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Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer.

ABSTRACT: Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR?=?1.08, P?=?3.9?×?10(-7)), and novel damaging coding variants in 3 genes previously tagged by GWAS efforts; rs16888728 (8q24) in UTP23 (OR?=?1.15, P?=?1.4?×?10(-7)); rs6580742 and rs12303082 (12q13) in FAM186A (OR?=?1.11, P?=?1.2?×?10(-7) and OR?=?1.09, P?=?7.4?×?10(-8)); rs1129406 (12q13) in ATF1 (OR?=?1.11, P?=?8.3?×?10(-9)), all reaching exome-wide significance levels. Gene based tests identified associations between CRC and PCDHGA genes (P?

SUBMITTER: Timofeeva MN 

PROVIDER: S-EPMC4639776 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Recurrent Coding Sequence Variation Explains Only A Small Fraction of the Genetic Architecture of Colorectal Cancer.

Timofeeva Maria N MN   Kinnersley Ben B   Farrington Susan M SM   Whiffin Nicola N   Palles Claire C   Svinti Victoria V   Lloyd Amy A   Gorman Maggie M   Ooi Li-Yin LY   Hosking Fay F   Barclay Ella E   Zgaga Lina L   Dobbins Sara S   Martin Lynn L   Theodoratou Evropi E   Broderick Peter P   Tenesa Albert A   Smillie Claire C   Grimes Graeme G   Hayward Caroline C   Campbell Archie A   Porteous David D   Deary Ian J IJ   Harris Sarah E SE   Northwood Emma L EL   Barrett Jennifer H JH   Smith Gillian G   Wolf Roland R   Forman David D   Morreau Hans H   Ruano Dina D   Tops Carli C   Wijnen Juul J   Schrumpf Melanie M   Boot Arnoud A   Vasen Hans F A HF   Hes Frederik J FJ   van Wezel Tom T   Franke Andre A   Lieb Wolgang W   Schafmayer Clemens C   Hampe Jochen J   Buch Stephan S   Propping Peter P   Hemminki Kari K   Försti Asta A   Westers Helga H   Hofstra Robert R   Pinheiro Manuela M   Pinto Carla C   Teixeira Manuel M   Ruiz-Ponte Clara C   Fernández-Rozadilla Ceres C   Carracedo Angel A   Castells Antoni A   Castellví-Bel Sergi S   Campbell Harry H   Bishop D Timothy DT   Tomlinson Ian P M IP   Dunlop Malcolm G MG   Houlston Richard S RS  

Scientific reports 20151110

Whilst common genetic variation in many non-coding genomic regulatory regions are known to impart risk of colorectal cancer (CRC), much of the heritability of CRC remains unexplained. To examine the role of recurrent coding sequence variation in CRC aetiology, we genotyped 12,638 CRCs cases and 29,045 controls from six European populations. Single-variant analysis identified a coding variant (rs3184504) in SH2B3 (12q24) associated with CRC risk (OR = 1.08, P = 3.9 × 10(-7)), and novel damaging c  ...[more]

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