%0 Journal Article %J Nat Genet %D 2010 %T New loci associated with kidney function and chronic kidney disease. %A Köttgen, Anna %A Pattaro, Cristian %A Böger, Carsten A %A Fuchsberger, Christian %A Olden, Matthias %A Glazer, Nicole L %A Parsa, Afshin %A Gao, Xiaoyi %A Yang, Qiong %A Smith, Albert V %A O'Connell, Jeffrey R %A Li, Man %A Schmidt, Helena %A Tanaka, Toshiko %A Isaacs, Aaron %A Ketkar, Shamika %A Hwang, Shih-Jen %A Johnson, Andrew D %A Dehghan, Abbas %A Teumer, Alexander %A Paré, Guillaume %A Atkinson, Elizabeth J %A Zeller, Tanja %A Lohman, Kurt %A Cornelis, Marilyn C %A Probst-Hensch, Nicole M %A Kronenberg, Florian %A Tönjes, Anke %A Hayward, Caroline %A Aspelund, Thor %A Eiriksdottir, Gudny %A Launer, Lenore J %A Harris, Tamara B %A Rampersaud, Evadnie %A Mitchell, Braxton D %A Arking, Dan E %A Boerwinkle, Eric %A Struchalin, Maksim %A Cavalieri, Margherita %A Singleton, Andrew %A Giallauria, Francesco %A Metter, Jeffrey %A de Boer, Ian H %A Haritunians, Talin %A Lumley, Thomas %A Siscovick, David %A Psaty, Bruce M %A Zillikens, M Carola %A Oostra, Ben A %A Feitosa, Mary %A Province, Michael %A de Andrade, Mariza %A Turner, Stephen T %A Schillert, Arne %A Ziegler, Andreas %A Wild, Philipp S %A Schnabel, Renate B %A Wilde, Sandra %A Munzel, Thomas F %A Leak, Tennille S %A Illig, Thomas %A Klopp, Norman %A Meisinger, Christa %A Wichmann, H-Erich %A Koenig, Wolfgang %A Zgaga, Lina %A Zemunik, Tatijana %A Kolcic, Ivana %A Minelli, Cosetta %A Hu, Frank B %A Johansson, Asa %A Igl, Wilmar %A Zaboli, Ghazal %A Wild, Sarah H %A Wright, Alan F %A Campbell, Harry %A Ellinghaus, David %A Schreiber, Stefan %A Aulchenko, Yurii S %A Felix, Janine F %A Rivadeneira, Fernando %A Uitterlinden, André G %A Hofman, Albert %A Imboden, Medea %A Nitsch, Dorothea %A Brandstätter, Anita %A Kollerits, Barbara %A Kedenko, Lyudmyla %A Mägi, Reedik %A Stumvoll, Michael %A Kovacs, Peter %A Boban, Mladen %A Campbell, Susan %A Endlich, Karlhans %A Völzke, Henry %A Kroemer, Heyo K %A Nauck, Matthias %A Völker, Uwe %A Polasek, Ozren %A Vitart, Veronique %A Badola, Sunita %A Parker, Alexander N %A Ridker, Paul M %A Kardia, Sharon L R %A Blankenberg, Stefan %A Liu, Yongmei %A Curhan, Gary C %A Franke, Andre %A Rochat, Thierry %A Paulweber, Bernhard %A Prokopenko, Inga %A Wang, Wei %A Gudnason, Vilmundur %A Shuldiner, Alan R %A Coresh, Josef %A Schmidt, Reinhold %A Ferrucci, Luigi %A Shlipak, Michael G %A van Duijn, Cornelia M %A Borecki, Ingrid %A Krämer, Bernhard K %A Rudan, Igor %A Gyllensten, Ulf %A Wilson, James F %A Witteman, Jacqueline C %A Pramstaller, Peter P %A Rettig, Rainer %A Hastie, Nick %A Chasman, Daniel I %A Kao, W H %A Heid, Iris M %A Fox, Caroline S %K Cohort Studies %K Creatinine %K Cystatin C %K Diet %K Europe %K Genetic Markers %K Genome-Wide Association Study %K Glomerular Filtration Rate %K Humans %K Kidney %K Kidney Failure, Chronic %K Models, Genetic %K Risk Factors %X

Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m(2); n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide-significant loci (P < 5 x 10(-8)) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.

