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 (FEV1) and the ratio of FEV1 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 ≤ 32,184 additional individuals) and in silico summary association data from the CHARGE Consortium (n = 21,209) and the Health 2000 survey (n ≤ 883). We confirmed the reported locus at 4q31 and identified associations with FEV1 or FEV1/FVC and common variants at five additional loci: 2q35 in TNS1 (P = 1.11 × 10−12), 4q24 in GSTCD (2.18 × 10−23), 5q33 in HTR4 (P = 4.29 × 10−9), 6p21 in AGER (P = 3.07 × 10−15) and 15q23 in THSD4 (P = 7.24 × 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.
At a glance
- Respiratory function and self-reported functional health: EPIC-Norfolk population study. Eur. Respir. J. 26, 494–502 (2005). et al.
- Pulmonary function is a long-term predictor of mortality in the general population: 29-year follow-up of the Buffalo Health Study. Chest 118, 656–664 (2000). , , , &
- Ventilatory function, height, and mortality among lifelong non-smokers. J. Epidemiol. Community Health 46, 66–70 (1992).
- Forced expiratory volume in one second: not just a lung function test but a marker of premature death from all causes. Eur. Respir. J. 30, 616–622 (2007). , &
- Genetic and environmental influences on pulmonary function in adult twins. Am. Rev. Respir. Dis. 125, 409–415 (1982). , , &
- Genetic and environmental influences on pulmonary function in aging Swedish twins. J. Gerontol. 49, 264–268 (1994). , , , &
- Genetic and environmental determinants of level of pulmonary function. Am. J. Epidemiol. 120, 518–530 (1984). , , , &
- Familial aggregation and heritability of adult lung function: results from the Busselton Health Study. Eur. Respir. J. 17, 696–702 (2001). et al.
- Common variants near MC4R are associated with fat mass, weight and risk of obesity. Nat. Genet. 40, 768–775 (2008). et al.
- A genome-wide association study in chronic obstructive pulmonary disease (COPD): identification of two major susceptibility loci. PLoS Genet. 5, e1000421 (2009). et al.
- A genome-wide association study of pulmonary function measures in the Framingham Heart Study. PLoS Genet. 5, e1000429 (2009). et al.
- Genome-wide association studies for complex traits: consensus, uncertainty and challenges. Nat. Rev. Genet. 9, 356–369 (2008). et al.
- Role of Sonic hedgehog in patterning of tracheal-bronchial cartilage and the peripheral lung. Dev. Dyn. 231, 57–71 (2004). et al.
- Glutathione transferases. Annu. Rev. Pharmacol. Toxicol. 45, 51–88 (2005). , &
- Integrator, a multiprotein mediator of small nuclear RNA processing, associates with the C-terminal repeat of RNA polymerase II. Cell 123, 265–276 (2005). et al.
- Occurrence of an actin-inserting domain in tensin. J. Mol. Biol. 227, 593–595 (1992). , , , &
- Tensin1 and a previously undocumented family member, tensin2, positively regulate cell migration. Proc. Natl. Acad. Sci. USA 99, 733–738 (2002). , , &
- 5–HT4(a) receptors avert opioid-induced breathing depression without loss of analgesia. Science 301, 226–229 (2003). et al.
- The effects of 5-HT on cholinergic contraction in human airways in vitro. Eur. Respir. J. 14, 642–649 (1999). et al.
- Serotoninergic receptors on human airway epithelial cells. Am. J. Respir. Cell Mol. Biol. 36, 85–93 (2007). et al.
- LEKTI, a novel 15-domain type of human serine proteinase inhibitor. J. Biol. Chem. 274, 21499–21502 (1999). et al.
- The F-box protein family. Genome Biol. 1, REVIEWS3002 (2000). &
- RAGE (Receptor for Advanced Glycation Endproducts), RAGE ligands, and their role in cancer and inflammation. J. Transl. Med. 7, 17 (2009). et al.
- Receptor for advanced glycation endproducts (RAGE) exhibits highly differential cellular and subcellular localisation in rat and human lung. Cell. Mol. Biol. 44, 1147–1157 (1998). et al.
- Gene expression profiles of acute exacerbations of Idiopathic Pulmonary Fibrosis. Am. J. Respir. Crit. Care Med. 180, 167–175 (2009). et al.
- A role for the receptor for advanced glycation end products in idiopathic pulmonary fibrosis. Am. J. Pathol. 172, 583–591 (2008). et al.
- Notch signaling: the core pathway and its posttranslational regulation. Dev. Cell 16, 633–647 (2009).
- Expression of genes involved in vascular development and angiogenesis in endothelial cells of adult lung. Am. J. Physiol. Heart Circ. Physiol. 285, H1917–H1938 (2003). et al.
- The cell biology of thrombospondin-1. Matrix Biol. 19, 597–614 (2000). , &
- Meta-analyses of genome-wide association studies identify multiple loci associated with pulmonary function. Nat. Genet. advance online publication, doi:10.1038/ng.500 (13 December 2009). et al.
- A variant associated with nicotine dependence, lung cancer and peripheral arterial disease. Nature 452, 638–642 (2008). et al.
- Molecular genetics of successful smoking cessation: convergent genome-wide association study results. Arch. Gen. Psychiatry 65, 683–693 (2008). et al.
- Genome-wide association analysis identifies 20 loci that influence adult height. Nat. Genet. 40, 575–583 (2008). et al.
- Many sequence variants affecting diversity of adult human height. Nat. Genet. 40, 609–615 (2008). et al.
- The natural history of chronic airflow obstruction revisited: an analysis of the framingham offspring cohort. Am. J. Respir. Crit. Care Med. 180, 3–10 (2009). et al.
- Mach 1.0: Rapid haplotype reconstruction and missing genotype inference. Am. J. Hum. Genet. S79, 2290 (2006). &
- A new multipoint method for genome-wide association studies by imputation of genotypes. Nat. Genet. 39, 906–913 (2007). , , , &
- Practical issues in imputation-based association mapping. PLoS Genet. 4, e1000279 (2008). &
- A fine-scale map of recombination rates and hotspots across the human genome. Science 310, 321–324 (2005). , , , &
- Genomic control for association studies. Biometrics 55, 997–1004 (1999). &
- The effect of beta2-adrenoceptor agonists on phospholipase C (beta1) signalling in human airway smooth muscle cells. Eur. J. Pharmacol. 531, 9–12 (2006). , &
- Glucocorticoids increase repair potential in a novel in vitro human airway epithelial wounding model. J. Clin. Immunol. 26, 376–387 (2006). , &