Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
22076443
TITLE
Refinement of the associations between risk of colorectal cancer and polymorphisms on chromosomes 1q41 and 12q13.13.
ABSTRACT
In genome-wide association studies (GWASs) of colorectal cancer, we have identified two genomic regions in which pairs of tagging-single nucleotide polymorphisms (tagSNPs) are associated with disease; these comprise chromosomes 1q41 (rs6691170, rs6687758) and 12q13.13 (rs7163702, rs11169552). We investigated these regions further, aiming to determine whether they contain more than one independent association signal and/or to identify the SNPs most strongly associated with disease. Genotyping of additional sample sets at the original tagSNPs showed that, for both regions, the two tagSNPs were unlikely to identify a single haplotype on which the functional variation lay. Conversely, one of the pair of SNPs did not fully capture the association signal in each region. We therefore undertook more detailed analyses, using imputation, logistic regression, genealogical analysis using the GENECLUSTER program and haplotype analysis. In the 1q41 region, the SNP rs11118883 emerged as a strong candidate based on all these analyses, sufficient to account for the signals at both rs6691170 and rs6687758. rs11118883 lies within a region with strong evidence of transcriptional regulatory activity and has been associated with expression of PDGFRB mRNA. For 12q13.13, a complex situation was found: SNP rs7972465 showed stronger association than either rs11169552 or rs7136702, and GENECLUSTER found no good evidence for a two-SNP model. However, logistic regression and haplotype analyses supported a two-SNP model, in which a signal at the SNP rs706793 was added to that at rs11169552. Post-GWAS fine-mapping studies are challenging, but the use of multiple tools can assist in identifying candidate functional variants in at least some cases.
DATE PUBLISHED
2012 Feb 15
HISTORY
PUBSTATUS PUBSTATUSDATE
aheadofprint 2011/11/10
aheadofprint 2011/11/25
entrez 2011/11/15 06:00
pubmed 2011/11/15 06:00
medline 2012/07/10 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Spain SL Spain Sarah L SL Nuffield Department of Clinical Medicine, University of Oxford, Oxford OX3 7BN, UK.
Carvajal-Carmona LG Carvajal-Carmona Luis G LG
Howarth KM Howarth Kimberley M KM
Jones AM Jones Angela M AM
Su Z Su Zhan Z
Cazier JB Cazier Jean-Baptiste JB
Williams J Williams Jennet J
Aaltonen LA Aaltonen Lauri A LA
Pharoah P Pharoah Paul P
Kerr DJ Kerr David J DJ
Cheadle J Cheadle Jeremy J
Li L Li Li L
Casey G Casey Graham G
Vodicka P Vodicka Pavel P
Sieber O Sieber Oliver O
Lipton L Lipton Lara L
Gibbs P Gibbs Peter P
Martin NG Martin Nicholas G NG
Montgomery GW Montgomery Grant W GW
Young J Young Joanne J
Baird PN Baird Paul N PN
Morreau H Morreau Hans H
van Wezel T van Wezel Tom T
Ruiz-Ponte C Ruiz-Ponte Clara C
Fernandez-Rozadilla C Fernandez-Rozadilla Ceres C
Carracedo A Carracedo Angel A
Castells A Castells Antoni A
Castellvi-Bel S Castellvi-Bel Sergi S
Dunlop M Dunlop Malcolm M
Houlston RS Houlston Richard S RS
Tomlinson IP Tomlinson Ian P M IP
INVESTIGATORS
JOURNAL
VOLUME: 21
ISSUE: 4
TITLE: Human molecular genetics
ISOABBREVIATION: Hum. Mol. Genet.
YEAR: 2012
MONTH: Feb
DAY: 15
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN:
ISSNTYPE:
MEDLINE JOURNAL
MEDLINETA: Hum Mol Genet
COUNTRY: England
ISSNLINKING: 0964-6906
NLMUNIQUEID: 9208958
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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Cites Nat Genet. 2007 Jul;39(7):906-13 17572673
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Cites PLoS Genet. 2011 Jun;7(6):e1002105 21655089
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Cites Hum Mutat. 2011 Feb;32(2):259-62 21280151
Cites Cancer Cell. 2011 Feb 15;19(2):273-82 21316605
Cites Mutat Res. 2011 Mar 18;721(1):74-80 21211571
Cites Bioinformatics. 2010 Oct 1;26(19):2474-6 20702402
GRANTS
GRANTID AGENCY COUNTRY
090532 Wellcome Trust United Kingdom
090532/Z/09/Z Wellcome Trust United Kingdom
12076 Cancer Research UK United Kingdom
G0000657-53203 Medical Research Council United Kingdom
G1001799 Medical Research Council United Kingdom
MC_U127527198 Medical Research Council United Kingdom
Cancer Research UK United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Chromosome Mapping
Chromosomes, Human, Pair 1 genetics
Chromosomes, Human, Pair 12 genetics
Colorectal Neoplasms genetics
Computational Biology genetics
Genetic Predisposition to Disease genetics
Genome-Wide Association Study genetics
Genotyping Techniques genetics
Haplotypes genetics
Humans genetics
Logistic Models genetics
Polymorphism, Single Nucleotide genetics
Software genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's
OTHERID SOURCE
PMC3263985 NLM