%0 Journal Article %J Nat Genet %D 2011 %T Genome-wide association and large-scale follow up identifies 16 new loci influencing lung function. %A Soler Artigas, Maria %A Loth, Daan W %A Wain, Louise V %A Gharib, Sina A %A Obeidat, Ma'en %A Tang, Wenbo %A Zhai, Guangju %A Zhao, Jing Hua %A Smith, Albert Vernon %A Huffman, Jennifer E %A Albrecht, Eva %A Jackson, Catherine M %A Evans, David M %A Cadby, Gemma %A Fornage, Myriam %A Manichaikul, Ani %A Lopez, Lorna M %A Johnson, Toby %A Aldrich, Melinda C %A Aspelund, Thor %A Barroso, Inês %A Campbell, Harry %A Cassano, Patricia A %A Couper, David J %A Eiriksdottir, Gudny %A Franceschini, Nora %A Garcia, Melissa %A Gieger, Christian %A Gislason, Gauti Kjartan %A Grkovic, Ivica %A Hammond, Christopher J %A Hancock, Dana B %A Harris, Tamara B %A Ramasamy, Adaikalavan %A Heckbert, Susan R %A Heliövaara, Markku %A Homuth, Georg %A Hysi, Pirro G %A James, Alan L %A Jankovic, Stipan %A Joubert, Bonnie R %A Karrasch, Stefan %A Klopp, Norman %A Koch, Beate %A Kritchevsky, Stephen B %A Launer, Lenore J %A Liu, Yongmei %A Loehr, Laura R %A Lohman, Kurt %A Loos, Ruth J F %A Lumley, Thomas %A Al Balushi, Khalid A %A Ang, Wei Q %A Barr, R Graham %A Beilby, John %A Blakey, John D %A Boban, Mladen %A Boraska, Vesna %A Brisman, Jonas %A Britton, John R %A Brusselle, Guy G %A Cooper, Cyrus %A Curjuric, Ivan %A Dahgam, Santosh %A Deary, Ian J %A Ebrahim, Shah %A Eijgelsheim, Mark %A Francks, Clyde %A Gaysina, Darya %A Granell, Raquel %A Gu, Xiangjun %A Hankinson, John L %A Hardy, Rebecca %A Harris, Sarah E %A Henderson, John %A Henry, Amanda %A Hingorani, Aroon D %A Hofman, Albert %A Holt, Patrick G %A Hui, Jennie %A Hunter, Michael L %A Imboden, Medea %A Jameson, Karen A %A Kerr, Shona M %A Kolcic, Ivana %A Kronenberg, Florian %A Liu, Jason Z %A Marchini, Jonathan %A McKeever, Tricia %A Morris, Andrew D %A Olin, Anna-Carin %A Porteous, David J %A Postma, Dirkje S %A Rich, Stephen S %A Ring, Susan M %A Rivadeneira, Fernando %A Rochat, Thierry %A Sayer, Avan Aihie %A Sayers, Ian %A Sly, Peter D %A Smith, George Davey %A Sood, Akshay %A Starr, John M %A Uitterlinden, André G %A Vonk, Judith M %A Wannamethee, S Goya %A Whincup, Peter H %A Wijmenga, Cisca %A Williams, O Dale %A Wong, Andrew %A Mangino, Massimo %A Marciante, Kristin D %A McArdle, Wendy L %A Meibohm, Bernd %A Morrison, Alanna C %A North, Kari E %A Omenaas, Ernst %A Palmer, Lyle J %A Pietiläinen, Kirsi H %A Pin, Isabelle %A Pola Sbreve Ek, Ozren %A Pouta, Anneli %A Psaty, Bruce M %A Hartikainen, Anna-Liisa %A Rantanen, Taina %A Ripatti, Samuli %A Rotter, Jerome I %A Rudan, Igor %A Rudnicka, Alicja R %A Schulz, Holger %A Shin, So-Youn %A Spector, Tim D %A Surakka, Ida %A Vitart, Veronique %A Völzke, Henry %A Wareham, Nicholas J %A Warrington, Nicole M %A Wichmann, H-Erich %A Wild, Sarah H %A Wilk, Jemma B %A Wjst, Matthias %A Wright, Alan F %A Zgaga, Lina %A Zemunik, Tatijana %A Pennell, Craig E %A Nyberg, Fredrik %A Kuh, Diana %A Holloway, John W %A Boezen, H Marike %A Lawlor, Debbie A %A Morris, Richard W %A Probst-Hensch, Nicole %A Kaprio, Jaakko %A Wilson, James F %A Hayward, Caroline %A Kähönen, Mika %A Heinrich, Joachim %A Musk, Arthur W %A Jarvis, Deborah L %A Gläser, Sven %A Jarvelin, Marjo-Riitta %A Ch Stricker, Bruno H %A Elliott, Paul %A O'Connor, George T %A Strachan, David P %A London, Stephanie J %A Hall, Ian P %A Gudnason, Vilmundur %A Tobin, Martin D %K Child %K European Continental Ancestry Group %K Genome-Wide Association Study %K Humans %K Pulmonary Disease, Chronic Obstructive %K Respiratory Function Tests %X

