%0 Journal Article %J Circ Cardiovasc Genet %D 2014 %T ADAM19 and HTR4 variants and pulmonary function: Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study. %A London, Stephanie J %A Gao, Wei %A Gharib, Sina A %A Hancock, Dana B %A Wilk, Jemma B %A House, John S %A Gibbs, Richard A %A Muzny, Donna M %A Lumley, Thomas %A Franceschini, Nora %A North, Kari E %A Psaty, Bruce M %A Kovar, Christie L %A Coresh, Josef %A Zhou, Yanhua %A Heckbert, Susan R %A Brody, Jennifer A %A Morrison, Alanna C %A Dupuis, Josée %K ADAM Proteins %K Aged %K Aged, 80 and over %K Aging %K Cohort Studies %K Female %K Genetic Variation %K Genome-Wide Association Study %K Genomics %K Heart Diseases %K Humans %K Lung %K Male %K Middle Aged %K Polymorphism, Single Nucleotide %K Sequence Analysis, DNA %X

BACKGROUND: The pulmonary function measures of forced expiratory volume in 1 second (FEV1) and its ratio to forced vital capacity (FVC) are used in the diagnosis and monitoring of lung diseases and predict cardiovascular mortality in the general population. Genome-wide association studies (GWASs) have identified numerous loci associated with FEV1 and FEV1/FVC, but the causal variants remain uncertain. We hypothesized that novel or rare variants poorly tagged by GWASs may explain the significant associations between FEV1/FVC and 2 genes: ADAM19 and HTR4.

METHODS AND RESULTS: We sequenced ADAM19 and its promoter region along with the ≈21-kb portion of HTR4 harboring GWAS single-nucleotide polymorphisms for pulmonary function and analyzed associations with FEV1/FVC among 3983 participants of European ancestry from Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium. Meta-analysis of common variants in each region identified statistically significant associations (316 tests; P<1.58×10(-4)) with FEV1/FVC for 14 ADAM19 single-nucleotide polymorphisms and 24 HTR4 single-nucleotide polymorphisms. After conditioning on the sentinel GWASs hit in each gene (ADAM19 rs1422795, minor allele frequency=0.33 and HTR4 rs11168048, minor allele frequency=0.40], 1 single-nucleotide polymorphism remained statistically significant (ADAM19 rs13155908, minor allele frequency=0.12; P=1.56×10(-4)). Analysis of rare variants (minor allele frequency <1%) using sequence kernel association test did not identify associations with either region.

CONCLUSIONS: Sequencing identified 1 common variant associated with FEV1/FVC independent of the sentinel ADAM19 GWAS hit and supports the original HTR4 GWAS findings. Rare variants do not seem to underlie GWAS associations with pulmonary function for common variants in ADAM19 and HTR4.

%B Circ Cardiovasc Genet %V 7 %P 350-8 %8 2014 Jun %G eng %N 3 %1 http://www.ncbi.nlm.nih.gov/pubmed/24951661?dopt=Abstract %R 10.1161/CIRCGENETICS.113.000066 %0 Journal Article %J Am J Hum Genet %D 2014 %T Effects of long-term averaging of quantitative blood pressure traits on the detection of genetic associations. %A Ganesh, Santhi K %A Chasman, Daniel I %A Larson, Martin G %A Guo, Xiuqing %A Verwoert, Germain %A Bis, Joshua C %A Gu, Xiangjun %A Smith, Albert V %A Yang, Min-Lee %A Zhang, Yan %A Ehret, Georg %A Rose, Lynda M %A Hwang, Shih-Jen %A Papanicolau, George J %A Sijbrands, Eric J %A Rice, Kenneth %A Eiriksdottir, Gudny %A Pihur, Vasyl %A Ridker, Paul M %A Vasan, Ramachandran S %A Newton-Cheh, Christopher %A Raffel, Leslie J %A Amin, Najaf %A Rotter, Jerome I %A Liu, Kiang %A Launer, Lenore J %A Xu, Ming %A Caulfield, Mark %A Morrison, Alanna C %A Johnson, Andrew D %A Vaidya, Dhananjay %A Dehghan, Abbas %A Li, Guo %A Bouchard, Claude %A Harris, Tamara B %A Zhang, He %A Boerwinkle, Eric %A Siscovick, David S %A Gao, Wei %A Uitterlinden, André G %A Rivadeneira, Fernando %A Hofman, Albert %A Willer, Cristen J %A Franco, Oscar H %A Huo, Yong %A Witteman, Jacqueline C M %A Munroe, Patricia B %A Gudnason, Vilmundur %A Palmas, Walter %A van Duijn, Cornelia %A Fornage, Myriam %A Levy, Daniel %A Psaty, Bruce M %A Chakravarti, Aravinda %K Blood Pressure %K Genome-Wide Association Study %K Humans %K Longitudinal Studies %K Phenotype %K Polymorphism, Single Nucleotide %K Quantitative Trait Loci %X

