Human Molecular Genetics Advance Access published online on August 21, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl231
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1 Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
* To whom correspondence should be addressed. To identify a novel susceptibility gene for colorectal cancer (CRC) we conducted a genome-wide linkage analysis of 69 pedigrees segregating colorectal neoplasia in which involvement of known loci had been excluded, using a high-density single nucleotide polymorphism (SNP) array containing 10,204 markers. Multipoint linkage analyses were undertaken using both non-parametric (model-free) and parametric (model-based) methods. After the removal of SNPs in strong linkage disequilibrium (LD) we obtained a maximum non parametric linkage (NPL) statistic of 3.40 (p = 0.0003) at chromosomal region 3q21-q24. The same genomic position also yielded the highest multipoint heterogeneity LOD (HLOD) score under a dominant model (HLOD = 3.10, genome-wide p = 0.038) with 62% of families linked to the locus. We provide evidence for a novel CRC susceptibility gene. Further studies are needed to confirm this localization and to evaluate the contribution of this locus to disease incidence.
Received June 6, 2006
Revised August 10, 2006
Accepted August 10, 2006
Article
Evidence for a colorectal cancer susceptibility locus on chromosome 3q21-q24 from a high-density SNP genome-wide linkage scan
London Research Institute Group, Zoe Kemp 1, Luis Carvajal-Carmona 1, Sarah Spain 1, Ella Barclay 1, Margaret Gorman 2, Lynn Martin 1, Emma Jaeger 1, Neil Brooks 3, D Timothy Bishop 4, Huw Thomas 5, Ian Tomlinson 2 *, Institute of Cancer Research Group, Elli Papaemmanuil 6, Emily Webb 6, Gabrielle S Sellick 6, Wendy Wood 6, Gareth Evans 7, Anneke Lucassen 8, Eamonn R Maher 9, and Richard S Houlston 6 *, The ColoRectal tumour Gene Identification (CoRGI) Study Consortium
2 Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, UK; Colorectal Cancer Unit, Cancer Research UK, St Mark's Hospital, Watford Road, Harrow HA1 3UJ, UK
3 Bioinformatics, Cancer Research UK, 44 Lincoln's Inn Fields, London WC2A 3PX, UK
4 Genetic Epidemiology Laboratory, Cancer Research UK, St James's University Hospital, Beckett Street, Leeds, LS9 7TF, UK
5 Colorectal Cancer Unit, Cancer Research UK, St Mark's Hospital, Watford Road, Harrow HA1 3UJ, UK
6 Institute of Cancer Research, 15 Cotswold Road, Sutton, Surrey, SM2 5NG, UK
7 Medical Genetics, St Mary's Hospital, Manchester, Hathersage Road, Manchester, M13 0JH, UK
8 Wessex Clinical Genetics Service, Princess Anne Hospital, Coxford Road, Southampton, SO16 5YA, UK
9 Section of Medical and Molecular Genetics, University of Birmingham School of Medicine and West Midlands Genetics Service, Birmingham Women's Hospital, Edgbaston, Birmingham, B15 2TG, UK
Ian Tomlinson, E-mail: ian.tomlinson{at}cancer.org.uk
Richard S Houlston, E-mail: richard.houlston{at}icr.ac.uk
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