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.

%B Nat Genet %V 43 %P 1082-90 %8 2011 Sep 25 %G eng %N 11 %1 http://www.ncbi.nlm.nih.gov/pubmed/21946350?dopt=Abstract %R 10.1038/ng.941 %0 Journal Article %J Am J Respir Crit Care Med %D 2012 %T Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction. %A Wilk, Jemma B %A Shrine, Nick R G %A Loehr, Laura R %A Zhao, Jing Hua %A Manichaikul, Ani %A Lopez, Lorna M %A Smith, Albert Vernon %A Heckbert, Susan R %A Smolonska, Joanna %A Tang, Wenbo %A Loth, Daan W %A Curjuric, Ivan %A Hui, Jennie %A Cho, Michael H %A Latourelle, Jeanne C %A Henry, Amanda P %A Aldrich, Melinda %A Bakke, Per %A Beaty, Terri H %A Bentley, Amy R %A Borecki, Ingrid B %A Brusselle, Guy G %A Burkart, Kristin M %A Chen, Ting-Hsu %A Couper, David %A Crapo, James D %A Davies, Gail %A Dupuis, Josée %A Franceschini, Nora %A Gulsvik, Amund %A Hancock, Dana B %A Harris, Tamara B %A Hofman, Albert %A Imboden, Medea %A James, Alan L %A Khaw, Kay-Tee %A Lahousse, Lies %A Launer, Lenore J %A Litonjua, Augusto %A Liu, Yongmei %A Lohman, Kurt K %A Lomas, David A %A Lumley, Thomas %A Marciante, Kristin D %A McArdle, Wendy L %A Meibohm, Bernd %A Morrison, Alanna C %A Musk, Arthur W %A Myers, Richard H %A North, Kari E %A Postma, Dirkje S %A Psaty, Bruce M %A Rich, Stephen S %A Rivadeneira, Fernando %A Rochat, Thierry %A Rotter, Jerome I %A Soler Artigas, Maria %A Starr, John M %A Uitterlinden, André G %A Wareham, Nicholas J %A Wijmenga, Cisca %A Zanen, Pieter %A Province, Michael A %A Silverman, Edwin K %A Deary, Ian J %A Palmer, Lyle J %A Cassano, Patricia A %A Gudnason, Vilmundur %A Barr, R Graham %A Loos, Ruth J F %A Strachan, David P %A London, Stephanie J %A Boezen, H Marike %A Probst-Hensch, Nicole %A Gharib, Sina A %A Hall, Ian P %A O'Connor, George T %A Tobin, Martin D %A Stricker, Bruno H %K Aged %K Female %K Forced Expiratory Volume %K Genome-Wide Association Study %K Humans %K Male %K Middle Aged %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Pulmonary Disease, Chronic Obstructive %K Receptors, Nicotinic %K Receptors, Serotonin, 5-HT4 %K Smoking %K Vital Capacity %X

RATIONALE: Genome-wide association studies (GWAS) have identified loci influencing lung function, but fewer genes influencing chronic obstructive pulmonary disease (COPD) are known.

