title: Genome-wide association study for colorectal cancer identifies risk polymorphisms in German familial cases and implicates MAPK signalling pathways in disease susceptibility.
abstract: Genetic susceptibility accounts for approximately 35% of all colorectal cancer (CRC). Ten common low-risk variants contributing to CRC risk have been identified through genome-wide association studies (GWASs). In our GWAS, 610 664 genotyped single-nucleotide polymorphisms (SNPs) passed the quality control filtering in 371 German familial CRC patients and 1263 controls, and replication studies were conducted in four additional case-control sets (4915 cases and 5607 controls). Known risk loci at 8q24.21 and 11q23 were confirmed, and a previously unreported association, rs12701937, located between the genes GLI3 (GLI family zinc finger 3) and INHBA (inhibin, beta A) [P = 1.1 x 10(-3), odds ratio (OR) 1.14, 95% confidence interval (CI) 1.05-1.23, dominant model in the combined cohort], was identified. The association was stronger in familial cases compared with unselected cases (P = 2.0 x 10(-4), OR 1.36, 95% CI 1.16-1.60, dominant model). Two other unreported SNPs, rs6038071, 40 kb upstream of CSNK2A1 (casein kinase 2, alpha 1 polypeptide) and an intronic marker in MYO3A (myosin IIIA), rs11014993, associated with CRC only in the familial CRC cases (P = 2.5 x 10(-3), recessive model, and P = 2.7 x 10(-4), dominant model). Three software tools successfully pointed to the overrepresentation of genes related to the mitogen-activated protein kinase (MAPK) signalling pathways among the 1340 most strongly associated markers from the GWAS (allelic P value < 10(-3)). The risk of CRC increased significantly with an increasing number of risk alleles in seven genes involved in MAPK signalling events (P(trend) = 2.2 x 10(-16), OR(per allele) = 1.34, 95% CI 1.11-1.61).
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. j.lascorz@dkfz.de
authors.forename: Jesús
authors.initials: J
authors.lastname: Lascorz
authors.forename: Asta
authors.initials: A
authors.lastname: Försti
authors.forename: Bowang
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authors.lastname: Chen
authors.forename: Stephan
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authors.lastname: Buch
authors.forename: Verena
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authors.lastname: Steinke
authors.forename: Nils
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authors.lastname: Rahner
authors.forename: Elke
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authors.lastname: Holinski-Feder
authors.forename: Monika
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authors.lastname: Morak
authors.forename: Hans K
authors.initials: HK
authors.lastname: Schackert
authors.forename: Heike
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authors.lastname: Görgens
authors.forename: Karsten
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authors.lastname: Schulmann
authors.forename: Timm
authors.initials: T
authors.lastname: Goecke
authors.forename: Matthias
authors.initials: M
authors.lastname: Kloor
authors.forename: Cristoph
authors.initials: C
authors.lastname: Engel
authors.forename: Reinhard
authors.initials: R
authors.lastname: Büttner
authors.forename: Nelli
authors.initials: N
authors.lastname: Kunkel
authors.forename: Marianne
authors.initials: M
authors.lastname: Weires
authors.forename: Michael
authors.initials: M
authors.lastname: Hoffmeister
authors.forename: Barbara
authors.initials: B
authors.lastname: Pardini
authors.forename: Alessio
authors.initials: A
authors.lastname: Naccarati
authors.forename: Ludmila
authors.initials: L
authors.lastname: Vodickova
authors.forename: Jan
authors.initials: J
authors.lastname: Novotny
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Michael
authors.initials: M
authors.lastname: Krawczak
authors.forename: Clemens D
authors.initials: CD
authors.lastname: Bröring
authors.forename: Henry
authors.initials: H
authors.lastname: Völzke
authors.forename: Clemens
authors.initials: C
authors.lastname: Schafmayer
authors.forename: Pavel
authors.initials: P
authors.lastname: Vodicka
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.forename: Barbara
authors.initials: B
authors.lastname: Burwinkel
authors.forename: Peter
authors.initials: P
authors.lastname: Propping
authors.forename: Jochen
authors.initials: J
authors.lastname: Hampe
authors.forename: Kari
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authors.lastname: Hemminki
mesh_terms: D016022:Case-Control Studies; D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005858:Germany / Q000453:epidemiology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics*; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics*; D044465:White People / Q000235:genetics*
chemical_list: D020928:Mitogen-Activated Protein Kinases