Author
Listed:
- Dana B Hancock
- María Soler Artigas
- Sina A Gharib
- Amanda Henry
- Ani Manichaikul
- Adaikalavan Ramasamy
- Daan W Loth
- Medea Imboden
- Beate Koch
- Wendy L McArdle
- Albert V Smith
- Joanna Smolonska
- Akshay Sood
- Wenbo Tang
- Jemma B Wilk
- Guangju Zhai
- Jing Hua Zhao
- Hugues Aschard
- Kristin M Burkart
- Ivan Curjuric
- Mark Eijgelsheim
- Paul Elliott
- Xiangjun Gu
- Tamara B Harris
- Christer Janson
- Georg Homuth
- Pirro G Hysi
- Jason Z Liu
- Laura R Loehr
- Kurt Lohman
- Ruth J F Loos
- Alisa K Manning
- Kristin D Marciante
- Ma'en Obeidat
- Dirkje S Postma
- Melinda C Aldrich
- Guy G Brusselle
- Ting-hsu Chen
- Gudny Eiriksdottir
- Nora Franceschini
- Joachim Heinrich
- Jerome I Rotter
- Cisca Wijmenga
- O Dale Williams
- Amy R Bentley
- Albert Hofman
- Cathy C Laurie
- Thomas Lumley
- Alanna C Morrison
- Bonnie R Joubert
- Fernando Rivadeneira
- David J Couper
- Stephen B Kritchevsky
- Yongmei Liu
- Matthias Wjst
- Louise V Wain
- Judith M Vonk
- André G Uitterlinden
- Thierry Rochat
- Stephen S Rich
- Bruce M Psaty
- George T O'Connor
- Kari E North
- Daniel B Mirel
- Bernd Meibohm
- Lenore J Launer
- Kay-Tee Khaw
- Anna-Liisa Hartikainen
- Christopher J Hammond
- Sven Gläser
- Jonathan Marchini
- Peter Kraft
- Nicholas J Wareham
- Henry Völzke
- Bruno H C Stricker
- Timothy D Spector
- Nicole M Probst-Hensch
- Deborah Jarvis
- Marjo-Riitta Jarvelin
- Susan R Heckbert
- Vilmundur Gudnason
- H Marike Boezen
- R Graham Barr
- Patricia A Cassano
- David P Strachan
- Myriam Fornage
- Ian P Hall
- Josée Dupuis
- Martin D Tobin
- Stephanie J London
Abstract
Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV1), and its ratio to forced vital capacity (FEV1/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV1 and FEV1/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest PJMA = 5.00×10−11), HLA-DQB1 and HLA-DQA2 (smallest PJMA = 4.35×10−9), and KCNJ2 and SOX9 (smallest PJMA = 1.28×10−8) were associated with FEV1/FVC or FEV1 in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects. Author Summary: Measures of pulmonary function provide important clinical tools for evaluating lung disease and its progression. Genome-wide association studies have identified numerous genetic risk factors for pulmonary function but have not considered interaction with cigarette smoking, which has consistently been shown to adversely impact pulmonary function. In over 50,000 study participants of European descent, we applied a recently developed joint meta-analysis method to simultaneously test associations of gene and gene-by-smoking interactions in relation to two major clinical measures of pulmonary function. Using this joint method to incorporate genetic main effects plus gene-by-smoking interaction, we identified three novel gene regions not previously related to pulmonary function: (1) DNER, (2) HLA-DQB1 and HLA-DQA2, and (3) KCNJ2 and SOX9. Expression analyses in human lung tissue from ours or prior studies indicate that these regions contain genes that are plausibly involved in pulmonary function. This work highlights the utility of employing novel methods for incorporating environmental interaction in genome-wide association studies to identify novel genetic regions.
Suggested Citation
Dana B Hancock & María Soler Artigas & Sina A Gharib & Amanda Henry & Ani Manichaikul & Adaikalavan Ramasamy & Daan W Loth & Medea Imboden & Beate Koch & Wendy L McArdle & Albert V Smith & Joanna Smol, 2012.
"Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function,"
PLOS Genetics, Public Library of Science, vol. 8(12), pages 1-1, December.
Handle:
RePEc:plo:pgen00:1003098
DOI: 10.1371/journal.pgen.1003098
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Citations
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Cited by:
- Jennifer E Huffman & Eva Albrecht & Alexander Teumer & Massimo Mangino & Karen Kapur & Toby Johnson & Zoltán Kutalik & Nicola Pirastu & Giorgio Pistis & Lorna M Lopez & Toomas Haller & Perttu Salo & A, 2015.
"Modulation of Genetic Associations with Serum Urate Levels by Body-Mass-Index in Humans,"
PLOS ONE, Public Library of Science, vol. 10(3), pages 1-21, March.
- Thomas W Winkler & Anne E Justice & L Adrienne Cupples & Florian Kronenberg & Zoltán Kutalik & Iris M Heid & the GIANT consortium, 2017.
"Approaches to detect genetic effects that differ between two strata in genome-wide meta-analyses: Recommendations based on a systematic evaluation,"
PLOS ONE, Public Library of Science, vol. 12(7), pages 1-23, July.
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