OBJECTIVES: Perform meta-analyses of GWAS for airflow obstruction, a key pathophysiologic characteristic of COPD assessed by spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases.

METHODS: Fifteen cohorts were studied for discovery (3,368 affected; 29,507 unaffected), and a population-based family study and a meta-analysis of case-control studies were used for replication and regional follow-up (3,837 cases; 4,479 control subjects). Airflow obstruction was defined as FEV(1) and its ratio to FVC (FEV(1)/FVC) both less than their respective lower limits of normal as determined by published reference equations.

MEASUREMENTS AND MAIN RESULTS: The discovery meta-analyses identified one region on chromosome 15q25.1 meeting genome-wide significance in ever smokers that includes AGPHD1, IREB2, and CHRNA5/CHRNA3 genes. The region was also modestly associated among never smokers. Gene expression studies confirmed the presence of CHRNA5/3 in lung, airway smooth muscle, and bronchial epithelial cells. A single-nucleotide polymorphism in HTR4, a gene previously related to FEV(1)/FVC, achieved genome-wide statistical significance in combined meta-analysis. Top single-nucleotide polymorphisms in ADAM19, RARB, PPAP2B, and ADAMTS19 were nominally replicated in the COPD meta-analysis.

CONCLUSIONS: These results suggest an important role for the CHRNA5/3 region as a genetic risk factor for airflow obstruction that may be independent of smoking and implicate the HTR4 gene in the etiology of airflow obstruction.

%B Am J Respir Crit Care Med %V 186 %P 622-32 %8 2012 Oct 01 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/22837378?dopt=Abstract %R 10.1164/rccm.201202-0366OC %0 Journal Article %J Hum Mol Genet %D 2015 %T Integrative pathway genomics of lung function and airflow obstruction. %A Gharib, Sina A %A Loth, Daan W %A Soler Artigas, Maria %A Birkland, Timothy P %A Wilk, Jemma B %A Wain, Louise V %A Brody, Jennifer A %A Obeidat, Ma'en %A Hancock, Dana B %A Tang, Wenbo %A Rawal, Rajesh %A Boezen, H Marike %A Imboden, Medea %A Huffman, Jennifer E %A Lahousse, Lies %A Alves, Alexessander C %A Manichaikul, Ani %A Hui, Jennie %A Morrison, Alanna C %A Ramasamy, Adaikalavan %A Smith, Albert Vernon %A Gudnason, Vilmundur %A Surakka, Ida %A Vitart, Veronique %A Evans, David M %A Strachan, David P %A Deary, Ian J %A Hofman, Albert %A Gläser, Sven %A Wilson, James F %A North, Kari E %A Zhao, Jing Hua %A Heckbert, Susan R %A Jarvis, Deborah L %A Probst-Hensch, Nicole %A Schulz, Holger %A Barr, R Graham %A Jarvelin, Marjo-Riitta %A O'Connor, George T %A Kähönen, Mika %A Cassano, Patricia A %A Hysi, Pirro G %A Dupuis, Josée %A Hayward, Caroline %A Psaty, Bruce M %A Hall, Ian P %A Parks, William C %A Tobin, Martin D %A London, Stephanie J %K Airway Obstruction %K Animals %K Cell Proliferation %K European Continental Ancestry Group %K Genetic Predisposition to Disease %K Genome-Wide Association Study %K Genomics %K Humans %K Immune System %K Lung %K Male %K Metabolic Networks and Pathways %K Mice %K Phenotype %K Polymorphism, Single Nucleotide %K Signal Transduction %X

