Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.

Author(s): McKay JD,  Hung RJ,  Han Y,  Zong X,  Carreras-Torres R,  Christiani DC,  Caporaso NE,  Johansson M,  Xiao X,  Li Y,  Byun J,  Dunning A,  Pooley KA,  Qian DC,  Ji X,  Liu G,  Timofeeva MN,  Bojesen SE,  Wu X,  Le Marchand L,  Albanes D,  Bickeböller H,  Aldrich MC,  Bush WS,  Tardon A,  Rennert G,  Teare MD,  Field JK,  Kiemeney LA,  Lazarus P,  Haugen A,  Lam S,  Schabath MB,  Andrew AS,  Shen H,  Hong YC,  Yuan JM,  Bertazzi PA,  Pesatori AC,  Ye Y,  Diao N,  Su L,  Zhang R,  Brhane Y,  Leighl N,  Johansen JS,  Mellemgaard A,  Saliba W,  Haiman CA,  Wilkens LR,  Fernandez-Somoano A,  Fernandez-Tardon G,  van der Heijden HFM,  Kim JH,  Dai J,  Hu Z,  Davies MPA,  Marcus MW,  Brunnström H,  Manjer J,  Melander O,  Muller DC,  Overvad K,  Trichopoulou A,  Tumino R,  Doherty JA,  Barnett MP,  Chen C,  Goodman GE,  Cox A,  Taylor F,  Woll P,  Brüske I,  Wichmann HE,  Manz J,  Muley TR,  Risch A,  Rosenberger A,  Grankvist K,  Johansson M,  Shepherd FA,  Tsao MS,  Arnold SM,  Haura EB,  Bolca C,  Holcatova I,  Janout V,  Kontic M,  Lissowska J,  Mukeria A,  Ognjanovic S,  Orlowski TM,  Scelo G,  Swiatkowska B,  Zaridze D,  Bakke P,  Skaug V,  Zienolddiny S,  Duell EJ,  Butler LM,  Koh WP,  Gao YT,  Houlston RS,  McLaughlin J,  Stevens VL,  Joubert P,  Lamontagne M,  Nickle DC,  Obeidat M,  Timens W,  Zhu B,  Song L,  Kachuri L,  Artigas MS,  Tobin MD,  Wain LV,  SpiroMeta Consortium,  Rafnar T,  Thorgeirsson TE,  Reginsson GW,  Stefansson K,  Hancock DB,  Bierut LJ,  Spitz MR,  Gaddis NC,  Lutz SM,  Gu F,  Johnson EO,  Kamal A,  Pikielny C,  Zhu D,  Lindströem S,  Jiang X,  Tyndale RF,  Chenevix-Trench G,  Beesley J,  Bossé Y,  Chanock S,  Brennan P,  Landi MT,  Amos CI

Journal: Nat Genet

Date: 2017 Jul

Major Program(s) or Research Group(s): PLCO

PubMed ID: 28604730

PMC ID: PMC5510465

Abstract: Although several lung cancer susceptibility loci have been identified, much of the heritability for lung cancer remains unexplained. Here 14,803 cases and 12,262 controls of European descent were genotyped on the OncoArray and combined with existing data for an aggregated genome-wide association study (GWAS) analysis of lung cancer in 29,266 cases and 56,450 controls. We identified 18 susceptibility loci achieving genome-wide significance, including 10 new loci. The new loci highlight the striking heterogeneity in genetic susceptibility across the histological subtypes of lung cancer, with four loci associated with lung cancer overall and six loci associated with lung adenocarcinoma. Gene expression quantitative trait locus (eQTL) analysis in 1,425 normal lung tissue samples highlights RNASET2, SECISBP2L and NRG1 as candidate genes. Other loci include genes such as a cholinergic nicotinic receptor, CHRNA2, and the telomere-related genes OFBC1 and RTEL1. Further exploration of the target genes will continue to provide new insights into the etiology of lung cancer.