Journal
PLOS ONE
Volume 7, Issue 12, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0052535
Keywords
-
Categories
Funding
- Hospital Clinical Research Program (PHRC)
- Regional Council of Pays de la Loire
- Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC)
- Association Anne de Bretagne Genetique
- Ligue Regionale Contre le Cancer (LRCC)
- National Cancer Institute, National Institutes of Health [U01 CA074783, U01 CA122839]
- Ontario Research Fund [GL2]
- Canadian Institutes of Health Research
- Cancer Risk Evaluation (CaRE) Program grant from the Canadian Cancer Society Research Institute
- Ontario Institute for Cancer Research
- National Cancer Institute [R01 CA60987]
- National Cancer Institute, National Institutes of Health under RFA [CA-95-011]
- Australasian Colorectal Cancer Family Registry [U01 CA097735]
- Seattle Colorectal Cancer Family Registry [U01 CA074794]
- Ontario Registry for Studies of Familial Colorectal Cancer [U01 CA074783]
- German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]
- German Federal Ministry of Education and Research [01KH0404, 01ER0814]
- National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services [R01 CA48998, U01 CA137088, R01 CA059045]
- National Institutes of Health [P01 CA 055075, R01 137178, P50 CA 127003, P01 CA 087969, CA42182, R01 CA076366]
- Intramural Research Program of the Division of Cancer Epidemiology and Genetics
- Division of Cancer Prevention, National Cancer Institute, NIH, DHHS
- Intramural Research Program of the National Cancer Institute
- National Institutes of Health, Genes, Environment and Health Initiative [NIH GEI] [Z01 CP 010200]
- National Cancer Institute
- Gene Environment Association Studies, GENEVA Coordinating Center [U01 HG004446]
- NIH GEI [U01 HG 004438]
- National Institutes of Health from the National Cancer Institute and Office of Dietary Supplements [K05 CA154337]
- National Heart, Lung, and Blood Institute, National Institutes of Health, U. S. Department of Health and Human Services [N01WH22110, 24152, 32100-2, 32105-6, 32108-9, 32111-13, 32115, 32118-32119, 32122, 42107-26, 42129-32, 44221, 268200764316C]
- [R37 CA54281]
- [P01 CA033619]
- [R01 CA63464]
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Genome-wide association studies (GWAS) have successfully identified a number of single-nucleotide polymorphisms (SNPs) associated with colorectal cancer (CRC) risk. However, these susceptibility loci known today explain only a small fraction of the genetic risk. Gene-gene interaction (GxG) is considered to be one source of the missing heritability. To address this, we performed a genome-wide search for pair-wise GxG associated with CRC risk using 8,380 cases and 10,558 controls in the discovery phase and 2,527 cases and 2,658 controls in the replication phase. We developed a simple, but powerful method for testing interaction, which we term the Average Risk Due to Interaction (ARDI). With this method, we conducted a genome-wide search to identify SNPs showing evidence for GxG with previously identified CRC susceptibility loci from 14 independent regions. We also conducted a genome-wide search for GxG using the marginal association screening and examining interaction among SNPs that pass the screening threshold (p < 10(-4)). For the known locus rs10795668 (10p14), we found an interacting SNP rs367615 (5q21) with replication p = 0.01 and combined p = 4.19x10(-8). Among the top marginal SNPs after LD pruning (n = 163), we identified an interaction between rs1571218 (20p12.3) and rs10879357 (12q21.1) (nominal combined p = 2.51x10(-6); Bonferroni adjusted p = 0.03). Our study represents the first comprehensive search for GxG in CRC, and our results may provide new insight into the genetic etiology of CRC.
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