Abstract 2190: Fine-mapping of common genetic variants associated with colorectal tumor risk identified potential functional variants
Authors: Du Mengmeng , Jiao Shuo , Rosse Stephanie A. , Gala Manish , Abecasis Goncalo , Bezieau Stephane , Brenner Hermann , Casey Graham , Chang-Claude Jenny , Gallinger Steven , Hudson Thomas J. , Küry Sébastien , Marchand Loic L. , Leal Suzanne M. , Newcomb Polly A. , Nickerson Deborah A. , Potter John D. , Slattery Martha L. , Hsu Li , Chan Andrew T. , White Emily , Berndt Sonja I. , Peters Ulrike 
Published: May 2015

Background: Genome-wide association studies (GWAS) have identified many common single nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. These SNPs may tag correlated variants with biological importance. Fine-mapping around GWAS loci facilitates detection of functional candidates and additional independent risk variants.

Methods: We analyzed 11,900 cases and 14,311 controls in the Genetics and Epidemiology of Colorectal Cancer Consortium and the Colon Cancer Family Registry. To fine-map genomic regions containing all known common risk variants, we imputed high-density genetic data from the 1000 Genomes Project. We tested associations with colorectal tumor risk for all variants spanning genomic regions 250-kb upstream or downstream of 31 GWAS-identified SNPs (index SNPs). We queried the University of California, Santa Cruz Genome Browser to examine evidence for biological function.

Results: Index SNPs did not show the strongest association signals with colorectal tumor risk in their respective genomic regions. However, in most regions the SNP showing the smallest P-value was correlated (r2≥0.2) with the index SNP. Bioinformatics analysis of SNPs showing smaller P-values in each region revealed 21 functional candidates in 12 loci (5q31.1, 8q24, 11q13.4, 11q23, 12p13.32, 12q24.21, 14q22,2, 15q13, 18q21, 19q13.1, 20p12.3, and 20q13.33). We observed evidence for an additional independent association signal in 8q24 located between POU5F1B and MYC (rs28629385; minor allele frequency=0.06; per-allele odds ratio=1.37; P=7.9E-06).

Conclusions: Our results support the utility of integrating data from comprehensive fine-mapping with expanding publicly available genomic databases to help clarify GWAS associations and identify functional candidates for laboratory follow-up. Such efforts may aid the eventual discovery of disease-causing variant(s).

Citation Format: Mengmeng Du, Shuo Jiao, Stephanie A. Rosse, Manish Gala, Goncalo Abecasis, Stephane Bezieau, Hermann Brenner, Graham Casey, Jenny Chang-Claude, Steven Gallinger, Thomas J. Hudson, Sébastien Küry, Loic Le Marchand, Suzanne M. Leal, Polly A. Newcomb, Deborah A. Nickerson, John D. Potter, Martha L. Slattery, Li Hsu, Andrew T. Chan, Emily White, Sonja I. Berndt, Ulrike Peters. Fine-mapping of common genetic variants associated with colorectal tumor risk identified potential functional variants. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2190. doi:10.1158/1538-7445.AM2014-2190