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


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.

SUBMITTER: McKay JD 

PROVIDER: S-EPMC5510465 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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

McKay James D JD   Hung Rayjean J RJ   Han Younghun Y   Zong Xuchen X   Carreras-Torres Robert R   Christiani David C DC   Caporaso Neil E NE   Johansson Mattias M   Xiao Xiangjun X   Li Yafang Y   Byun Jinyoung J   Dunning Alison A   Pooley Karen A KA   Qian David C DC   Ji Xuemei X   Liu Geoffrey G   Timofeeva Maria N MN   Bojesen Stig E SE   Wu Xifeng X   Le Marchand Loic L   Albanes Demetrios D   Bickeböller Heike H   Aldrich Melinda C MC   Bush William S WS   Tardon Adonina A   Rennert Gad G   Teare M Dawn MD   Field John K JK   Kiemeney Lambertus A LA   Lazarus Philip P   Haugen Aage A   Lam Stephen S   Schabath Matthew B MB   Andrew Angeline S AS   Shen Hongbing H   Hong Yun-Chul YC   Yuan Jian-Min JM   Bertazzi Pier Alberto PA   Pesatori Angela C AC   Ye Yuanqing Y   Diao Nancy N   Su Li L   Zhang Ruyang R   Brhane Yonathan Y   Leighl Natasha N   Johansen Jakob S JS   Mellemgaard Anders A   Saliba Walid W   Haiman Christopher A CA   Wilkens Lynne R LR   Fernandez-Somoano Ana A   Fernandez-Tardon Guillermo G   van der Heijden Henricus F M HFM   Kim Jin Hee JH   Dai Juncheng J   Hu Zhibin Z   Davies Michael P A MPA   Marcus Michael W MW   Brunnström Hans H   Manjer Jonas J   Melander Olle O   Muller David C DC   Overvad Kim K   Trichopoulou Antonia A   Tumino Rosario R   Doherty Jennifer A JA   Barnett Matt P MP   Chen Chu C   Goodman Gary E GE   Cox Angela A   Taylor Fiona F   Woll Penella P   Brüske Irene I   Wichmann H-Erich HE   Manz Judith J   Muley Thomas R TR   Risch Angela A   Rosenberger Albert A   Grankvist Kjell K   Johansson Mikael M   Shepherd Frances A FA   Tsao Ming-Sound MS   Arnold Susanne M SM   Haura Eric B EB   Bolca Ciprian C   Holcatova Ivana I   Janout Vladimir V   Kontic Milica M   Lissowska Jolanta J   Mukeria Anush A   Ognjanovic Simona S   Orlowski Tadeusz M TM   Scelo Ghislaine G   Swiatkowska Beata B   Zaridze David D   Bakke Per P   Skaug Vidar V   Zienolddiny Shanbeh S   Duell Eric J EJ   Butler Lesley M LM   Koh Woon-Puay WP   Gao Yu-Tang YT   Houlston Richard S RS   McLaughlin John J   Stevens Victoria L VL   Joubert Philippe P   Lamontagne Maxime M   Nickle David C DC   Obeidat Ma'en M   Timens Wim W   Zhu Bin B   Song Lei L   Kachuri Linda L   Artigas María Soler MS   Tobin Martin D MD   Wain Louise V LV   Rafnar Thorunn T   Thorgeirsson Thorgeir E TE   Reginsson Gunnar W GW   Stefansson Kari K   Hancock Dana B DB   Bierut Laura J LJ   Spitz Margaret R MR   Gaddis Nathan C NC   Lutz Sharon M SM   Gu Fangyi F   Johnson Eric O EO   Kamal Ahsan A   Pikielny Claudio C   Zhu Dakai D   Lindströem Sara S   Jiang Xia X   Tyndale Rachel F RF   Chenevix-Trench Georgia G   Beesley Jonathan J   Bossé Yohan Y   Chanock Stephen S   Brennan Paul P   Landi Maria Teresa MT   Amos Christopher I CI  

Nature genetics 20170612 7


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 striki  ...[more]

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