Abstract Genetic risk factors identified by genome-wide association studies (GWAS) are thought to function through allele-specific regulation of gene expression. Long-range chromatin looping interactions, as revealed by chromosome conformation capture (3C)-based techniques, bring risk variants into spatial proximity with loci otherwise distal on the linear genome. Hi-C, using next generation sequencing (NGS), allows for genome-wide agnostic characterization of chromatin contacts, however, detection of functional enhancer-promoter interactions is precluded by its limited resolution. Here we apply Targeted Hi-C, a novel technique combining the unbiased coverage of Hi-C with target sequence capture to identify functional chromatin interactions for 15 colorectal cancer risk loci at high resolution. We depicted the CRC risk interactome as a set of generic highly significant genome-wide interactions, predominantly overlaying the strongest risk association signals. Integrative analyses involving profiles for epigenetic marks, evolutionary conservation and transcription factor binding, revealed regulatory function of long-range chromatin interactions. At the 8q24.21 risk locus, we could extend a previously reported contact between rs6983267 and the MYC promoter to a network of interactions involving CCAT1 (colorectal cancer associated transcript 1). At other risk loci, our data supports the central role of TERC, BMP4, GREM1, BMP2, SMAD7 and in CRC pathogenesis. Additionally, distal to the risk loci we identified contacts with the genes such as TRPS1, TPO, ETS1, VEZT and RAN, previously implicated in cancer and mutated in CRC. Our results demonstrate the capability of high resolution chromatin interaction analyses in conjunction with combinatorial integrative analyses to decipher disease risk loci. Citation Format: Roland Jäger, Gabriele Migliorini, Marc Henrion, Nicola Whiffin, Laura Broome, Nicola Dryden, Takashi Nagano, Stefan Schoenfelder, Peter Fraser, Olivia Fletcher, Richard Houlston. Targeted Hi-C and integrative analyses reveal functionality of colorectal cancer risk loci. [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 407. doi:10.1158/1538-7445.AM2014-407