A genome-wide association study of upper aerodigestive tract cancers conducted within the INHANCE consortium.
paper
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- Authors
- McKay, James D; Truong, Therese; Gaborieau, Valerie; Chabrier, Amelie; Chuang, Shu-Chun; Byrnes, Graham; Zaridze, David; Shangina, Oxana; Szeszenia-Dabrowska, Neonila; Lissowska, Jolanta; Rudnai, Peter; Fabianova, Eleonora; Bucur, Alexandru; Bencko, Vladimir; Holcatova, Ivana; Janout, Vladimir; Foretova, Lenka; Lagiou, Pagona; Trichopoulos, Dimitrios; Benhamou, Simone; Bouchardy, Christine; Ahrens, Wolfgang; Merletti, Franco; Richiardi, Lorenzo; Talamini, Renato; Barzan, Luigi; Kjaerheim, Kristina; Macfarlane, Gary J; Macfarlane, Tatiana V; Simonato, Lorenzo; Canova, Cristina; Agudo, Antonio; CastellsaguΓ©, Xavier; Lowry, Ray; Conway, David I; McKinney, Patricia A; Healy, Claire M; Toner, Mary E; Znaor, Ariana; Curado, Maria Paula; Koifman, Sergio; Menezes, Ana; WΓΌnsch-Filho, Victor; Neto, JosΓ© Eluf; Garrote, Leticia FernΓ‘ndez; Boccia, Stefania; Cadoni, Gabriella; Arzani, Dario; Olshan, Andrew F; Weissler, Mark C; Funkhouser, William K; Luo, Jingchun; LubiΕski, Jan; Trubicka, Joanna; Lener, Marcin; Oszutowska, Dorota; Schwartz, Stephen M; Chen, Chu; Fish, Sherianne; Doody, David R; Muscat, Joshua E; Lazarus, Philip; Gallagher, Carla J; Chang, Shen-Chih; Zhang, Zuo-Feng; Wei, Qingyi; Sturgis, Erich M; Wang, Li-E; Franceschi, Silvia; Herrero, Rolando; Kelsey, Karl T; McClean, Michael D; Marsit, Carmen J; Nelson, Heather H; Romkes, Marjorie; Buch, Shama; Nukui, Tomoko; Zhong, Shilong; Lacko, Martin; Manni, Johannes J; Peters, Wilbert H M; Hung, Rayjean J; McLaughlin, John; Vatten, Lars; NjΓΈlstad, Inger; Goodman, Gary E; Field, John K; Liloglou, Triantafillos; Vineis, Paolo; Clavel-Chapelon, Francoise; Palli, Domenico; Tumino, Rosario; Krogh, Vittorio; Panico, Salvatore; GonzΓ‘lez, Carlos A; QuirΓ³s, J RamΓ³n; MartΓnez, Carmen; Navarro, Carmen; Ardanaz, Eva; LarraΓ±aga, Nerea; Khaw, Kay-Tee; Key, Timothy; Bueno-de-Mesquita, H Bas; Peeters, Petra H M; Trichopoulou, Antonia; Linseisen, Jakob; Boeing, Heiner; Hallmans, GΓΆran; Overvad, Kim; TjΓΈnneland, Anne; Kumle, Merethe; Riboli, Elio; VΓ€lk, Kristjan; Vooder, TΓ΅nu; Metspalu, Andres; Zelenika, Diana; Boland, Anne; Delepine, Marc; Foglio, Mario; Lechner, Doris; BlanchΓ©, HΓ©lΓ¨ne; Gut, Ivo G; Galan, Pilar; Heath, Simon; Hashibe, Mia; Hayes, Richard B; Boffetta, Paolo; Lathrop, Mark; Brennan, Paul
- Year
- 2011
- Journal
- PLoS genetics
- PMID
- 21437268
- DOI
- 10.1371/journal.pgen.1001333
- PMCID
- PMC3060072
Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p β€ 5 Γ 10β»β·). Two novel variants were identified, a 4q21 variant (rs1494961, pβ=β1Γ10β»βΈ) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p =2 Γ 10β»βΈ) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 Γ 10β»βΈ); rs1229984-ADH1B, p = 7 Γ 10β»βΉ; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.
Manhattan plot of the ARCAGE and CE UADT cancer GWAS discovery phase.One clearly outlying marker, rs971074 is highly correlated with rs1573496, a SNP previously associated with UADT cancer risk. Right panel QQ plot for the UADT cancer GWAS.
Imputation and LD patterns.Imputation and LD patterns across the (a) 4q23 (ADH loci), (b) 12q24 (ALDH2), and (c) 4q21 (HEL308). Upper panel: Single marker association results for imputed (green) and directly genotyped variants (blue). Imputation performed on 2,091 cases and 3,513 study specific controls (excluded generic controls). After adjustment for the five variants that presented with replication, no variant had a p<0.0005 at any loci. Lower panel, pairwise LD estimates increasing intensities of black and red indicate higher r2 or D' statistics, respectively. Blue colour indicates that the pairwise comparison is not informative.
Stratified analysis of 4 replicated SNPs located near alcohol metabolism genes.Estimates for rs1229984 (ADH1B), rs1573496 (ADH7), rs1042758 (ADH1C) and rs4767364 (ALDH2) were derived from a log-additive genetic model. ORs were adjusted by age, sex, study and were derived from fixed effects models. βGenericβ controls were not included in this analysis.
