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Dive into the research topics where Sarah L. Spain is active.

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Featured researches published by Sarah L. Spain.


Nature Genetics | 2007

A genome-wide association scan of tag SNPs identifies a susceptibility variant for colorectal cancer at 8q24.21.

Ian Tomlinson; Emily L. Webb; Luis Carvajal-Carmona; Peter Broderick; Zoe Kemp; Sarah L. Spain; Steven Penegar; Ian Chandler; Maggie Gorman; Wendy Wood; Ella Barclay; Steven Lubbe; Lynn Martin; Gabrielle S. Sellick; Emma Jaeger; Richard A. Hubner; Ruth Wild; Andrew Rowan; Sarah Fielding; Kimberley Howarth; Andrew Silver; Wendy Atkin; Kenneth Muir; Richard F. Logan; David Kerr; Elaine Johnstone; Oliver M. Sieber; Richard Gray; Huw D. Thomas; Julian Peto

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.


Nature Genetics | 2008

Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer

Richard S. Houlston; Emily L. Webb; Peter Broderick; Alan Pittman; Maria Chiara Di Bernardo; Steven Lubbe; Ian Chandler; Jayaram Vijayakrishnan; Kate Sullivan; Steven Penegar; Luis Carvajal-Carmona; Kimberley Howarth; Emma Jaeger; Sarah L. Spain; Axel Walther; Ella Barclay; Lynn Martin; Maggie Gorman; Enric Domingo; Ana Teixeira; David Kerr; Jean-Baptiste Cazier; Iina Niittymäki; Sari Tuupanen; Auli Karhu; Lauri A. Aaltonen; Ian Tomlinson; Susan M. Farrington; Albert Tenesa; James Prendergast

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.


Nature Genetics | 2013

Germline mutations affecting the proofreading domains of POLE and POLD1 predispose to colorectal adenomas and carcinomas

Claire Palles; Jean-Baptiste Cazier; Kimberley Howarth; Enric Domingo; Angela Jones; Peter Broderick; Zoe Kemp; Sarah L. Spain; Estrella Guarino; Israel Salguero; Amy Sherborne; Daniel Chubb; Luis Carvajal-Carmona; Yusanne Ma; Kulvinder Kaur; Sara E. Dobbins; Ella Barclay; Maggie Gorman; Lynn Martin; Michal Kovac; Sean Humphray; Anneke Lucassen; Christopher Holmes; David R. Bentley; Peter Donnelly; Jenny C. Taylor; Christos Petridis; Rebecca Roylance; Elinor Sawyer; David Kerr

Many individuals with multiple or large colorectal adenomas or early-onset colorectal cancer (CRC) have no detectable germline mutations in the known cancer predisposition genes. Using whole-genome sequencing, supplemented by linkage and association analysis, we identified specific heterozygous POLE or POLD1 germline variants in several multiple-adenoma and/or CRC cases but in no controls. The variants associated with susceptibility, POLE p.Leu424Val and POLD1 p.Ser478Asn, have high penetrance, and POLD1 mutation was also associated with endometrial cancer predisposition. The mutations map to equivalent sites in the proofreading (exonuclease) domain of DNA polymerases ɛ and δ and are predicted to cause a defect in the correction of mispaired bases inserted during DNA replication. In agreement with this prediction, the tumors from mutation carriers were microsatellite stable but tended to acquire base substitution mutations, as confirmed by yeast functional assays. Further analysis of published data showed that the recently described group of hypermutant, microsatellite-stable CRCs is likely to be caused by somatic POLE mutations affecting the exonuclease domain.


Nature Genetics | 2007

A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk

Peter Broderick; Luis Carvajal-Carmona; Alan Pittman; Emily L. Webb; Kimberley Howarth; Andrew Rowan; Steven Lubbe; Sarah L. Spain; Kate Sullivan; Sarah Fielding; Emma Jaeger; Jayaram Vijayakrishnan; Zoe Kemp; Maggie Gorman; Ian Chandler; Elli Papaemmanuil; Steven Penegar; Wendy Wood; Gabrielle S. Sellick; Mobshra Qureshi; Ana Teixeira; Enric Domingo; Ella Barclay; Lynn Martin; Oliver M. Sieber; David Kerr; Richard Gray; Julian Peto; Jean Baptiste Cazier; Ian Tomlinson

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 (Ptrend = 1.0 × 10−12).