Chronic respiratory disorders are important contributors to the global burden of disease. Genome-wide association studies (GWASs) of lung function measures have identified several trait-associated loci, but explain only a modest portion of the phenotypic variability. We postulated that integrating pathway-based methods with GWASs of pulmonary function and airflow obstruction would identify a broader repertoire of genes and processes influencing these traits. We performed two independent GWASs of lung function and applied gene set enrichment analysis to one of the studies and validated the results using the second GWAS. We identified 131 significantly enriched gene sets associated with lung function and clustered them into larger biological modules involved in diverse processes including development, immunity, cell signaling, proliferation and arachidonic acid. We found that enrichment of gene sets was not driven by GWAS-significant variants or loci, but instead by those with less stringent association P-values. Next, we applied pathway enrichment analysis to a meta-analyzed GWAS of airflow obstruction. We identified several biologic modules that functionally overlapped with those associated with pulmonary function. However, differences were also noted, including enrichment of extracellular matrix (ECM) processes specifically in the airflow obstruction study. Network analysis of the ECM module implicated a candidate gene, matrix metalloproteinase 10 (MMP10), as a putative disease target. We used a knockout mouse model to functionally validate MMP10's role in influencing lung's susceptibility to cigarette smoke-induced emphysema. By integrating pathway analysis with population-based genomics, we unraveled biologic processes underlying pulmonary function traits and identified a candidate gene for obstructive lung disease.

%B Hum Mol Genet %V 24 %P 6836-48 %8 2015 Dec 1 %G eng %N 23 %1 http://www.ncbi.nlm.nih.gov/pubmed/26395457?dopt=Abstract %R 10.1093/hmg/ddv378 %0 Journal Article %J Wellcome Open Res %D 2018 %T Meta-analysis of exome array data identifies six novel genetic loci for lung function. %A Jackson, Victoria E %A Latourelle, Jeanne C %A Wain, Louise V %A Smith, Albert V %A Grove, Megan L %A Bartz, Traci M %A Obeidat, Ma'en %A Province, Michael A %A Gao, Wei %A Qaiser, Beenish %A Porteous, David J %A Cassano, Patricia A %A Ahluwalia, Tarunveer S %A Grarup, Niels %A Li, Jin %A Altmaier, Elisabeth %A Marten, Jonathan %A Harris, Sarah E %A Manichaikul, Ani %A Pottinger, Tess D %A Li-Gao, Ruifang %A Lind-Thomsen, Allan %A Mahajan, Anubha %A Lahousse, Lies %A Imboden, Medea %A Teumer, Alexander %A Prins, Bram %A Lyytikäinen, Leo-Pekka %A Eiriksdottir, Gudny %A Franceschini, Nora %A Sitlani, Colleen M %A Brody, Jennifer A %A Bossé, Yohan %A Timens, Wim %A Kraja, Aldi %A Loukola, Anu %A Tang, Wenbo %A Liu, Yongmei %A Bork-Jensen, Jette %A Justesen, Johanne M %A Linneberg, Allan %A Lange, Leslie A %A Rawal, Rajesh %A Karrasch, Stefan %A Huffman, Jennifer E %A Smith, Blair H %A Davies, Gail %A Burkart, Kristin M %A Mychaleckyj, Josyf C %A Bonten, Tobias N %A Enroth, Stefan %A Lind, Lars %A Brusselle, Guy G %A Kumar, Ashish %A Stubbe, Beate %A Kähönen, Mika %A Wyss, Annah B %A Psaty, Bruce M %A Heckbert, Susan R %A Hao, Ke %A Rantanen, Taina %A Kritchevsky, Stephen B %A Lohman, Kurt %A Skaaby, Tea %A Pisinger, Charlotta %A Hansen, Torben %A Schulz, Holger %A Polasek, Ozren %A Campbell, Archie %A Starr, John M %A Rich, Stephen S %A Mook-Kanamori, Dennis O %A Johansson, Asa %A Ingelsson, Erik %A Uitterlinden, André G %A Weiss, Stefan %A Raitakari, Olli T %A Gudnason, Vilmundur %A North, Kari E %A Gharib, Sina A %A Sin, Don D %A Taylor, Kent D %A O'Connor, George T %A Kaprio, Jaakko %A Harris, Tamara B %A Pederson, Oluf %A Vestergaard, Henrik %A Wilson, James G %A Strauch, Konstantin %A Hayward, Caroline %A Kerr, Shona %A Deary, Ian J %A Barr, R Graham %A de Mutsert, Renée %A Gyllensten, Ulf %A Morris, Andrew P %A Ikram, M Arfan %A Probst-Hensch, Nicole %A Gläser, Sven %A Zeggini, Eleftheria %A Lehtimäki, Terho %A Strachan, David P %A Dupuis, Josée %A Morrison, Alanna C %A Hall, Ian P %A Tobin, Martin D %A London, Stephanie J %X