Blood pressure (BP) is a heritable, quantitative trait with intraindividual variability and susceptibility to measurement error. Genetic studies of BP generally use single-visit measurements and thus cannot remove variability occurring over months or years. We leveraged the idea that averaging BP measured across time would improve phenotypic accuracy and thereby increase statistical power to detect genetic associations. We studied systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP) averaged over multiple years in 46,629 individuals of European ancestry. We identified 39 trait-variant associations across 19 independent loci (p < 5 × 10(-8)); five associations (in four loci) uniquely identified by our LTA analyses included those of SBP and MAP at 2p23 (rs1275988, near KCNK3), DBP at 2q11.2 (rs7599598, in FER1L5), and PP at 6p21 (rs10948071, near CRIP3) and 7p13 (rs2949837, near IGFBP3). Replication analyses conducted in cohorts with single-visit BP data showed positive replication of associations and a nominal association (p < 0.05). We estimated a 20% gain in statistical power with long-term average (LTA) as compared to single-visit BP association studies. Using LTA analysis, we identified genetic loci influencing BP. LTA might be one way of increasing the power of genetic associations for continuous traits in extant samples for other phenotypes that are measured serially over time.

%B Am J Hum Genet %V 95 %P 49-65 %8 2014 Jul 03 %G eng %N 1 %1 http://www.ncbi.nlm.nih.gov/pubmed/24975945?dopt=Abstract %R 10.1016/j.ajhg.2014.06.002 %0 Journal Article %J Nat Genet %D 2014 %T Genome-wide association analysis identifies six new loci associated with forced vital capacity. %A Loth, Daan W %A Soler Artigas, Maria %A Gharib, Sina A %A Wain, Louise V %A Franceschini, Nora %A Koch, Beate %A Pottinger, Tess D %A Smith, Albert Vernon %A Duan, Qing %A Oldmeadow, Chris %A Lee, Mi Kyeong %A Strachan, David P %A James, Alan L %A Huffman, Jennifer E %A Vitart, Veronique %A Ramasamy, Adaikalavan %A Wareham, Nicholas J %A Kaprio, Jaakko %A Wang, Xin-Qun %A Trochet, Holly %A Kähönen, Mika %A Flexeder, Claudia %A Albrecht, Eva %A Lopez, Lorna M %A de Jong, Kim %A Thyagarajan, Bharat %A Alves, Alexessander Couto %A Enroth, Stefan %A Omenaas, Ernst %A Joshi, Peter K %A Fall, Tove %A Viñuela, Ana %A Launer, Lenore J %A Loehr, Laura R %A Fornage, Myriam %A Li, Guo %A Wilk, Jemma B %A Tang, Wenbo %A Manichaikul, Ani %A Lahousse, Lies %A Harris, Tamara B %A North, Kari E %A Rudnicka, Alicja R %A Hui, Jennie %A Gu, Xiangjun %A Lumley, Thomas %A Wright, Alan F %A Hastie, Nicholas D %A Campbell, Susan %A Kumar, Rajesh %A Pin, Isabelle %A Scott, Robert A %A Pietiläinen, Kirsi H %A Surakka, Ida %A Liu, Yongmei %A Holliday, Elizabeth G %A Schulz, Holger %A