Schmit, SL and Edlund, CK and Schumacher, FR and Gong, J and Harrison, TA and FitzGerald, LM and Gruber, SB, et al, Novel common genetic susceptibility loci for colorectal cancer, Journal of the National Cancer Institute, 111, (2) pp. 146-157. ISSN 0027-8874 (2019) [Refereed Article]
Copyright 2018 The Authors
Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.
Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.
Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
|Item Type:||Refereed Article|
|Keywords:||genetic susceptibility, colorectal cancer, genome, cancer risk|
|Research Division:||Biological Sciences|
|Research Field:||Epigenetics (incl. genome methylation and epigenomics)|
|Objective Group:||Clinical health|
|Objective Field:||Clinical health not elsewhere classified|
|UTAS Author:||FitzGerald, LM (Dr Liesel Fitzgerald)|
|Year Published:||2019 (online first 2018)|
|Web of Science® Times Cited:||39|
|Deposited By:||Menzies Institute for Medical Research|
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