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Discovery of common and rare genetic risk variants for colorectal cancer

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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Fig. 1: Conditionally independent association signals at the BMP2 locus.
Fig. 2: Functional genomic annotation of new CRC risk locus overlapping with KLF5 super-enhancer.
Fig. 3: Recommended age to start CRC screening based on a polygenic risk score.

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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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Acknowledgements

A full list of acknowledgements appears in the Supplementary Note.

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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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Correspondence to Ulrike Peters.

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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

Reporting Summary

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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