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. We carried out meta-analyses of exome array data and three lung function measures: forced expiratory volume in one second (FEV ), forced vital capacity (FVC) and the ratio of FEV to FVC (FEV /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. We identified significant (P<2·8x10 ) associations with six SNPs: a nonsynonymous variant in , which is predicted to be damaging, three intronic SNPs ( and ) and two intergenic SNPs near to and Expression quantitative trait loci analyses found evidence for regulation of gene expression at three signals and implicated several genes, including and . Further interrogation of these loci could provide greater understanding of the determinants of lung function and pulmonary disease.

%B Wellcome Open Res %V 3 %P 4 %8 2018 %G eng %R 10.12688/wellcomeopenres.12583.3 %0 Journal Article %J Nat Genet %D 2018 %T Multiancestry association study identifies new asthma risk loci that colocalize with immune-cell enhancer marks. %A Demenais, Florence %A Margaritte-Jeannin, Patricia %A Barnes, Kathleen C %A Cookson, William O C %A Altmüller, Janine %A Ang, Wei %A Barr, R Graham %A Beaty, Terri H %A Becker, Allan B %A Beilby, John %A Bisgaard, Hans %A Bjornsdottir, Unnur Steina %A Bleecker, Eugene %A Bønnelykke, Klaus %A Boomsma, Dorret I %A Bouzigon, Emmanuelle %A Brightling, Christopher E %A Brossard, Myriam %A Brusselle, Guy G %A Burchard, Esteban %A Burkart, Kristin M %A Bush, Andrew %A Chan-Yeung, Moira %A Chung, Kian Fan %A Couto Alves, Alexessander %A Curtin, John A %A Custovic, Adnan %A Daley, Denise %A de Jongste, Johan C %A Del-Rio-Navarro, Blanca E %A Donohue, Kathleen M %A Duijts, Liesbeth %A Eng, Celeste %A Eriksson, Johan G %A Farrall, Martin %A Fedorova, Yuliya %A Feenstra, Bjarke %A Ferreira, Manuel A %A Freidin, Maxim B %A Gajdos, Zofia %A Gauderman, Jim %A Gehring, Ulrike %A Geller, Frank %A Genuneit, Jon %A Gharib, Sina A %A Gilliland, Frank %A Granell, Raquel %A Graves, Penelope E %A Gudbjartsson, Daniel F %A Haahtela, Tari %A Heckbert, Susan R %A Heederik, Dick %A Heinrich, Joachim %A Heliövaara, Markku %A Henderson, John %A Himes, Blanca E %A Hirose, Hiroshi %A Hirschhorn, Joel N %A Hofman, Albert %A Holt, Patrick %A Hottenga, Jouke %A Hudson, Thomas J %A Hui, Jennie %A Imboden, Medea %A Ivanov, Vladimir %A Jaddoe, Vincent W V %A James, Alan %A Janson, Christer %A Jarvelin, Marjo-Riitta %A Jarvis, Deborah %A Jones, Graham %A Jonsdottir, Ingileif %A Jousilahti, Pekka %A Kabesch, Michael %A Kähönen, Mika %A Kantor, David B %A Karunas, Alexandra S %A Khusnutdinova, Elza %A Koppelman, Gerard H %A Kozyrskyj, Anita L %A Kreiner, Eskil %A