Nature Genetics | 2010

Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33

Richard S. Houlston; Jeremy Peter Cheadle; Sara E. Dobbins; Albert Tenesa; Angela Jones; Kimberley Howarth; Sarah L. Spain; Peter Broderick; Enric Domingo; Susan M. Farrington; James Prendergast; Alan Pittman; Evi Theodoratou; Christopher Smith; Bianca Olver; Axel Walther; Rebecca A. Barnetson; Michael Churchman; Emma Jaeger; Steven Penegar; Ella Barclay; Lynn Martin; Maggie Gorman; Rachel Mager; Elaine Johnstone; Rachel Midgley; Iina Niittymäki; Sari Tuupanen; James Colley; Shelley Idziaszczyk

Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10−10 and rs6687758, OR = 1.09, P = 2.27 × 10−9), 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10−8), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10−10 and rs7136702, OR = 1.06, P = 4.02 × 10−8) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10−10). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.


Nature Genetics | 2008

Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk

Emma Jaeger; Emily L. Webb; Kimberley Howarth; Luis Carvajal-Carmona; Andrew Rowan; Peter Broderick; Axel Walther; Sarah L. Spain; Alan Pittman; Zoe Kemp; Kate Sullivan; Karl Heinimann; Steven Lubbe; Enric Domingo; Ella Barclay; Lynn Martin; Maggie Gorman; Ian Chandler; Jayaram Vijayakrishnan; Wendy Wood; Elli Papaemmanuil; Steven Penegar; Mobshra Qureshi; Susan M. Farrington; Albert Tenesa; Jean Baptiste Cazier; David Kerr; Richard Gray; Julian Peto; Malcolm G. Dunlop

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).


Nature Genetics | 2012

Common variation near CDKN1A , POLD3 and SHROOM2 influences colorectal cancer risk

Malcolm G. Dunlop; Sara E. Dobbins; Susan M. Farrington; Angela Jones; Claire Palles; Nicola Whiffin; Albert Tenesa; Sarah L. Spain; Peter Broderick; Li-Yin Ooi; Enric Domingo; Claire Smillie; Marc Henrion; Matthew Frampton; Lynn Martin; Graeme Grimes; Maggie Gorman; Colin A. Semple; Yusanne P Ma; Ella Barclay; James Prendergast; Jean-Baptiste Cazier; Bianca Olver; Steven Penegar; Steven Lubbe; Ian Chander; Luis Carvajal-Carmona; Stephane Ballereau; Amy Lloyd; Jayaram Vijayakrishnan

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.


Gut | 2006

Disease severity and genetic pathways in attenuated familial adenomatous polyposis vary greatly but depend on the site of the germline mutation

Oliver M. Sieber; Stefania Segditsas; Anne Knudsen; Jian Zhang; Judith Luz; Andrew Rowan; Sarah L. Spain; Christina Thirlwell; Kimberley Howarth; Emma Jaeger; James P. Robinson; Emmanouil Volikos; Andrew Silver; Gavin Kelly; Stefan Aretz; Ian Frayling; Pierre Hutter; Malcolm G. Dunlop; Thomas Guenther; Kay Neale; Robin K. S. Phillips; Karl Heinimann; Ian Tomlinson