%B Nat Genet %V 42 %P 376-84 %8 2010 May %G eng %N 5 %1 http://www.ncbi.nlm.nih.gov/pubmed/20383146?dopt=Abstract %R 10.1038/ng.568 %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 PLoS Genet %D 2012 %T Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function. %A Hancock, Dana B %A Soler Artigas, Maria %A Gharib, Sina A %A Henry, Amanda %A Manichaikul, Ani %A Ramasamy, Adaikalavan %A Loth, Daan W %A Imboden, Medea %A Koch, Beate %A McArdle, Wendy L %A Smith, Albert V %A Smolonska, Joanna %A Sood, Akshay %A Tang, Wenbo %A Wilk, Jemma B %A Zhai, Guangju %A Zhao, Jing Hua %A Aschard, Hugues %A Burkart, Kristin M %A Curjuric, Ivan %A Eijgelsheim, Mark %A Elliott, Paul %A Gu, Xiangjun %A Harris, Tamara B %A Janson, Christer %A Homuth, Georg %A Hysi, Pirro G %A Liu, Jason Z %A Loehr, Laura R %A Lohman, Kurt %A Loos, Ruth J F %A Manning, Alisa K %A Marciante, Kristin D %A Obeidat, Ma'en %A Postma, Dirkje S %A Aldrich, Melinda C %A Brusselle, Guy G %A Chen, Ting-Hsu %A Eiriksdottir, Gudny %A Franceschini, Nora %A Heinrich, Joachim %A Rotter, Jerome I %A Wijmenga, Cisca %A Williams, O Dale %A Bentley, Amy R %A Hofman, Albert %A Laurie, Cathy C %A Lumley, Thomas %A Morrison, Alanna C %A Joubert, Bonnie R %A Rivadeneira, Fernando %A Couper, David J %A Kritchevsky, Stephen B %A Liu, Yongmei %A Wjst, Matthias %A Wain, Louise V %A Vonk, Judith M %A Uitterlinden, André G %A Rochat, Thierry %A Rich, Stephen S %A Psaty, Bruce M %A O'Connor, George T %A North, Kari E %A Mirel, Daniel B %A Meibohm, Bernd %A Launer, Lenore J %A Khaw, Kay-Tee %A Hartikainen, Anna-Liisa %A Hammond, Christopher J %A Gläser, Sven %A Marchini, Jonathan %A Kraft, Peter %A Wareham, Nicholas J %A Völzke, Henry %A Stricker, Bruno H C %A Spector, Timothy D %A Probst-Hensch, Nicole M %A Jarvis, Deborah %A Jarvelin, Marjo-Riitta %A Heckbert, Susan R %A Gudnason, Vilmundur %A Boezen, H Marike %A Barr, R Graham %A Cassano, Patricia A %A Strachan, David P %A Fornage, Myriam %A Hall, Ian P %A Dupuis, Josée %A Tobin, Martin D %A London, Stephanie J %K Forced Expiratory Volume %K Gene Expression %K Genome, Human %K Genome-Wide Association Study %K HLA-DQ Antigens %K HLA-DQ beta-Chains %K Humans %K Lung %K Nerve Tissue Proteins %K Polymorphism, Single Nucleotide %K Potassium Channels, Inwardly Rectifying %K Pulmonary Disease, Chronic Obstructive %K Receptors, Cell Surface %K Smoking %K SOX9 Transcription Factor %K Vital Capacity %X

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects.

%B PLoS Genet %V 8 %P e1003098 %8 2012 %G eng %N 12 %1 http://www.ncbi.nlm.nih.gov/pubmed/23284291?dopt=Abstract %R 10.1371/journal.pgen.1003098