Kubo, Michiaki %A Kumar, Rajesh %A Kumar, Ashish %A Kuokkanen, Mikko %A Lahousse, Lies %A Laitinen, Tarja %A Laprise, Catherine %A Lathrop, Mark %A Lau, Susanne %A Lee, Young-Ae %A Lehtimäki, Terho %A Letort, Sébastien %A Levin, Albert M %A Li, Guo %A Liang, Liming %A Loehr, Laura R %A London, Stephanie J %A Loth, Daan W %A Manichaikul, Ani %A Marenholz, Ingo %A Martinez, Fernando J %A Matheson, Melanie C %A Mathias, Rasika A %A Matsumoto, Kenji %A Mbarek, Hamdi %A McArdle, Wendy L %A Melbye, Mads %A Melén, Erik %A Meyers, Deborah %A Michel, Sven %A Mohamdi, Hamida %A Musk, Arthur W %A Myers, Rachel A %A Nieuwenhuis, Maartje A E %A Noguchi, Emiko %A O'Connor, George T %A Ogorodova, Ludmila M %A Palmer, Cameron D %A Palotie, Aarno %A Park, Julie E %A Pennell, Craig E %A Pershagen, Göran %A Polonikov, Alexey %A Postma, Dirkje S %A Probst-Hensch, Nicole %A Puzyrev, Valery P %A Raby, Benjamin A %A Raitakari, Olli T %A Ramasamy, Adaikalavan %A Rich, Stephen S %A Robertson, Colin F %A Romieu, Isabelle %A Salam, Muhammad T %A Salomaa, Veikko %A Schlünssen, Vivi %A Scott, Robert %A Selivanova, Polina A %A Sigsgaard, Torben %A Simpson, Angela %A Siroux, Valérie %A Smith, Lewis J %A Solodilova, Maria %A Standl, Marie %A Stefansson, Kari %A Strachan, David P %A Stricker, Bruno H %A Takahashi, Atsushi %A Thompson, Philip J %A Thorleifsson, Gudmar %A Thorsteinsdottir, Unnur %A Tiesler, Carla M T %A Torgerson, Dara G %A Tsunoda, Tatsuhiko %A Uitterlinden, André G %A van der Valk, Ralf J P %A Vaysse, Amaury %A Vedantam, Sailaja %A von Berg, Andrea %A von Mutius, Erika %A Vonk, Judith M %A Waage, Johannes %A Wareham, Nick J %A Weiss, Scott T %A White, Wendy B %A Wickman, Magnus %A Widen, Elisabeth %A Willemsen, Gonneke %A Williams, L Keoki %A Wouters, Inge M %A Yang, James J %A Zhao, Jing Hua %A Moffatt, Miriam F %A Ober, Carole %A Nicolae, Dan L %X

We examined common variation in asthma risk by conducting a meta-analysis of worldwide asthma genome-wide association studies (23,948 asthma cases, 118,538 controls) of individuals from ethnically diverse populations. We identified five new asthma loci, found two new associations at two known asthma loci, established asthma associations at two loci previously implicated in the comorbidity of asthma plus hay fever, and confirmed nine known loci. Investigation of pleiotropy showed large overlaps in genetic variants with autoimmune and inflammatory diseases. The enrichment in enhancer marks at asthma risk loci, especially in immune cells, suggested a major role of these loci in the regulation of immunologically related mechanisms.

%B Nat Genet %V 50 %P 42-53 %8 2018 Jan %G eng %N 1 %R 10.1038/s41588-017-0014-7