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. 2010 Jan;42(1):36-44.
doi: 10.1038/ng.501. Epub 2009 Dec 13.

Genome-wide association study identifies five loci associated with lung function

Emmanouela Repapi  1 , Ian Sayers, Louise V Wain, Paul R Burton, Toby Johnson, Ma'en Obeidat, Jing Hua Zhao, Adaikalavan Ramasamy, Guangju Zhai, Veronique Vitart, Jennifer E Huffman, Wilmar Igl, Eva Albrecht, Panos Deloukas, John Henderson, Raquel Granell, Wendy L McArdle, Alicja R Rudnicka; Wellcome Trust Case Control Consortium; Inês Barroso, Ruth J F Loos, Nicholas J Wareham, Linda Mustelin, Taina Rantanen, Ida Surakka, Medea Imboden, H Erich Wichmann, Ivica Grkovic, Stipan Jankovic, Lina Zgaga, Anna-Liisa Hartikainen, Leena Peltonen, Ulf Gyllensten, Asa Johansson, Ghazal Zaboli, Harry Campbell, Sarah H Wild, James F Wilson, Sven Gläser, Georg Homuth, Henry Völzke, Massimo Mangino, Nicole Soranzo, Tim D Spector, Ozren Polasek, Igor Rudan, Alan F Wright, Markku Heliövaara, Samuli Ripatti, Anneli Pouta, Asa Torinsson Naluai, Anna-Carin Olin, Kjell Torén, Matthew N Cooper, Alan L James, Lyle J Palmer, Aroon D Hingorani, S Goya Wannamethee, Peter H Whincup, George Davey Smith, Shah Ebrahim, Tricia M McKeever, Ian D Pavord, Andrew K MacLeod, Andrew D Morris, David J Porteous, Cyrus Cooper, Elaine Dennison, Seif Shaheen, Stefan Karrasch, Eva Schnabel, Holger Schulz, Harald Grallert, Nabila Bouatia-Naji, Jérôme Delplanque, Philippe Froguel, John D Blakey; NSHD Respiratory Study Team; John R Britton, Richard W Morris, John W Holloway, Debbie A Lawlor, Jennie Hui, Fredrik Nyberg, Marjo-Riitta Jarvelin, Cathy Jackson, Mika Kähönen, Jaakko Kaprio, Nicole M Probst-Hensch, Beate Koch, Caroline Hayward, David M Evans, Paul Elliott, David P Strachan, Ian P Hall, Martin D Tobin
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Genome-wide association study identifies five loci associated with lung function

Emmanouela Repapi et al. Nat Genet. 2010 Jan.

Abstract

Pulmonary function measures are heritable traits that predict morbidity and mortality and define chronic obstructive pulmonary disease (COPD). We tested genome-wide association with forced expiratory volume in 1 s (FEV(1)) and the ratio of FEV(1) to forced vital capacity (FVC) in the SpiroMeta consortium (n = 20,288 individuals of European ancestry). We conducted a meta-analysis of top signals with data from direct genotyping (n < or = 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n < or = 883). We confirmed the reported locus at 4q31 and identified associations with FEV(1) or FEV(1)/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 x 10(-12)), 4q24 in GSTCD (2.18 x 10(-23)), 5q33 in HTR4 (P = 4.29 x 10(-9)), 6p21 in AGER (P = 3.07 x 10(-15)) and 15q23 in THSD4 (P = 7.24 x 10(-15)). mRNA analyses showed expression of TNS1, GSTCD, AGER, HTR4 and THSD4 in human lung tissue. These associations offer mechanistic insight into pulmonary function regulation and indicate potential targets for interventions to alleviate respiratory disease.

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Figures

Figure 1
Figure 1
Manhattan plots of association results for FEV1 and FEV1/FVC (analysis stage 1). (a,b) Manhattan plots ordered by chromosome position. SNPs for which −log10 P > 5 are indicated in red. The six loci indicated by arrows showed association with FEV1 (a) or FEV1/FVC (b; P < 5 × 10−8) in the meta-analysis of data from stages 1, 2a and 2b.
Figure 2
Figure 2
Regional association plots of six lung function–associated loci. (a–f) Statistical significance of each SNP on the −log10 scale as a function of chromosome position (NCBI build 36) in the meta-analysis of stage 1 data alone. The sentinel SNP at each locus is shown in blue; the correlations (r2) of each of the surrounding SNPs to the sentinel SNP are shown in the indicated colors. The six loci included are those that showed association with FEV1 or FEV1/FVC (P < 5 × 10–8) in the meta-analysis of data from stages 1, 2a and 2b. The combined P values for all stages are indicated by arrows. The relevant trait (FEV1 or FEV1/FVC ratio) is indicated for each plot. For rs12504628, the plot shows only the association of FEV1/FVC; this SNP was associated (P < 5 × 10−8) with both FEV1 and FEV1/FVC. Fine-scale recombination rate is plotted in blue. Combined P value from stages 1 and 2a only; SNP rs3995090 had low imputation quality in the CHARGE Consortium data and so was not included in stage 2b.
Figure 3
Figure 3
Forest plots of the stage 1 meta-analysis for the six lung function–associated loci. Each of the SNPs included in the figure showed genome-wide significant association (P < 5 × 10−8) with either FEV1 or FEV1/FVC in the data from stages 1, 2a and 2b. The plots show the meta-analysis of the stage 1 data for each sentinel SNP. The contributing effect (transformed beta) from each study is shown by a square, with confidence intervals indicated by horizontal lines. The contributing weight of each study to the meta-analysis is indicated by the size of the square. The combined meta-analysis estimate in the stage 1 data is shown at the bottom of each graph.
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