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Meta-Analysis
. 2017 Jul;49(7):1126-1132.
doi: 10.1038/ng.3892. Epub 2017 Jun 12.

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

James D McKay  1 , Rayjean J Hung  2 , Younghun Han  3 , Xuchen Zong  2 , Robert Carreras-Torres  1 , David C Christiani  4 , Neil E Caporaso  5 , Mattias Johansson  1 , Xiangjun Xiao  3 , Yafang Li  3 , Jinyoung Byun  3 , Alison Dunning  6 , Karen A Pooley  6 , David C Qian  3 , Xuemei Ji  3 , Geoffrey Liu  2 , Maria N Timofeeva  1 , Stig E Bojesen  7   8   9 , Xifeng Wu  10 , Loic Le Marchand  11 , Demetrios Albanes  5 , Heike Bickeböller  12 , Melinda C Aldrich  13 , William S Bush  14 , Adonina Tardon  15 , Gad Rennert  16 , M Dawn Teare  17 , John K Field  18 , Lambertus A Kiemeney  19 , Philip Lazarus  20 , Aage Haugen  21 , Stephen Lam  22 , Matthew B Schabath  23 , Angeline S Andrew  24 , Hongbing Shen  25 , Yun-Chul Hong  26 , Jian-Min Yuan  27 , Pier Alberto Bertazzi  28   29 , Angela C Pesatori  29 , Yuanqing Ye  10 , Nancy Diao  4 , Li Su  4 , Ruyang Zhang  4 , Yonathan Brhane  2 , Natasha Leighl  30 , Jakob S Johansen  31 , Anders Mellemgaard  31 , Walid Saliba  16 , Christopher A Haiman  32 , Lynne R Wilkens  11 , Ana Fernandez-Somoano  15 , Guillermo Fernandez-Tardon  15 , Henricus F M van der Heijden  19 , Jin Hee Kim  33 , Juncheng Dai  25 , Zhibin Hu  25 , Michael P A Davies  18 , Michael W Marcus  18 , Hans Brunnström  34 , Jonas Manjer  35 , Olle Melander  35 , David C Muller  36 , Kim Overvad  37 , Antonia Trichopoulou  38 , Rosario Tumino  39 , Jennifer A Doherty  24   40   41   42 , Matt P Barnett  40 , Chu Chen  40 , Gary E Goodman  43 , Angela Cox  44 , Fiona Taylor  44 , Penella Woll  44 , Irene Brüske  45 , H-Erich Wichmann  45   46   47 , Judith Manz  48 , Thomas R Muley  49   50 , Angela Risch  48   49   50   51   52 , Albert Rosenberger  12 , Kjell Grankvist  53 , Mikael Johansson  54 , Frances A Shepherd  30 , Ming-Sound Tsao  30 , Susanne M Arnold  55 , Eric B Haura  56 , Ciprian Bolca  57 , Ivana Holcatova  58 , Vladimir Janout  59 , Milica Kontic  60   61 , Jolanta Lissowska  62 , Anush Mukeria  63 , Simona Ognjanovic  64 , Tadeusz M Orlowski  65 , Ghislaine Scelo  1 , Beata Swiatkowska  66 , David Zaridze  63 , Per Bakke  67 , Vidar Skaug  21 , Shanbeh Zienolddiny  21 , Eric J Duell  68 , Lesley M Butler  27 , Woon-Puay Koh  69 , Yu-Tang Gao  70 , Richard S Houlston  71 , John McLaughlin  72 , Victoria L Stevens  73 , Philippe Joubert  74 , Maxime Lamontagne  74 , David C Nickle  75 , Ma'en Obeidat  76 , Wim Timens  77 , Bin Zhu  5 , Lei Song  5 , Linda Kachuri  2 , María Soler Artigas  78   79 , Martin D Tobin  78   79 , Louise V Wain  78   79 ; SpiroMeta Consortium; Thorunn Rafnar  80 , Thorgeir E Thorgeirsson  80 , Gunnar W Reginsson  80 , Kari Stefansson  80 , Dana B Hancock  81 , Laura J Bierut  82 , Margaret R Spitz  83 , Nathan C Gaddis  84 , Sharon M Lutz  85 , Fangyi Gu  5 , Eric O Johnson  86 , Ahsan Kamal  3 , Claudio Pikielny  3 , Dakai Zhu  3 , Sara Lindströem  87 , Xia Jiang  88 , Rachel F Tyndale  89   90 , Georgia Chenevix-Trench  91 , Jonathan Beesley  91 , Yohan Bossé  74   92 , Stephen Chanock  5 , Paul Brennan  1 , Maria Teresa Landi  5 , Christopher I Amos  3
Affiliations
Meta-Analysis

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

James D McKay et al. Nat Genet. 2017 Jul.

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.

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Figures

Figure 1
Figure 1. Manhattan plots of lung cancer risk overall and by histological subtypes
(a) lung cancer risk overall, 29,266 cases and 56,450 controls (b) adenocarcinoma, 11,273 cases and 55,483 controls (c) squamous cell carcinoma 7,426 cases and 55,627 controls. Each locus is annotated by their cytoband locations. The X‐axis represents chromosomal locations and the Y‐axis represents −log10(P‐value). Black denotes the previously known loci and Red denotes the new loci identified in this analysis
Figure 2
Figure 2. Scatter plots comparing variants across the 6q27, 15q21.1, 8p12 and 11q23.3 susceptibility loci and (Y-axis) their associated with lung cancer (or lung adenocarcinoma, as relevant) and (X-axis) the lung cis–eQTL (GTEx)
Each variant (dot) is colored relative the degree of linkage disequilibrium (r2) with sentinel lung cancer variant (marked) at that locus. Indented table, association between sentinel variant and lung cancer (or histological subtype) as well as the eQTL evidence in lung epithelium for the microarray (Laval, UBC, Groningen) and RNAseq (NCI and GTEx) cohorts. At 6q27, 15q21.1 and 8p12, the variants associated with lung cancer also tend to be those that that are lung cis-eQTL’s for RNASET2, SECISBP2L and NRG1, respectively. At 11q23.3, while the sentinel variant (rs1056562) is a lung cis-eQTL for AMICA1, additional variants are AMICA1 lung cis-eQTL’s, but not associated with lung adenocarcinoma and vice versa suggesting an alternate candidate gene may be responsible for this association or a pleiotropic effect at this locus.
Figure 3
Figure 3. eQTL and smoking behavior analysis of the 8p21 lung cancer susceptibility locus. Upper panel
Scatter plots of variants across the 8p21 locus and their associated with lung cancer (Y-axis) and CHRNA2 eQTL (X-axis) in lung epithelial tissues (panel a) and CHRNA2 eQTL in brain cerebellum tissues (panel b). Panel C. eQTL association between rs11780471 across tissues from different parts of the brain from GTEx and Braineac consortia noting CHRNA2 cis- eQTL effect appears restricted to the brain cerebellum. Panel D. Association between rs11780471 and smoking phenotypes, noting evidence for association between smoking status (ever vs never) and age of initiation, with lung cancer risk allele carriers (G) more likely to be ever smokers and take up smoking earlier. Fagerström Test for Nicotine Dependence (FTND) index, error bars indicate the 95% confidence intervals.
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