Abstract 4582: Enrichment of colorectal cancer and inflammatory bowel disease risk variants in colon expression quantitative trait loci in African Americans
Authors: Kupfer Sonia S. , Hulur Imge , Gamazon Eric , Skol Andrew , Llor Xavier , Onel Kenan , Ellis Nathan A. 
Published: August 2015

Abstract
Background: Genome wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with diseases of the colon including colorectal cancer (CRC) and inflammatory bowel diseases (IBD). However, the functional role of many of these SNPs is largely unknown. Expression quantitative trait loci (eQTL) mapping is a tool to identify target genes of disease-associated SNPs. We have comprehensively assessed eQTLs in the human colon and tested for enrichment of GWAS-associated variants of colon diseases. We also characterized the genetic and functional properties of colonic eQTLs.
Methods: Distal colonic biopsies were obtained from 48 healthy African American males and total RNA was extracted. Genomic DNA was obtained from the same patients and genotyped using the Axiom Pan-African array. In total, 8.4 million genotyped and imputed SNPs were included. RNA expression levels were estimated using the Illumina HT-12v4 Expression Beadchip. eQTLs were identified using Matrix eQTL. False discovery rate calculations were performed according to the Benjamini and Hochberg method. Significance thresholds for other associations were determined using permutation-based methods.
Results: 1941 significant cis-eQTLs, corresponding to 122 independent signals, were identified at a false discovery rate of 0.01. There was substantial overlap between cis-eQTLs found in liver and ileum and less overlap in lymphoblastoid cells, brain, and skin fibroblasts. Overall, there was enrichment for GWAS variants associated with CRC and IBD, as well as 2 metabolic traits–Type 2 diabetes and body mass index–among colon cis-eQTLs. The CRC-associated eQTL rs3802842 was significantly associated with the expression of C11orf93 (COLCA2). The CRC-associated SNP rs1862748 is associated with 2 cis-eQTLs that are associated with expression differences in the NFATC3 gene, which regulates beta-catenin activation in response to WNT signaling. We also identified UBA7, INPP5E, ERAP2, SFMBT1, NXPE1, REXO2 as target genes for IBD-associated variants. There was significant enrichment of colonic cis-eQTLs near the transcription start sites (TSSs), for active histone marks and for SNPs with high population differentiation.
Conclusion: Through this comprehensive study of eQTLs in the human colon, we have identified novel and known target genes for IBD- and CRC-associated genetic variants. The cis-eQTLs are useful in identification of the causal functional variation underlying IBD and CRC associations. The eQTL catalog is now expanded to include the human colon and the functional characteristics of colonic eQTLs.
Note: This abstract was not presented at the meeting.
Citation Format: Sonia S. Kupfer, Imge Hulur, Eric Gamazon, Andrew Skol, Xavier Llor, Kenan Onel, Nathan A. Ellis. Enrichment of colorectal cancer and inflammatory bowel disease risk variants in colon expression quantitative trait loci in African Americans. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4582. doi:10.1158/1538-7445.AM2015-4582