Heinrich, Joachim %A Davies, Gail %A Vonk, Judith M %A Wojczynski, Mary %A Pouta, Anneli %A Johansson, Asa %A Wild, Sarah H %A Ingelsson, Erik %A Rivadeneira, Fernando %A Völzke, Henry %A Hysi, Pirro G %A Eiriksdottir, Gudny %A Morrison, Alanna C %A Rotter, Jerome I %A Gao, Wei %A Postma, Dirkje S %A White, Wendy B %A Rich, Stephen S %A Hofman, Albert %A Aspelund, Thor %A Couper, David %A Smith, Lewis J %A Psaty, Bruce M %A Lohman, Kurt %A Burchard, Esteban G %A Uitterlinden, André G %A Garcia, Melissa %A Joubert, Bonnie R %A McArdle, Wendy L %A Musk, A Bill %A Hansel, Nadia %A Heckbert, Susan R %A Zgaga, Lina %A van Meurs, Joyce B J %A Navarro, Pau %A Rudan, Igor %A Oh, Yeon-Mok %A Redline, Susan %A Jarvis, Deborah L %A Zhao, Jing Hua %A Rantanen, Taina %A O'Connor, George T %A Ripatti, Samuli %A Scott, Rodney J %A Karrasch, Stefan %A Grallert, Harald %A Gaddis, Nathan C %A Starr, John M %A Wijmenga, Cisca %A Minster, Ryan L %A Lederer, David J %A Pekkanen, Juha %A Gyllensten, Ulf %A Campbell, Harry %A Morris, Andrew P %A Gläser, Sven %A Hammond, Christopher J %A Burkart, Kristin M %A Beilby, John %A Kritchevsky, Stephen B %A Gudnason, Vilmundur %A Hancock, Dana B %A Williams, O Dale %A Polasek, Ozren %A Zemunik, Tatijana %A Kolcic, Ivana %A Petrini, Marcy F %A Wjst, Matthias %A Kim, Woo Jin %A Porteous, David J %A Scotland, Generation %A Smith, Blair H %A Viljanen, Anne %A Heliövaara, Markku %A Attia, John R %A Sayers, Ian %A Hampel, Regina %A Gieger, Christian %A Deary, Ian J %A Boezen, H Marike %A Newman, Anne %A Jarvelin, Marjo-Riitta %A Wilson, James F %A Lind, Lars %A Stricker, Bruno H %A Teumer, Alexander %A Spector, Timothy D %A Melén, Erik %A Peters, Marjolein J %A Lange, Leslie A %A Barr, R Graham %A Bracke, Ken R %A Verhamme, Fien M %A Sung, Joohon %A Hiemstra, Pieter S %A Cassano, Patricia A %A Sood, Akshay %A Hayward, Caroline %A Dupuis, Josée %A Hall, Ian P %A Brusselle, Guy G %A Tobin, Martin D %A London, Stephanie J %K Cohort Studies %K Databases, Genetic %K Follow-Up Studies %K Forced Expiratory Volume %K Genetic Loci %K Genetic Predisposition to Disease %K Genome, Human %K Genome-Wide Association Study %K Humans %K Lung Diseases %K Meta-Analysis as Topic %K Polymorphism, Single Nucleotide %K Prognosis %K Quantitative Trait Loci %K Respiratory Function Tests %K Spirometry %K Vital Capacity %X

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10(-8)) with FVC in or near EFEMP1, BMP6, MIR129-2-HSD17B12, PRDM11, WWOX and KCNJ2. Two loci previously associated with spirometric measures (GSTCD and PTCH1) were related to FVC. Newly implicated regions were followed up in samples from African-American, Korean, Chinese and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and the pathogenesis of restrictive lung disease.

