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. 2011 Sep 25;43(11):1082-90.
doi: 10.1038/ng.941.

Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function

María Soler Artigas  1 , Daan W Loth, Louise V Wain, Sina A Gharib, Ma'en Obeidat, Wenbo Tang, Guangju Zhai, Jing Hua Zhao, Albert Vernon Smith, Jennifer E Huffman, Eva Albrecht, Catherine M Jackson, David M Evans, Gemma Cadby, Myriam Fornage, Ani Manichaikul, Lorna M Lopez, Toby Johnson, Melinda C Aldrich, Thor Aspelund, Inês Barroso, Harry Campbell, Patricia A Cassano, David J Couper, Gudny Eiriksdottir, Nora Franceschini, Melissa Garcia, Christian Gieger, Gauti Kjartan Gislason, Ivica Grkovic, Christopher J Hammond, Dana B Hancock, Tamara B Harris, Adaikalavan Ramasamy, Susan R Heckbert, Markku Heliövaara, Georg Homuth, Pirro G Hysi, Alan L James, Stipan Jankovic, Bonnie R Joubert, Stefan Karrasch, Norman Klopp, Beate Koch, Stephen B Kritchevsky, Lenore J Launer, Yongmei Liu, Laura R Loehr, Kurt Lohman, Ruth J F Loos, Thomas Lumley, Khalid A Al Balushi, Wei Q Ang, R Graham Barr, John Beilby, John D Blakey, Mladen Boban, Vesna Boraska, Jonas Brisman, John R Britton, Guy G Brusselle, Cyrus Cooper, Ivan Curjuric, Santosh Dahgam, Ian J Deary, Shah Ebrahim, Mark Eijgelsheim, Clyde Francks, Darya Gaysina, Raquel Granell, Xiangjun Gu, John L Hankinson, Rebecca Hardy, Sarah E Harris, John Henderson, Amanda Henry, Aroon D Hingorani, Albert Hofman, Patrick G Holt, Jennie Hui, Michael L Hunter, Medea Imboden, Karen A Jameson, Shona M Kerr, Ivana Kolcic, Florian Kronenberg, Jason Z Liu, Jonathan Marchini, Tricia McKeever, Andrew D Morris, Anna-Carin Olin, David J Porteous, Dirkje S Postma, Stephen S Rich, Susan M Ring, Fernando Rivadeneira, Thierry Rochat, Avan Aihie Sayer, Ian Sayers, Peter D Sly, George Davey Smith, Akshay Sood, John M Starr, André G Uitterlinden, Judith M Vonk, S Goya Wannamethee, Peter H Whincup, Cisca Wijmenga, O Dale Williams, Andrew Wong, Massimo Mangino, Kristin D Marciante, Wendy L McArdle, Bernd Meibohm, Alanna C Morrison, Kari E North, Ernst Omenaas, Lyle J Palmer, Kirsi H Pietiläinen, Isabelle Pin, Ozren Pola Sbreve Ek, Anneli Pouta, Bruce M Psaty, Anna-Liisa Hartikainen, Taina Rantanen, Samuli Ripatti, Jerome I Rotter, Igor Rudan, Alicja R Rudnicka, Holger Schulz, So-Youn Shin, Tim D Spector, Ida Surakka, Veronique Vitart, Henry Völzke, Nicholas J Wareham, Nicole M Warrington, H-Erich Wichmann, Sarah H Wild, Jemma B Wilk, Matthias Wjst, Alan F Wright, Lina Zgaga, Tatijana Zemunik, Craig E Pennell, Fredrik Nyberg, Diana Kuh, John W Holloway, H Marike Boezen, Debbie A Lawlor, Richard W Morris, Nicole Probst-Hensch; International Lung Cancer Consortium; GIANT consortium; Jaakko Kaprio, James F Wilson, Caroline Hayward, Mika Kähönen, Joachim Heinrich, Arthur W Musk, Deborah L Jarvis, Sven Gläser, Marjo-Riitta Järvelin, Bruno H Ch Stricker, Paul Elliott, George T O'Connor, David P Strachan, Stephanie J London, Ian P Hall, Vilmundur Gudnason, Martin D Tobin
Affiliations

Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function

María Soler Artigas et al. Nat Genet. .

Abstract

Pulmonary function measures reflect respiratory health and are used in the diagnosis of chronic obstructive pulmonary disease. We tested genome-wide association with forced expiratory volume in 1 second and the ratio of forced expiratory volume in 1 second to forced vital capacity in 48,201 individuals of European ancestry with follow up of the top associations in up to an additional 46,411 individuals. We identified new regions showing association (combined P < 5 × 10(-8)) with pulmonary function in or near MFAP2, TGFB2, HDAC4, RARB, MECOM (also known as EVI1), SPATA9, ARMC2, NCR3, ZKSCAN3, CDC123, C10orf11, LRP1, CCDC38, MMP15, CFDP1 and KCNE2. Identification of these 16 new loci may provide insight into the molecular mechanisms regulating pulmonary function and into molecular targets for future therapy to alleviate reduced lung function.

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Figures

Figure 1
Figure 1
Study design. A total of 34 SNPs showing novel evidence of association (P<3×10−6) with FEV1 and/or FEV1/FVC in a meta-analysis of the Stage 1 studies were followed up in Stage 2. Studies with a combined total of 24,737 individuals undertook genotyping and association testing of the top 10 SNPs. Seven studies (*) with a combined total of 11,275 individuals had genome-wide association data and provided results for up to 34 SNPs. #GS:SFHS undertook genotyping on a 32-SNP multiplex genotyping platform and so included the 32 top ranking SNPs (including proxies and both SNPs from regions which showed association with both FEV1 and FEV1/FVC). This assay failed for one SNP (rs3769124) which was subsequently replaced with the 33rd SNP (rs4762767). SNP rs2284746 was excluded due to poor clustering. Although rs3743563 was chosen as proxy for rs12447804 which had N effective <80% in the Stage 1 meta-analysis, BHS2 were unable to genotype rs3743563 and so undertook genotyping for rs12447804 instead. See Table 1 for definitions of abbreviations.
Figure 2
Figure 2
Manhattan plots of association results for (a) FEV1/FVC and (b) FEV1. Manhattan plots ordered by chromosome position. SNPs for which −log10P>5 are indicated in red. Novel regions which reached genome-wide significance after Stage 1 + Stage 2 are labelled.
Figure 2
Figure 2
Manhattan plots of association results for (a) FEV1/FVC and (b) FEV1. Manhattan plots ordered by chromosome position. SNPs for which −log10P>5 are indicated in red. Novel regions which reached genome-wide significance after Stage 1 + Stage 2 are labelled.
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