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Title: Rare variants of large effect in BRCA2 and CHEK2 affect risk of lung cancer.
Authors: Wang Y,  McKay JD,  Rafnar T,  Wang Z,  Timofeeva MN,  Broderick P,  Zong X,  Laplana M,  Wei Y,  Han Y,  Lloyd A,  Delahaye-Sourdeix M,  Chubb D,  Gaborieau V,  Wheeler W,  Chatterjee N,  Thorleifsson G,  Sulem P,  Liu G,  Kaaks R,  Henrion M,  Kinnersley B,  Vallée M,  LeCalvez-Kelm F,  Stevens VL,  Gapstur SM,  Chen WV,  Zaridze D,  Szeszenia-Dabrowska N,  Lissowska J,  Rudnai P,  Fabianova E,  Mates D,  Bencko V,  Foretova L,  Janout V,  Krokan HE,  Gabrielsen ME,  Skorpen F,  Vatten L,  Njølstad I,  Chen C,  Goodman G,  Benhamou S,  Vooder T,  Välk K,  Nelis M,  Metspalu A,  Lener M,  Lubiński J,  Johansson M,  Vineis P,  Agudo A,  Clavel-Chapelon F,  Bueno-de-Mesquita HB,  Trichopoulos D,  Khaw KT,  Johansson M,  Weiderpass E,  Tjønneland A,  Riboli E,  Lathrop M,  Scelo G,  Albanes D,  Caporaso NE,  Ye Y,  Gu J,  Wu X,  Spitz MR,  Dienemann H,  Rosenberger A,  Su L,  Matakidou A,  Eisen T,  Stefansson K,  Risch A,  Chanock SJ,  Christiani DC,  Hung RJ,  Brennan P,  Landi MT,  Houlston RS,  Amos CI
Journal: Nat Genet
Date: 2014 Jul
Branches: BB, CGR, GEB, LTG, NEB, OD, OEEB
PubMed ID: 24880342
PMC ID: PMC4074058
Abstract: We conducted imputation to the 1000 Genomes Project of four genome-wide association studies of lung cancer in populations of European ancestry (11,348 cases and 15,861 controls) and genotyped an additional 10,246 cases and 38,295 controls for follow-up. We identified large-effect genome-wide associations for squamous lung cancer with the rare variants BRCA2 p.Lys3326X (rs11571833, odds ratio (OR) = 2.47, P = 4.74 × 10(-20)) and CHEK2 p.Ile157Thr (rs17879961, OR = 0.38, P = 1.27 × 10(-13)). We also showed an association between common variation at 3q28 (TP63, rs13314271, OR = 1.13, P = 7.22 × 10(-10)) and lung adenocarcinoma that had been previously reported only in Asians. These findings provide further evidence for inherited genetic susceptibility to lung cancer and its biological basis. Additionally, our analysis demonstrates that imputation can identify rare disease-causing variants with substantive effects on cancer risk from preexisting genome-wide association study data.