Genome-wide association study identifies five loci associated with lung function.
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- Repapi, Emmanouela; Sayers, Ian; Wain, Louise V; Burton, Paul R; Johnson, Toby; Obeidat, Ma'en; Zhao, Jing Hua; Ramasamy, Adaikalavan; Zhai, Guangju; Vitart, Veronique; Huffman, Jennifer E; Igl, Wilmar; Albrecht, Eva; Deloukas, Panos; Henderson, John; Granell, Raquel; McArdle, Wendy L; Rudnicka, Alicja R; Wellcome Trust Case Control Consortium; Barroso, InΓͺs; Loos, Ruth J F; Wareham, Nicholas J; Mustelin, Linda; Rantanen, Taina; Surakka, Ida; Imboden, Medea; Wichmann, H Erich; Grkovic, Ivica; Jankovic, Stipan; Zgaga, Lina; Hartikainen, Anna-Liisa; Peltonen, Leena; Gyllensten, Ulf; Johansson, Asa; Zaboli, Ghazal; Campbell, Harry; Wild, Sarah H; Wilson, James F; GlΓ€ser, Sven; Homuth, Georg; VΓΆlzke, Henry; Mangino, Massimo; Soranzo, Nicole; Spector, Tim D; Polasek, Ozren; Rudan, Igor; Wright, Alan F; HeliΓΆvaara, Markku; Ripatti, Samuli; Pouta, Anneli; Naluai, Asa Torinsson; Olin, Anna-Carin; TorΓ©n, Kjell; Cooper, Matthew N; James, Alan L; Palmer, Lyle J; Hingorani, Aroon D; Wannamethee, S Goya; Whincup, Peter H; Smith, George Davey; Ebrahim, Shah; McKeever, Tricia M; Pavord, Ian D; MacLeod, Andrew K; Morris, Andrew D; Porteous, David J; Cooper, Cyrus; Dennison, Elaine; Shaheen, Seif; Karrasch, Stefan; Schnabel, Eva; Schulz, Holger; Grallert, Harald; Bouatia-Naji, Nabila; Delplanque, JΓ©rΓ΄me; Froguel, Philippe; Blakey, John D; NSHD Respiratory Study Team; Britton, John R; Morris, Richard W; Holloway, John W; Lawlor, Debbie A; Hui, Jennie; Nyberg, Fredrik; Jarvelin, Marjo-Riitta; Jackson, Cathy; KΓ€hΓΆnen, Mika; Kaprio, Jaakko; Probst-Hensch, Nicole M; Koch, Beate; Hayward, Caroline; Evans, David M; Elliott, Paul; Strachan, David P; Hall, Ian P; Tobin, Martin D
- Year
- 2010
- Journal
- Nature genetics
- PMID
- 20010834
- DOI
- 10.1038/ng.501
- PMCID
- PMC2862965
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.
Manhattan plots of association results for FEV1 and FEV1/FVC (analysis stage 1). (a,b) Manhattan plots ordered by chromosome position. SNPs for which βlog10 P > 5 are indicated in red. The six loci indicated by arrows showed association with FEV1 (a) or FEV1/FVC (b; P < 5 Γ 10β8) in the meta-analysis of data from stages 1, 2a and 2b.
Regional association plots of six lung functionβassociated loci. (aβf) Statistical significance of each SNP on the βlog10 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 Γ 10β8) 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 Γ 10β8) with both FEV1 and FEV1/FVC. Fine-scale recombination rate is plotted in blue39. 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.
Forest plots of the stage 1 meta-analysis for the six lung functionβassociated loci. Each of the SNPs included in the figure showed genome-wide significant association (P < 5 Γ 10β8) 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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