymäki, Sari Tuupanen, Auli Karhu, Lauri Aaltonen, Jean-Baptiste Cazier, Harry Campbell, Malcolm G Dunlop, Richard S Houlston
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  ABSTRACT: 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 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 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.
  Nature Genetics 05/2008; 40(5):623-30. · 35.53 Impact Factor
• Article: The common D302H variant of CASP8 is associated with risk of glioma.

  Lara Bethke, Kate Sullivan, Emily Webb, Anne Murray, Minouk Schoemaker, Anssi Auvinen, Anne Kiuru, Tiina Salminen, Christoffer Johansen, Helle Collatz Christensen, [......], Sarah Hepworth, Polyxeni Dimitropoulou, Artitaya Lophatananon, Maria Feychting, Stefan Lönn, Anders Ahlbom, Beatrice Malmer, Roger Henriksson, Anthony Swerdlow, Richard Houlston
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  ABSTRACT: Caspase 8 (CASP8) is a key regulator of apoptosis or programmed cell death, and, hence, a defense against cancer. We tested the hypothesis that the CASP8 polymorphism D302H influences risk of glioma through analysis of five series of glioma case patients and controls (n = 1,005 and 1,011, respectively). Carrier status for the rare allele of D302H was associated with a 1.37-fold increased risk (95% confidence interval, 1.10-1.70; P = 0.004). The association of CASP8 D302H with glioma risk indicates the importance of inherited variation in the apoptosis pathway in susceptibility to this form of primary brain tumor.
  Cancer Epidemiology Biomarkers &amp Prevention 05/2008; 17(4):987-9. · 4.12 Impact Factor
• Article: A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3

  Ian PM Tomlinson, Emily Webb, Luis Carvajal-Carmona, Peter Broderick, Kimberley Howarth, Alan M Pittman, Sarah Spain, Steven Lubbe, Axel Walther, Kate Sullivan, [......], Miguel de la Hoya, Trinidad Cald|[eacute]|s, Iina Niittym|[auml]|ki, Sari Tuupanen, Auli Karhu, Lauri Aaltonen, Jean-Baptiste Cazier, Harry Campbell, Malcolm G Dunlop, Richard S Houlston
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  ABSTRACT: 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
  Nature Genetics 03/2008; 40(5):623-630. · 35.53 Impact Factor
• Article: Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk.

  Emma Jaeger, Emily Webb, Kimberley Howarth, Luis Carvajal-Carmona, Andrew Rowan, Peter Broderick, Axel Walther, Sarah Spain, Alan Pittman, Zoe Kemp, [......], Albert Tenesa, Jean-Baptiste Cazier, David Kerr, Richard Gray, Julian Peto, Malcolm Dunlop, Harry Campbell, Huw Thomas, Richard Houlston, Ian Tomlinson
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  ABSTRACT: 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 x 10(-14)).
  Nature Genetics 02/2008; 40(1):26-8. · 35.53 Impact Factor
• Article: A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk.

  Peter Broderick, Luis Carvajal-Carmona, Alan M Pittman, Emily Webb, Kimberley Howarth, Andrew Rowan, Steven Lubbe, Sarah Spain, Kate Sullivan, Sarah Fielding, [......], Enric Domingo, Ella Barclay, Lynn Martin, Oliver Sieber, David Kerr, Richard Gray, Julian Peto, Jean-Baptiste Cazier, Ian Tomlinson, Richard S Houlston
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  ABSTRACT: 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-beta 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 x 10(-12)).
  Nature Genetics 12/2007; 39(11):1315-7. · 35.53 Impact Factor
• Article: CHEK2*1100delC and risk of chronic lymphocytic leukemia.

  Gabrielle S Sellick, Kate Sullivan, Daniel Catovsky, Richard S Houlston
  Leukemia and Lymphoma 01/2007; 47(12):2659-60. · 2.58 Impact Factor
• Article: A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3

  Ian PM Tomlinson, Emily Webb, Luis Carvajal-Carmona, Peter Broderick, Kimberley Howarth, Alan M Pittman, Sarah Spain, Steven Lubbe, Axel Walther, Kate Sullivan, [......], Miguel de la Hoya, Trinidad Caldés, Iina Niittymäki, Sari Tuupanen, Auli Karhu, Lauri Aaltonen, Jean-Baptiste Cazier, Harry Campbell, Malcolm G Dunlop, Richard S Houlston