%B Nat Genet %V 46 %P 669-77 %8 2014 Jul %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/24929828?dopt=Abstract %R 10.1038/ng.3011 %0 Journal Article %J PLoS One %D 2014 %T Large-scale genome-wide association studies and meta-analyses of longitudinal change in adult lung function. %A Tang, Wenbo %A Kowgier, Matthew %A Loth, Daan W %A Soler Artigas, Maria %A Joubert, Bonnie R %A Hodge, Emily %A Gharib, Sina A %A Smith, Albert V %A Ruczinski, Ingo %A Gudnason, Vilmundur %A Mathias, Rasika A %A Harris, Tamara B %A Hansel, Nadia N %A Launer, Lenore J %A Barnes, Kathleen C %A Hansen, Joyanna G %A Albrecht, Eva %A Aldrich, Melinda C %A Allerhand, Michael %A Barr, R Graham %A Brusselle, Guy G %A Couper, David J %A Curjuric, Ivan %A Davies, Gail %A Deary, Ian J %A Dupuis, Josée %A Fall, Tove %A Foy, Millennia %A Franceschini, Nora %A Gao, Wei %A Gläser, Sven %A Gu, Xiangjun %A Hancock, Dana B %A Heinrich, Joachim %A Hofman, Albert %A Imboden, Medea %A Ingelsson, Erik %A James, Alan %A Karrasch, Stefan %A Koch, Beate %A Kritchevsky, Stephen B %A Kumar, Ashish %A Lahousse, Lies %A Li, Guo %A Lind, Lars %A Lindgren, Cecilia %A Liu, Yongmei %A Lohman, Kurt %A Lumley, Thomas %A McArdle, Wendy L %A Meibohm, Bernd %A Morris, Andrew P %A Morrison, Alanna C %A Musk, Bill %A North, Kari E %A Palmer, Lyle J %A Probst-Hensch, Nicole M %A Psaty, Bruce M %A Rivadeneira, Fernando %A Rotter, Jerome I %A Schulz, Holger %A Smith, Lewis J %A Sood, Akshay %A Starr, John M %A Strachan, David P %A Teumer, Alexander %A Uitterlinden, André G %A Völzke, Henry %A Voorman, Arend %A Wain, Louise V %A Wells, Martin T %A Wilk, Jemma B %A Williams, O Dale %A Heckbert, Susan R %A Stricker, Bruno H %A London, Stephanie J %A Fornage, Myriam %A Tobin, Martin D %A O'Connor, George T %A Hall, Ian P %A Cassano, Patricia A %K Adult %K Chromosomes, Human, Pair 11 %K Female %K Gene Expression Regulation %K Genetic Loci %K Genome-Wide Association Study %K Humans %K Longitudinal Studies %K Male %K Respiration %X

BACKGROUND: Genome-wide association studies (GWAS) have identified numerous loci influencing cross-sectional lung function, but less is known about genes influencing longitudinal change in lung function.

METHODS: We performed GWAS of the rate of change in forced expiratory volume in the first second (FEV1) in 14 longitudinal, population-based cohort studies comprising 27,249 adults of European ancestry using linear mixed effects model and combined cohort-specific results using fixed effect meta-analysis to identify novel genetic loci associated with longitudinal change in lung function. Gene expression analyses were subsequently performed for identified genetic loci. As a secondary aim, we estimated the mean rate of decline in FEV1 by smoking pattern, irrespective of genotypes, across these 14 studies using meta-analysis.

RESULTS: The overall meta-analysis produced suggestive evidence for association at the novel IL16/STARD5/TMC3 locus on chromosome 15 (P  =  5.71 × 10(-7)). In addition, meta-analysis using the five cohorts with ≥3 FEV1 measurements per participant identified the novel ME3 locus on chromosome 11 (P  =  2.18 × 10(-8)) at genome-wide significance. Neither locus was associated with FEV1 decline in two additional cohort studies. We confirmed gene expression of IL16, STARD5, and ME3 in multiple lung tissues. Publicly available microarray data confirmed differential expression of all three genes in lung samples from COPD patients compared with controls. Irrespective of genotypes, the combined estimate for FEV1 decline was 26.9, 29.2 and 35.7 mL/year in never, former, and persistent smokers, respectively.

CONCLUSIONS: In this large-scale GWAS, we identified two novel genetic loci in association with the rate of change in FEV1 that harbor candidate genes with biologically plausible functional links to lung function.