Background: Attenuated familial adenomatous polyposis (AFAP) is associated with germline mutations in the 5′, 3′, and exon 9 of the adenomatous polyposis coli (APC) gene. These mutations probably encode a limited amount of functional APC protein. Methods and results: We found that colonic polyp number varied greatly among AFAP patients but members of the same family tended to have more similar disease severity. 5′ Mutants generally had more polyps than other patients. We analysed somatic APC mutations/loss of heterozygosity (LOH) in 235 tumours from 35 patients (16 families) with a variety of AFAP associated germline mutations. In common with two previous studies of individual kindreds, we found biallelic changes (“third hits”) in some polyps. We found that the “third hit” probably initiated tumorigenesis. Somatic mutation spectra were similar in 5′ and 3′ mutant patients, often resembling classical FAP. In exon 9 mutants, in contrast, “third hits” were more common. Most “third hits” left three 20 amino acid repeats (20AARs) on the germline mutant APC allele, with LOH (or proximal somatic mutation) of the wild-type allele; but some polyps had loss of the germline mutant with mutation leaving one 20AAR on the wild-type allele. Conclusions: We propose that mutations, such as nt4661insA, that leave three 20AARs are preferentially selected in cis with some AFAP mutations because the residual protein function is near optimal for tumorigenesis. Not all AFAP polyps appear to need “three hits” however. AFAP is phenotypically and genetically heterogeneous. In addition to effects of different germline mutations, modifier genes may be acting on the AFAP phenotype, perhaps influencing the quantity of functional protein produced by the germline mutant allele.


Human Molecular Genetics | 2008

Refinement of the basis and impact of common 11q23.1 variation to the risk of developing colorectal cancer

Alan Pittman; Emily L. Webb; Luis Carvajal-Carmona; Kimberley Howarth; Maria Chiara Di Bernardo; Peter Broderick; Sarah L. Spain; Axel Walther; Amy Price; Kate Sullivan; Philip Twiss; Sarah Fielding; Andrew Rowan; Emma Jaeger; Jayaram Vijayakrishnan; Ian Chandler; Steven Penegar; Mobshra Qureshi; Steven Lubbe; Enric Domingo; Zoe Kemp; Ella Barclay; Wendy Wood; Lynn Martin; Maggie Gorman; Huw D. Thomas; Julian Peto; Timothy Bishop; Richard Gray; Eamonn R. Maher

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.


Nature Communications | 2015

Enhanced meta-analysis and replication studies identify five new psoriasis susceptibility loci.

Lam C. Tsoi; Sarah L. Spain; Eva Ellinghaus; Philip E. Stuart; Francesca Capon; Jo Knight; Trilokraj Tejasvi; Hyun Min Kang; Michael H. Allen; Sylviane Lambert; Stefan W. Stoll; Stephan Weidinger; Johann E. Gudjonsson; Sulev Kõks; Külli Kingo; Tonu Esko; Sayantan Das; Andres Metspalu; Michael Weichenthal; Charlotta Enerbäck; Gerald G. Krueger; John J. Voorhees; Vinod Chandran; Cheryl F. Rosen; Proton Rahman; Dafna D. Gladman; André Reis; Rajan P. Nair; Andre Franke; Jonathan Barker

Psoriasis is a chronic autoimmune disease with complex genetic architecture. Previous genomewide association studies (GWAS) and a recent meta-analysis using Immunochip data have uncovered 36 susceptibility loci. Here, we extend our previous meta-analysis of European ancestry by refined genotype calling and imputation and by the addition of 5,033 cases and 5,707 controls. The combined analysis, consisting of over 15,000 cases and 27,000 controls, identifies five new psoriasis susceptibility loci at genomewide significance (p < 5 × 10−8). The newly identified signals include two that reside in intergenic regions (1q31.1 and 5p13.1) and three residing near PLCL2 (3p24.3), NFKBIZ (3q12.3), and CAMK2G (10q22.2). We further demonstrate that NFKBIZ is a TRAF3IP2–dependent target of IL-17 signaling in human skin keratinocytes, thereby functionally linking two strong candidate genes. These results further integrate the genetics and immunology of psoriasis, suggesting new avenues for functional analysis and improved therapies.

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Ian Tomlinson

University of Birmingham

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Kimberley Howarth

Wellcome Trust Centre for Human Genetics

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Peter Broderick

Institute of Cancer Research

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Richard S. Houlston

Institute of Cancer Research

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