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

Content Provider	PubMed Central
Author	Timofeeva, Maria N. Kinnersley, Ben Farrington, Susan M. Nicola, Whiffin Palles, Claire Victoria, Svinti Lloyd, Amy Gorman, Maggie Ooi, Li-yin Hosking, Fay Barclay, Ella Lina, Zgaga Dobbins, Sara Martin, Lynn Theodoratou, Evropi Broderick, Peter Albert, Tenesa Smillie, Claire Grimes, Graeme Hayward, Caroline Campbell, Archie Porteous, David Deary, Ian J. Harris, Sarah E. Northwood, Emma L. Barrett, Jennifer H. Smith, Gillian Wolf, Roland Forman, David Morreau, Hans Ruano, Dina Tops, Carli Wijnen, Juul Schrumpf, Melanie Boot, Arnoud Vasen, Hans F. A. Hes, Frederik J. Wezel, Tom Van Franke, Andre Lieb, Wolgang Clemens, Schafmayer Hampe, Jochen Buch, Stephan Peter, Propping Kari, Hemminki Asta, Försti Westers, Helga Hofstra, Robert Pinheiro, Manuela Pinto, Carla Teixeira, Manuel Clara, Ruiz-ponte Ceres, Fernández-rozadilla Carracedo, Angel Castells, Antoni Sergi, Castellví-bel Campbell, Harry Bishop, D. Timothy Tomlinson, Ian P. M. Dunlop, Malcolm G. Houlston, Richard S.
Copyright Year	2015
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 < 2.90 × 10−6). We found an excess of rare, damaging variants in base-excision (P = 2.4 × 10−4) and DNA mismatch repair genes (P = 6.1 × 10−4) consistent with a recessive mode of inheritance. This study comprehensively explores the contribution of coding sequence variation to CRC risk, identifying associations with coding variation in 4 genes and PCDHG gene cluster and several candidate recessive alleles. However, these findings suggest that recurrent, low-frequency coding variants account for a minority of the unexplained heritability of CRC.
Related Links	http://dx.doi.org/10.1038/srep16286
Starting Page	16286
File Format	PDF
ISSN	20452322
e-ISSN	20452322
Journal	Scientific Reports
Volume Number	5
Language	English
Publisher	Nature Publishing Group
Publisher Date	2015-11-01
Access Restriction	Open
Rights Holder	Nature Publishing Group
Subject Keyword	Science and technology Research in Higher Education
Content Type	Text
Resource Type	Article
Subject	Multidisciplinary

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1	Ministry of Education (GoI), Department of Higher Education	Sanctioning Authority	https://www.education.gov.in/ict-initiatives
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4	Project PI / Joint PI	Principal Investigator and Joint Principal Investigators of the project	Dr. B. Sutradhar bsutra@ndl.gov.in Prof. Saswat Chakrabarti will be added soon
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