%B PLoS One %V 9 %P e100776 %8 2014 %G eng %N 7 %1 http://www.ncbi.nlm.nih.gov/pubmed/24983941?dopt=Abstract %R 10.1371/journal.pone.0100776 %0 Journal Article %J Nat Genet %D 2017 %T Exome-wide association study of plasma lipids in >300,000 individuals. %A Liu, Dajiang J %A Peloso, Gina M %A Yu, Haojie %A Butterworth, Adam S %A Wang, Xiao %A Mahajan, Anubha %A Saleheen, Danish %A Emdin, Connor %A Alam, Dewan %A Alves, Alexessander Couto %A Amouyel, Philippe %A Di Angelantonio, Emanuele %A Arveiler, Dominique %A Assimes, Themistocles L %A Auer, Paul L %A Baber, Usman %A Ballantyne, Christie M %A Bang, Lia E %A Benn, Marianne %A Bis, Joshua C %A Boehnke, Michael %A Boerwinkle, Eric %A Bork-Jensen, Jette %A Bottinger, Erwin P %A Brandslund, Ivan %A Brown, Morris %A Busonero, Fabio %A Caulfield, Mark J %A Chambers, John C %A Chasman, Daniel I %A Chen, Y Eugene %A Chen, Yii-Der Ida %A Chowdhury, Rajiv %A Christensen, Cramer %A Chu, Audrey Y %A Connell, John M %A Cucca, Francesco %A Cupples, L Adrienne %A Damrauer, Scott M %A Davies, Gail %A Deary, Ian J %A Dedoussis, George %A Denny, Joshua C %A Dominiczak, Anna %A Dubé, Marie-Pierre %A Ebeling, Tapani %A Eiriksdottir, Gudny %A Esko, Tõnu %A Farmaki, Aliki-Eleni %A Feitosa, Mary F %A Ferrario, Marco %A Ferrieres, Jean %A Ford, Ian %A Fornage, Myriam %A Franks, Paul W %A Frayling, Timothy M %A Frikke-Schmidt, Ruth %A Fritsche, Lars G %A Frossard, Philippe %A Fuster, Valentin %A Ganesh, Santhi K %A Gao, Wei %A Garcia, Melissa E %A Gieger, Christian %A Giulianini, Franco %A Goodarzi, Mark O %A Grallert, Harald %A Grarup, Niels %A Groop, Leif %A Grove, Megan L %A Gudnason, Vilmundur %A Hansen, Torben %A Harris, Tamara B %A Hayward, Caroline %A Hirschhorn, Joel N %A Holmen, Oddgeir L %A Huffman, Jennifer %A Huo, Yong %A Hveem, Kristian %A Jabeen, Sehrish %A Jackson, Anne U %A Jakobsdottir, Johanna %A Jarvelin, Marjo-Riitta %A Jensen, Gorm B %A Jørgensen, Marit E %A Jukema, J Wouter %A Justesen, Johanne M %A Kamstrup, Pia R %A Kanoni, Stavroula %A Karpe, Fredrik %A Kee, Frank %A Khera, Amit V %A Klarin, Derek %A Koistinen, Heikki A %A Kooner, Jaspal S %A Kooperberg, Charles %A Kuulasmaa, Kari %A Kuusisto, Johanna %A Laakso, Markku %A Lakka, Timo %A Langenberg, Claudia %A Langsted, Anne %A Launer, Lenore J %A Lauritzen, Torsten %A Liewald, David C M %A Lin, Li An %A Linneberg, Allan %A Loos, Ruth J F %A Lu, Yingchang %A Lu, Xiangfeng %A Mägi, Reedik %A Mälarstig, Anders %A Manichaikul, Ani %A