Abstract
To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10−8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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Data availability
All whole-genome sequence data have been deposited in the database of Genotypes and Phenotypes (dbGaP), which is hosted by NCBI, under accession number phs001554.v1.p1. All custom Infinium OncoArray-500K array data for the studies in the stage 2 meta-analysis have been deposited at dbGaP under accession number phs001415.v1.p1. All Illumina HumanOmniExpressExome-8v1-2 array data for the studies in the stage 2 meta-analysis have been deposited at dbGaP under accession number phs001315.v1.p1. Genotype data for the studies included in the stage 1 meta-analysis have been deposited at dbGaP under accession number phs001078.v1.p1. The UK Biobank resource was accessed through application number 8614. CRC-relevant epigenome data were obtained from the NCBI Gene Expression Omnibus (GEO) database under accession number GSE77737.
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J.R.H., S.A.B., T.A.H., H.M.K., D.V.C., M.W., F.R.S., J.D.S., D.A., M.H.A., K.A., C.A.-C., V.A., C.B., J.A.B., S.I.B., S.B., D.T.B., J.B., H.Boeing, H.Brenner, S.Brezina, S.Buch, D.D.B., A.B.-H., K.B., B.J.C., P.T.C., S.C.-B., A.T.C., J.C.-C., S.J.C., M.-D.C., S.H.C., A.J.C., K.C., A.d.l.C., D.F.E., S.G.E., F.E., D.R.E., E.J.M.F., J.C.F., D.F., S.G., G.G.G., E.G., P.J.G., J.S.G., A.G., M.J.G., R.W.H., J.H., H.H., R.B.H., P.H., M.H., J.L.H., W.-Y.H., T.J.H., D.J.H., R.J., E.J.J., M.A.J., T.O.K., T.J.K., H.R.K., L.N.K., C.K., S.K., S.-S.K., L.L.M., S.C.L., C.I.L., L.L., A.L., N.M.L., S.M., S.D.M., V.M., G.M., M.M., R.L.M., L.M., R.M., A.N., P.A.N., K.O., N.C.O.-M., B.P., P.S.P., R.P., V.P., P.D.P.P., E.A.P., R.L.P., G.R., H.S.R., E.R., M.R.-B., C.S., R.E.S., D.S., M.-H.S., S.S., M.L.S., C.M.T., S.N.T., A.T., C.M.U., F.J.B.v.D., B.V.G., H.v.K., J.V., K.V., P.V., L.V., V.V., E.W., C.R.W., A.W., M.O.W., A.H.W., B.W.Z., W.Z., P.C.S., J.D.P., M.C.B., G.C., V.M., G.R.A., D.A.N., S.B.G., L.H. and U.P. conceived and designed the experiments. T.A.H., M.W., J.D.S., K.F.D., D.D., R.I., E.K., H.L., C.E.M., E.P., J.R., T.S., S.S.T., D.J.V.D.B., M.C.B. and D.A.N. performed the experiments. J.R.H., H.M.K., S.C., S.L.S., D.V.C., C.Q., J.J., C.K.E., P.G., F.R.S., D.M.L., S.C.N., N.A.S.-A., C.A.L., M.L., T.L.L., Y.-R.S., A.K., G.R.A. and L.H. performed statistical analysis. J.R.H., S.A.B., T.A.H., H.M.K., S.C., S.L.S., D.V.C., C.Q., J.J., C.K.E., P.G., M.W., F.R.S., D.M.L., S.C.N., N.A.S.-A., B.L.B., C.S.C., C.M.C., K.R.C., J.G., W.-L.H., C.A.L., S.M.L., M.L., Y.L., T.L.L., M.S., Y.-R.S., A.K., G.R.A., L.H. and U.P. analyzed the data. H.M.K., C.K.E., D.A., M.H.A., K.A., C.A.-C., V.A., C.B., J.A.B., S.I.B., S.B., D.T.B., J.B., H.Boeing, H.Brenner, S.Brezina, S.Buch, D.D.B., A.B.-H., K.B., B.J.C., P.T.C., S.C.-B., A.T.C., J.C.-C., S.J.C., M.-D.C., S.H.C., A.J.C., K.C., A.d.l.C., D.F.E., S.G.E., F.E., D.R.E., E.J.M.F., J.C.F., R.F., L.M.F., D.F., M.G., S.G., W.J.G., G.G.G., P.J.G., W.M.G., J.S.G., A.G., M.J.G., R.W.H., J.H., H.H., S.H., R.B.H., P.H., M.H., J.L.H., W.-Y.H., T.J.H., D.J.H., G.I.-S., G.E.I., R.J., E.J.J., M.A.J., A.D.J., C.E.J., T.O.K., T.J.K., H.R.K., L.N.K., C.K., T.K., S.K., S.-S.K., S.C.L., L.L.M., S.C.L., F.L., C.I.L., L.L., W.L., A.L., N.M.L., S.M., S.D.M., V.M., G.M., M.M., R.L.M., L.M., N.M., R.M., A.N., P.A.N., K.O., S.O, N.C.O.-M., B.P., P.S.P., R.P., V.P., P.D.P.P., M.P., E.A.P., R.L.P., L.R., G.R., H.S.R., E.R., M.R.-B., L.C.S., C.S., R.E.S., M.S., M.-H.S., K.S., S.S., M.L.S., M.C.S., Z.K.S., C.S., C.M.T., S.N.T., D.C.T., A.E.T., A.T., C.M.U., F.J.B.v.D., B.V.G., H.v.K., J.V., K.V., P.V., L.V., V.V., K.W., S.J.W., E.W., A.K.W., C.R.W., A.W., M.O.W., A.H.W., S.H.Z., B.W.Z., Q.Z., W.Z., P.C.S., J.D.P., M.C.B., A.K., G.C., V.M., G.R.A., S.B.G. and U.P. contributed reagents, materials and analysis tools. J.R.H., S.A.B., T.A.H., J.J., L.H. and U.P. wrote the paper.