Association between 4q21 variant (rs1494961) and UADT and lung cancers.Estimates were derived from a log-additive model. ORs were adjusted by age, sex, study and were derived from fixed effects models. βGenericβ controls were not included in this analysis.
1β20 of 35
Next β
| Name | Type |
|---|---|
| 12q21 local | variant |
| 12q24 local | variant |
| 15q25 locus | variant |
| 1958 British Birth Cohort | cohort |
| 4q21 local | variant |
| 4q23 local | variant |
| 8 participating genotyping laboratories local | cohort |
| acetaldehyde | drug |
| additional UADT cases and controls local | cohort |
| ADH | gene |
| ADH1B | gene |
| ADH1C | gene |
| ADH1C variant local | variant |
| ADH7 | gene |
| ADH7 variant local | variant |
| ADH/ALDH2 variants local | variant |
| ADH gene cluster | gene |
| African | cohort |
| African American | cohort |
| African American UADT cancer cases local | cohort |
| alcohol | phenotype |
| alcohol consumption behaviour local | phenotype |
| alcohol metabolism | phenotype |
| ALDH2 | gene |
| Applied Biosystems Taqman assays local | drug |
| ARCAGE local | cohort |
| ARCAGE study local | cohort |
| arthritis local | phenotype |
| Asian | cohort |
| Banska Bystrika (Slovakia) local | cohort |
| BRCA1 | gene |
| Bucharest (Romania) local | cohort |
| CARET cohort local | cohort |
| cases | cohort |
| Caucasian | cohort |
| CE local | cohort |
| Central European lung cancer study local | cohort |
| Central European UADT cancer study local | cohort |
| central European UADT study local | cohort |
| central Europe (IARC) local | cohort |
| Central Europe (IARC) local | cohort |
| central Europe study local | cohort |
| Centre National Genotypage local | cohort |
| CEPH HapMap (CEU) trios local | cohort |
| CEU | cohort |
| combined sample | cohort |
| controls | cohort |
| coronary artery disease | phenotype |
| discovery series local | cohort |
| east-Asian local | cohort |
| EPIC-lung | cohort |
| esophageal cancer | phenotype |
| Estonia | cohort |
| ethanol consumption | phenotype |
| European ethnicity local | cohort |
| European population | cohort |
| ever drinkers local | cohort |
| Ever drinkers-Never smokers local | cohort |
| FAM175A local | gene |
| France | cohort |
| French controls local | cohort |
| generic controls local | cohort |
| Haploview local | drug |
| HapMap | cohort |
| HapMap genotypes local | cohort |
| heavy drinking | phenotype |
| HEL308 local | gene |
| hematocrit | phenotype |
| hemoglobin concentration local | phenotype |
| HumanHap 300 BeadChip panel local | drug |
| Human papillomavirus local | drug |
| HUNT2/Tromso local | cohort |
| IARC | cohort |
| Illumina beadchips local | drug |
| Illumina HumanHap300 | drug |
| Illumina HumanHap300 Beadchip | drug |
| independent replication series local | cohort |
| INHANCE consortium local | cohort |
| INHANCE studies local | cohort |
| International Agency for Research on Cancer central Europe study local | cohort |
| kidney cancer local | phenotype |
| kidney function | phenotype |
| laryngeal cancer local | phenotype |
| Latin American study local | cohort |
| Liverpool Lung Project (LLP) local | cohort |
| Lodz (Poland) local | cohort |
| lung cancer | phenotype |
| MaCH | drug |
| MD Anderson study local | cohort |
| Moscow (Russia) local | cohort |
| Never drinkers-Ever smokers local | cohort |
| nineteen variants local | variant |
| Norwegian controls local | cohort |
| novel variant | cohort |
| Olomouc (Czech Republic) local | cohort |
| oral/pharyngeal cancer local | phenotype |
| Paris France local | cohort |
| Philadelphia/New York study local | cohort |
| Prague (Czech Republic) local | cohort |
| previously identified variant local | variant |
| ProbABEL | drug |
| propensity to smoke | phenotype |
| replication series local | cohort |
| rs1229984 | variant |
| rs12827056 local | variant |
| rs1494691 local | variant |
| rs1494961 local | variant |
| rs1573496 local | variant |
| rs1789924 local | variant |
| rs4648328 local | variant |
| rs4767364 local | variant |
| rs671 | variant |
| rs698 | variant |
| rs737280 local | variant |
| rs971074 local | variant |
| SA local | cohort |
| Seattle case-control study local | cohort |
| sex | phenotype |
| squamous cell carcinoma local | phenotype |
| standard DNAs local | drug |
| Structure | drug |
| study specific controls local | cohort |
| Szczecin case-control study local | cohort |
| Szczecin study local | cohort |
| TaqMan genotyping platform local | drug |
| The Netherlands study local | cohort |
| tobacco use | phenotype |
| Toronto (McGill) local | cohort |
| type 1 diabetes | phenotype |
| UADT cancer local | phenotype |
| UADT cancer cases local | cohort |
| UADT cancer cohort local | cohort |
| UADT cancer familial risk local | phenotype |
| UADT cancer risk local | phenotype |
| UADT cancers local | phenotype |
| UCLA case-control study local | cohort |
| Upper aerodigestive tract cancer local | phenotype |
| variant at 12q24 local | variant |
| variant at 4q21 local | variant |
| variant at 4q23 local | variant |
| waist-to-hip ratio | phenotype |
| Wellcome Trust case control consortium | cohort |
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