Manning, Alisa K %A Mäntyselkä, Pekka %A Marouli, Eirini %A Masca, Nicholas G D %A Maschio, Andrea %A Meigs, James B %A Melander, Olle %A Metspalu, Andres %A Morris, Andrew P %A Morrison, Alanna C %A Mulas, Antonella %A Müller-Nurasyid, Martina %A Munroe, Patricia B %A Neville, Matt J %A Nielsen, Jonas B %A Nielsen, Sune F %A Nordestgaard, Børge G %A Ordovas, Jose M %A Mehran, Roxana %A O'Donnell, Christoper J %A Orho-Melander, Marju %A Molony, Cliona M %A Muntendam, Pieter %A Padmanabhan, Sandosh %A Palmer, Colin N A %A Pasko, Dorota %A Patel, Aniruddh P %A Pedersen, Oluf %A Perola, Markus %A Peters, Annette %A Pisinger, Charlotta %A Pistis, Giorgio %A Polasek, Ozren %A Poulter, Neil %A Psaty, Bruce M %A Rader, Daniel J %A Rasheed, Asif %A Rauramaa, Rainer %A Reilly, Dermot F %A Reiner, Alex P %A Renstrom, Frida %A Rich, Stephen S %A Ridker, Paul M %A Rioux, John D %A Robertson, Neil R %A Roden, Dan M %A Rotter, Jerome I %A Rudan, Igor %A Salomaa, Veikko %A Samani, Nilesh J %A Sanna, Serena %A Sattar, Naveed %A Schmidt, Ellen M %A Scott, Robert A %A Sever, Peter %A Sevilla, Raquel S %A Shaffer, Christian M %A Sim, Xueling %A Sivapalaratnam, Suthesh %A Small, Kerrin S %A Smith, Albert V %A Smith, Blair H %A Somayajula, Sangeetha %A Southam, Lorraine %A Spector, Timothy D %A Speliotes, Elizabeth K %A Starr, John M %A Stirrups, Kathleen E %A Stitziel, Nathan %A Strauch, Konstantin %A Stringham, Heather M %A Surendran, Praveen %A Tada, Hayato %A Tall, Alan R %A Tang, Hua %A Tardif, Jean-Claude %A Taylor, Kent D %A Trompet, Stella %A Tsao, Philip S %A Tuomilehto, Jaakko %A Tybjaerg-Hansen, Anne %A van Zuydam, Natalie R %A Varbo, Anette %A Varga, Tibor V %A Virtamo, Jarmo %A Waldenberger, Melanie %A Wang, Nan %A Wareham, Nick J %A Warren, Helen R %A Weeke, Peter E %A Weinstock, Joshua %A Wessel, Jennifer %A Wilson, James G %A Wilson, Peter W F %A Xu, Ming %A Yaghootkar, Hanieh %A Young, Robin %A Zeggini, Eleftheria %A Zhang, He %A Zheng, Neil S %A Zhang, Weihua %A Zhang, Yan %A Zhou, Wei %A Zhou, Yanhua %A Zoledziewska, Magdalena %A Howson, Joanna M M %A Danesh, John %A McCarthy, Mark I %A Cowan, Chad A %A Abecasis, Goncalo %A Deloukas, Panos %A Musunuru, Kiran %A Willer, Cristen J %A Kathiresan, Sekar %K Coronary Artery Disease %K Diabetes Mellitus, Type 2 %K Exome %K Genetic Association Studies %K Genetic Predisposition to Disease %K Genetic Variation %K Genotype %K Humans %K Lipids %K Macular Degeneration %K Phenotype %K Risk Factors %X

