title: Informed genome-wide association analysis with family history as a secondary phenotype identifies novel loci of lung cancer.
abstract: Lung cancer is the leading cause of cancer death worldwide. Although several genetic variants associated with lung cancer have been identified in the past, stringent selection criteria of genome-wide association studies (GWAS) can lead to missed variants. The objective of this study was to uncover missed variants by using the known association between lung cancer and first-degree family history of lung cancer to enrich the variant prioritization for lung cancer susceptibility regions. In this two-stage GWAS study, we first selected a list of variants associated with both lung cancer and family history of lung cancer in four GWAS (3,953 cases, 4,730 controls), then replicated our findings for 30 variants in a meta-analysis of four additional studies (7,510 cases, 7,476 controls). The top ranked genetic variant rs12415204 in chr10q23.33 encoding FFAR4 in the Discovery set was validated in the Replication set with an overall OR of 1.09 (95% CI=1.04, 1.14, P=1.63×10(-4)). When combining the two stages of the study, the strongest association was found in rs1158970 at Ch4p15.2 encoding KCNIP4 with an OR of 0.89 (95% CI=0.85, 0.94, P=9.64×10(-6)). We performed a stratified analysis of rs12415204 and rs1158970 across all eight studies by age, gender, smoking status, and histology, and found consistent results across strata. Four of the 30 replicated variants act as expression quantitative trait loci (eQTL) sites in 1,111 nontumor lung tissues and meet the genome-wide 10% FDR threshold.
authors: Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
authors: Julia G
authors: JG
authors: Poirier
authors: Paul
authors: P
authors: Brennan
authors: James D
authors: JD
authors: McKay
authors: Margaret R
authors: MR
authors: Spitz
authors: Heike
authors: H
authors: Bickeböller
authors: Angela
authors: A
authors: Risch
authors: Geoffrey
authors: G
authors: Liu
authors: Loic
authors: L
authors: Le Marchand
authors: Shelley
authors: S
authors: Tworoger
authors: John
authors: J
authors: McLaughlin
authors: Albert
authors: A
authors: Rosenberger
authors: Joachim
authors: J
authors: Heinrich
authors: Irene
authors: I
authors: Brüske
authors: Thomas
authors: T
authors: Muley
authors: Brian E
authors: BE
authors: Henderson
authors: Lynne R
authors: LR
authors: Wilkens
authors: Xuchen
authors: X
authors: Zong
authors: Yafang
authors: Y
authors: Li
authors: Ke
authors: K
authors: Hao
authors: Wim
authors: W
authors: Timens
authors: Yohan
authors: Y
authors: Bossé
authors: Don D
authors: DD
authors: Sin
authors: Ma'en
authors: M
authors: Obeidat
authors: Christopher I
authors: CI
authors: Amos
authors: Rayjean J
authors: RJ
authors: Hung
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D010641:Phenotype
chemical_list: D014408:Biomarkers, Tumor
keywords: eQTL; family history; genetic susceptibility; genome-wide association studies; lung cancer; secondary phenotype
references: J Womens Health. 1997 Feb;6(1):49-62
references: 9065374
references: Oncogene. 2015 Feb 5;34(6):752-60
references: 24469060
references: Epidemiology. 2007 Jul;18(4):441-5
references: 17473707
references: Am J Hum Genet. 2007 Aug;81(2):208-27
references: 17668372
references: Am J Hum Genet. 2007 Sep;81(3):559-75
references: 17701901
references: Cancer Genet Cytogenet. 2007 Nov;179(1):11-8
references: 17981209
references: Nature. 2008 Apr 3;452(7187):633-7
references: 18385738
references: Nat Genet. 2008 May;40(5):616-22
references: 18385676
references: Biochem J. 2008 Jun 1;412(2):265-73
references: 18294141
references: Cancer Epidemiol Biomarkers Prev. 2008 May;17(5):1127-35
references: 18483334
references: BMC Public Health. 2008;8:203
references: 18538025
references: Nat Genet. 2008 Dec;40(12):1407-9
references: 18978787
references: Nat Genet. 2008 Dec;40(12):1404-6
references: 18978790
references: Cancer Epidemiol Biomarkers Prev. 2008 Dec;17(12):3526-35
references: 19029401
references: Genet Epidemiol. 2009 Apr;33(3):256-65
references: 19051285
references: Genet Epidemiol. 2009 Jan;33(1):79-86
references: 18642345
references: Am J Hum Genet. 2009 Nov;85(5):679-91
references: 19836008
references: Traffic. 2009 Dec;10(12):1765-72
references: 19804566
references: Genet Epidemiol. 2009 Dec;33(8):717-28
references: 19365863
references: BMC Bioinformatics. 2010;11:288
references: 20509871
references: Int J Cancer. 2010 Dec 15;127(12):2893-917
references: 21351269
references: Nat Genet. 2011 Jun;43(6):527-9
references: 21552266
references: Nature. 2012 Mar 15;483(7389):350-4
references: 22343897
references: Cancer Discov. 2012 Feb;2(2):131-9
references: 22585858
references: Eur J Cancer. 2012 Sep;48(13):1957-68
references: 22436981
references: Hum Mol Genet. 2012 Nov 15;21(22):4980-95
references: 22899653
references: PLoS Genet. 2012;8(11):e1003029
references: 23209423
references: PLoS One. 2013;8(2):e56179
references: 23457522
references: PLoS One. 2013;8(7):e70220
references: 23936167
references: PLoS Genet. 2013;9(8):e1003585
references: 23990791
references: PLoS One. 2013;8(9):e74630
references: 24058608
references: Oncogene. 2013 Dec 5;32(49):5541-50
references: 23851494
references: PLoS Genet. 2014 May;10(5):e1004314
references: 24786987
references: Nat Genet. 2014 Jul;46(7):736-41
references: 24880342
references: Nat Rev Neurosci. 2007 Mar;8(3):182-93
references: 17311005