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Competing interests
G.R.A. has received compensation from 23andMe and Helix. He is currently an employee of Regeneron Pharmaceuticals. H.H. performs collaborative research with Ambry Genetics, InVitae Genetics, and Myriad Genetic Laboratories, is on the scientific advisory board for InVitae Genetics and Genome Medical, and has stock in Genome Medical. R.P. has participated in collaborative funded research with Myriad Genetics Laboratories and Invitae Genetics but has no financial competitive interest.
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Supplementary information
Supplementary Text and Figures
Supplementary Figures 1–8 and Supplementary Note
Supplementary Table 1
Characteristics of studies and study participants contributing to the whole-genome sequencing analysis and GWAS meta-analysis
Supplementary Table 2
Association results broken down by sample set together with imputation qualities, and heterogeneity statistics for new loci reported in Table 1
Supplementary Table 3
Colorectal cancer risk signals previously associated at genome-wide significance
Supplementary Table 4
Conditional association results broken down by sample set together with imputation qualities, and heterogeneity statistics for new conditionally independent association signals reported in Table 2
Supplementary Table 5
Known and newly identified CRC risk loci with multiple conditionally independent association signals that reach a significance threshold of P < 1 × 10–5 in the combined meta-analysis of up to 125,478 individuals
Supplementary Table 6
Reported associations of colorectal cancer risk variants with (non-colorectal cancer) diseases and traits in the NHGRI-EBI GWAS catalog
Supplementary Table 7
Summary of 99% credible sets for the 40 new association signals for colorectal cancer risk
Supplementary Table 8
CRC relevant annotations, bioinformatic follow-up of newly identified loci, and bioinformatic follow-up of secondary signals
Supplementary Table 9
Enrichment of CRC risk associations in 1,005 genomic annotations from the ENCODE, Roadmap Epigenomics and GENCODE projects at the 1 × 10–5 and 1 × 10–8 significance thresholds
Supplementary Table 10
MAGENTA pathway enrichment results
Supplementary Table 11
Risk allele frequencies (RAFs) across populations for the 95 variants used in the polygenic risk score analyses
Supplementary Table 12
Covariates included in the association analysis
Supplementary Table 13
CRC relevant regulatory genomic datasets
Supplementary Table 14
Results from ATAC-QC
Supplementary Table 15
Colorectal cancer risk variants and effect size estimates used in the familial risk explained and genetic risk score analyses
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Huyghe, J.R., Bien, S.A., Harrison, T.A. et al. Discovery of common and rare genetic risk variants for colorectal cancer. Nat Genet 51, 76–87 (2019). https://doi.org/10.1038/s41588-018-0286-6
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DOI: https://doi.org/10.1038/s41588-018-0286-6
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