We screened variants on an exome-focused genotyping array in >300,000 participants (replication in >280,000 participants) and identified 444 independent variants in 250 loci significantly associated with total cholesterol (TC), high-density-lipoprotein cholesterol (HDL-C), low-density-lipoprotein cholesterol (LDL-C), and/or triglycerides (TG). At two loci (JAK2 and A1CF), experimental analysis in mice showed lipid changes consistent with the human data. We also found that: (i) beta-thalassemia trait carriers displayed lower TC and were protected from coronary artery disease (CAD); (ii) excluding the CETP locus, there was not a predictable relationship between plasma HDL-C and risk for age-related macular degeneration; (iii) only some mechanisms of lowering LDL-C appeared to increase risk for type 2 diabetes (T2D); and (iv) TG-lowering alleles involved in hepatic production of TG-rich lipoproteins (TM6SF2 and PNPLA3) tracked with higher liver fat, higher risk for T2D, and lower risk for CAD, whereas TG-lowering alleles involved in peripheral lipolysis (LPL and ANGPTL4) had no effect on liver fat but decreased risks for both T2D and CAD.

%B Nat Genet %V 49 %P 1758-1766 %8 2017 Dec %G eng %N 12 %R 10.1038/ng.3977 %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 Commun %D 2018 %T Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function. %A Wyss, Annah B %A Sofer, Tamar %A Lee, Mi Kyeong %A Terzikhan, Natalie %A Nguyen, Jennifer N %A Lahousse, Lies %A Latourelle, Jeanne C %A Smith, Albert Vernon %A Bartz, Traci M %A Feitosa, Mary F %A Gao, Wei %A Ahluwalia, Tarunveer S %A Tang, Wenbo %A Oldmeadow, Christopher %A Duan, Qing %A de Jong, Kim %A Wojczynski, Mary K %A Wang, Xin-Qun %A Noordam, Raymond %A Hartwig, Fernando Pires %A Jackson, Victoria E %A Wang, Tianyuan %A Obeidat, Ma'en %A Hobbs, Brian D %A Huan, Tianxiao %A Gui, Hongsheng %A Parker, Margaret M %A Hu, Donglei %A Mogil, Lauren S %A Kichaev, Gleb %A Jin, Jianping %A Graff, Mariaelisa %A Harris, Tamara B %A Kalhan, Ravi %A Heckbert, Susan R %A Paternoster, Lavinia %A Burkart, Kristin M %A Liu, Yongmei %A Holliday, Elizabeth G %A Wilson, James G %A Vonk, Judith M %A Sanders, Jason L %A Barr, R Graham %A de Mutsert, Renée %A Menezes, Ana Maria Baptista %A Adams, Hieab H H %A van den Berge, Maarten %A Joehanes, Roby %A Levin, Albert M %A Liberto, Jennifer %A Launer, Lenore J %A Morrison, Alanna C %A Sitlani, Colleen M %A Celedón, Juan C %A Kritchevsky, Stephen B %A Scott, Rodney J %A Christensen, Kaare %A Rotter, Jerome I %A Bonten, Tobias N %A Wehrmeister, Fernando César %A Bossé, Yohan %A Xiao, Shujie %A Oh, Sam %A Franceschini, Nora %A Brody, Jennifer A %A Kaplan, Robert C %A Lohman, Kurt %A McEvoy, Mark %A Province, Michael A %A Rosendaal, Frits R %A Taylor, Kent D %A Nickle, David C %A Williams, L Keoki %A Burchard, Esteban G %A Wheeler, Heather E %A Sin, Don D %A Gudnason, Vilmundur %A North, Kari E %A Fornage, Myriam %A Psaty, Bruce M %A Myers, Richard H %A O'Connor, George %A Hansen, Torben %A Laurie, Cathy C %A Cassano, Patricia A %A Sung, Joohon %A Kim, Woo Jin %A Attia, John R %A Lange, Leslie %A Boezen, H Marike %A Thyagarajan, Bharat %A Rich, Stephen S %A Mook-Kanamori, Dennis O %A Horta, Bernardo Lessa %A Uitterlinden, André G %A Im, Hae Kyung %A Cho, Michael H %A Brusselle, Guy G %A Gharib, Sina A %A Dupuis, Josée %A Manichaikul, Ani %A London, Stephanie J %X

Nearly 100 loci have been identified for pulmonary function, almost exclusively in studies of European ancestry populations. We extend previous research by meta-analyzing genome-wide association studies of 1000 Genomes imputed variants in relation to pulmonary function in a multiethnic population of 90,715 individuals of European (N = 60,552), African (N = 8429), Asian (N = 9959), and Hispanic/Latino (N = 11,775) ethnicities. We identify over 50 additional loci at genome-wide significance in ancestry-specific or multiethnic meta-analyses. Using recent fine-mapping methods incorporating functional annotation, gene expression, and differences in linkage disequilibrium between ethnicities, we further shed light on potential causal variants and genes at known and newly identified loci. Several of the novel genes encode proteins with predicted or established drug targets, including KCNK2 and CDK12. Our study highlights the utility of multiethnic and integrative genomics approaches to extend existing knowledge of the genetics of lung function and clinical relevance of implicated loci.

%B Nat Commun %V 9 %P 2976 %8 2018 Jul 30 %G eng %N 1 %R 10.1038/s41467-018-05369-0