Primary GWAS

We analysed data from five primary GWAS (Supplementary Data ² and Supplementary Data ³):

The NSCCG-OncoArray GWAS comprised 6240 cases ascertained through the National Study of Colorectal Cancer Genetics (NSCCG)⁴³ and 1041 cases collected through the CORGI consortium, genotyped using the Illumina OncoArray. Patients were selected for having a family history of CRC (at least one first-degree relative) or age of diagnosis below 58. Controls were also genotyped using the OncoArray and comprised (i) 3031 cancer-free men recruited by the PRACTICAL Consortium—the UK Genetic Prostate Cancer Study (UKGPCS) (age <65 years), a study conducted through the Royal Marsden NHS Foundation Trust and SEARCH (Study of Epidemiology & Risk Factors in Cancer), recruited via GP practices in East Anglia (2003–2009) and (ii) 4,488 cancer-free women across the UK, recruited via the Breast Cancer Association Consortium (BCAC).

The SCOT GWAS comprised 3076 cases from the Short Course Oncology Treatment (SCOT) trial—a study of adjuvant chemotherapy in colorectal cancer by the CACTUS and OCTO groups⁴⁴. Controls comprised 4349 cancer-free individuals from The Heinz Nixdorf Recall study⁴⁵. Both cases and controls were genotyped using the Illumina Global Screening Array.

SOCCS/Generation Scotland (SOCCS/GS) comprised 4772 cases from the Study of Colorectal Cancer in Scotland (SOCCS)^12,13 and 12,158 controls including 2221 population-based controls from SOCCS and additional 9937 population controls without prior history of colorectal cancer from Generation Scotland-Scottish Family Health Study (GS:SFHS)⁴⁶.

SOCCS/Lothian Birth Cohort (SOCCS/LBC) GWAS comprised 1037 cases from the Study of Colorectal Cancer in Scotland (SOCCS)⁴⁷ and 1522 population-based controls without prior history of malignant tumours from the Lothian Birth Cohorts (LBC) of 1921 and 1936⁴⁸.

UK Biobank (UKBB) GWAS comprised 6360 cases and 25,440 population-based control individuals. UK Biobank is a large cohort study with more than 500,000 individuals recruited. Biological samples of these participants were genotyped using the custom-designed Affymetrix UK BiLEVE Axiom array on an initial 50,000 participants and Affymetrix UK Biobank Axiom array on the remaining 450,000 participants. The two arrays had over 95% common content. Genotyping was done at the Affymetrix Research Services Laboratory in Santa Clara, California, USA. Details on genotyping and quality control were previously reported⁴⁹. Self-reported cases of cancers of bowel, colon or rectum, if not confirmed by the ICD9 or ICD10 codes were excluded from the analysis. Healthy control individuals without history of cancer and/or colorectal adenoma were included in the analysis after matching one case to four controls by age, gender, date of blood draw, ethnicity and region of residence (two first letters of postal code).