Meta-analysis of exome array data identifies six novel genetic loci for lung function
Jackson VE., Latourelle JC., Wain LV., Smith AV., Grove ML., Bartz TM., Obeidat M., Province MA., Gao W., Qaiser B., Porteous DJ., Cassano PA., Ahluwalia TS., Grarup N., Li J., Altmaier E., Marten J., Harris SE., Manichaikul A., Pottinger TD., Li-Gao R., Lind-Thomsen A., Mahajan A., Lahousse L., Imboden M., Teumer A., Prins B., Lyytikäinen L-P., Eiriksdottir G., Franceschini N., Sitlani CM., Brody JA., Bossé Y., Timens W., Kraja A., Loukola A., Tang W., Liu Y., Bork-Jensen J., Justesen JM., Linneberg A., Lange LA., Rawal R., Karrasch S., Huffman JE., Smith BH., Davies G., Burkart KM., Mychaleckyj JC., Bonten TN., Enroth S., Lind L., Brusselle GG., Kumar A., Stubbe B., Kähönen M., Wyss AB., Psaty BM., Heckbert SR., Hao K., Rantanen T., Kritchevsky SB., Lohman K., Skaaby T., Pisinger C., Hansen T., Schulz H., Polasek O., Campbell A., Starr JM., Rich SS., Mook-Kanamori DO., Johansson Å., Ingelsson E., Uitterlinden AG., Weiss S., Raitakari OT., Gudnason V., North KE., Gharib SA., Sin DD., Taylor KD., O'Connor GT., Kaprio J., Harris TB., Pederson O., Vestergaard H., Wilson JG., Strauch K., Hayward C., Kerr S., Deary IJ., Barr RG., de Mutsert R., Gyllensten U., Morris AP., Ikram MA., Probst-Hensch N., Gläser S., Zeggini E., Lehtimäki T., Strachan DP., Dupuis J., Morrison AC., Hall IP., Tobin MD., London SJ.
<ns4:p><ns4:bold>Background:</ns4:bold> Over 90 regions of the genome have been associated with lung function to date, many of which have also been implicated in chronic obstructive pulmonary disease.</ns4:p><ns4:p> <ns4:bold>Methods:</ns4:bold> We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV<ns4:sub>1</ns4:sub>), forced vital capacity (FVC) and the ratio of FEV<ns4:sub>1</ns4:sub> to FVC (FEV<ns4:sub>1</ns4:sub>/FVC). These analyses by the SpiroMeta and CHARGE consortia included 60,749 individuals of European ancestry from 23 studies, and 7,721 individuals of African Ancestry from 5 studies in the discovery stage, with follow-up in up to 111,556 independent individuals.</ns4:p><ns4:p> <ns4:bold>Results:</ns4:bold> We identified significant (P<2·8x10<ns4:sup>-7</ns4:sup>) associations with six SNPs: a nonsynonymous variant in <ns4:italic>RPAP1</ns4:italic>, which is predicted to be damaging, three intronic SNPs (<ns4:italic>SEC24C, CASC17 </ns4:italic>and <ns4:italic>UQCC1</ns4:italic>) and two intergenic SNPs near to<ns4:italic> LY86 </ns4:italic>and <ns4:italic>FGF10.</ns4:italic> Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including <ns4:italic>TYRO3</ns4:italic> and <ns4:italic>PLAU</ns4:italic>.</ns4:p><ns4:p> <ns4:bold>Conclusions: </ns4:bold>Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.</ns4:p>