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Whole-genome sequencing (WGS) has started a new era in human genetics in which data can be used to more fully understand the role of genetic variation in common complex diseases, including the role of less frequent and rare variants and structural variation. To explore the impact of these variants on colorectal cancer risk we conducted the first large scale WGS study for colorectal cancer (CRC) including 1,961 CRC cases and 981 controls. These WGS data as well as those from the Haplotype Reference Consortium were imputed in 13,104 CRC cases and 15,521 controls with genome-wide association study (GWAS) data that are part of the Colorectal Cancer Family Registry (CCFR) and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO). Focusing on rare and less frequent variants, insertions and deletions we observed potentially novel variants: a less frequent variant (MAF = 0.026) on chromosome 5 located in NREP/STARD4-AS1 (p = value 4E-08); and a novel rare multi-allelic variant (MAF = 0.003) on chromosome 9 near KLF9 and TRPM3 (p-value 2E-09; the other allele of this multi-allelic variant had a MAF of 0.0003 and p-value of 0.55). Furthermore, we observed an independent locus close to the known region 8q24 that was located upstream of GSDMC (MAF = 0.16, p-value 5E-08). Within the known region 8q23/EIF3H we identified several low frequency variants with similar MAF (0.0181 to 0.0204) including a 6bp deletion with p-values between 4E-08 and 1E-09 that were independent of the common variant signal in this region. In addition, we identified statistically significant (p Citation Format: Jeroen Huyghe, Sai Chen, Hyun M. Kang, Tabitha A. Harrison, Sonja I. Berndt, Stephane Bézieau, Hermann Brenner, Graham Casey, Andrew T. Chan, Jenny Chang-Claude, Gallinger J. Steven, Stephen B. Gruber, Andrea Gsur, Michael Hoffmeister, Thomas J. Hudson, Loic Le Marchand, Polly A. Newcomb, John D. Potter, Conghui Qu, Martha L. Slattery, Joshua D. Smith, Emily White, Li Hsu, Goncalo R. Abecasis, Deborah A. Nickerson, Ulrike Peters. Large scale whole genome sequencing with imputation into GWAS improves our understanding of the genetic architecture of colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5230.

International audience; Cilia are specialized organelles that exert critical functions in numerous organisms, including that of cell motility, fluid transport and protozoan locomotion. Ciliary architecture and function strictly depend on basal body formation, migration and axoneme elongation. Numerous ultrastructural studies have been undertaken in different species to elucidate the process of ciliogenesis. Recent analyses have led to identification of genes specifically expressed in ciliated organisms, but most proteins involved in ciliogenesis remain uncharacterized. Using human nasal epithelial cells capable of ciliary differentiation in vitro, differential display was carried out to identify new proteins associated with ciliogenesis. We isolated a new gene, ICIS-1 (Involved in CIlia Stability-1), upregulated during mucociliary differentiation. This gene is localized within the TGF-beta1 promoter and is ubiquitously expressed in human tissues. Functional analyses of gene expression inhibition by RNA interference in Paramecium tetraurelia indicated that the ICIS-1 homologue interfered with cilia stability or formation. These findings demonstrate that ICIS-1 is a new protein associated with ciliated cells and potentially related to cilia stability.