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1. Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression

Author: Van Der Plaat, D.A. (Diana A), Vonk, J.M. (Judith), Terzikhan, N. (Natalie), Jong, K. (Kim) de, De Vries, M. (Maaike), La Bastide-van Gemert, S. (Sacha), Van Diemen, C.C. (Cleo C), Lahousse, L. (Lies), Brusselle, G.G. (Guy), Prokić, I. (Ivana), Amin, N. (Najaf), Kromhout, H. (Hans), Vermeulen, R. (Roel), Postma, D.S. (Dirkje S), Duijn, C.M. (Cornelia) van, Boezen, H.M. (Marike), Van Der Plaat, D.A. (Diana A), Vonk, J.M. (Judith), Terzikhan, N. (Natalie), Jong, K. (Kim) de, De Vries, M. (Maaike), La Bastide-van Gemert, S. (Sacha), Van Diemen, C.C. (Cleo C), Lahousse, L. (Lies), Brusselle, G.G. (Guy), Prokić, I. (Ivana), Amin, N. (Najaf), Kromhout, H. (Hans), Vermeulen, R. (Roel), Postma, D.S. (Dirkje S), Duijn, C.M. (Cornelia) van, and Boezen, H.M. (Marike)
Abstract: Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were associated with gases/fumes and 7 with mineral dust. Three of these DMRs were associated with both exposures (RPLP1 and LINC02169 (2×)) and 11 DMRs were located within transcript start sites of gene expression regulating genes. We replicated two DMRs with gases/fumes (VTRNA2-1 and GNAS) and one with mineral dust (CCDC144NL). In addition, nine gases/fumes DMRs and six mineral
Published: 2019
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2. Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression

Author: van Der Plaat, D., Vonk, J.M. (Judith), Terzikhan, N. (Natalie), de Jong, K., Boersma - de Vries, M., la Bastide-van Gemert, S, Boezen, H.M. (Marike), van Der Plaat, D., Vonk, J.M. (Judith), Terzikhan, N. (Natalie), de Jong, K., Boersma - de Vries, M., la Bastide-van Gemert, S, and Boezen, H.M. (Marike)
Abstract: Many workers are daily exposed to occupational agents like gases/fumes, mineral dust or biological dust, which could induce adverse health effects. Epigenetic mechanisms, such as DNA methylation, have been suggested to play a role. We therefore aimed to identify differentially methylated regions (DMRs) upon occupational exposures in never-smokers and investigated if these DMRs associated with gene expression levels. To determine the effects of occupational exposures independent of smoking, 903 never-smokers of the LifeLines cohort study were included. We performed three genome-wide methylation analyses (Illumina 450 K), one per occupational exposure being gases/fumes, mineral dust and biological dust, using robust linear regression adjusted for appropriate confounders. DMRs were identified using comb-p in Python. Results were validated in the Rotterdam Study (233 never-smokers) and methylation-expression associations were assessed using Biobank-based Integrative Omics Study data (n = 2802). Of the total 21 significant DMRs, 14 DMRs were a
Published: 2019
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3. DNA methylation is associated with lung function in never smokers

Author: de Vries, M. (Maaike), Prokić, I. (Ivana), van der Plaat, D.A. (Diana A.), Zhernakova, A. (Alexandra), Lahousse, L. (Lies), Brusselle, G.G. (Guy), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Vonk, J.M. (Judith), Boezen, H.M. (Marike), de Vries, M. (Maaike), Prokić, I. (Ivana), van der Plaat, D.A. (Diana A.), Zhernakova, A. (Alexandra), Lahousse, L. (Lies), Brusselle, G.G. (Guy), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Vonk, J.M. (Judith), and Boezen, H.M. (Marike)
Abstract: BACKGROUND: Active smoking is the main risk factor for COPD. Here, epigenetic mechanisms may play a role, since cigarette smoking is associated with differential DNA methylation in whole blood. So far, it is unclear whether epigenetics also play a role in subjects with COPD who never smoked. Therefore, we aimed to identify differential DNA methylation associated with lung function in never smokers. METHODS: We determined epigenome-wide DNA methylation levels of 396,243 CpG-sites (Illumina 450 K) in blood of never smokers in four independent cohorts, LifeLines COPD&C (N = 903), LifeLines DEEP (N = 166), Rotterdam Study (RS)-III (N = 150) and RS-BIOS (N = 206). We meta-analyzed the cohort-specific methylation results t
Published: 2019
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4. Limited overlap in significant hits between genome-wide association studies on two airflow obstruction definitions in the same population

Author: Plaat, D.A.D., Vonk, J.M. (Judith), Lahousse, L. (Lies), de Jong, K., Faiz, A., Nedeljkovic, I., Amin, N. (Najaf), Diemen, C.C. (Cleo) van, Brusselle, G.G. (Guy), Bossé, Y. (Yohan), Brandsma, CA, Hao, K. (Ke), Pare, P.D., Duijn, C.M., Postma, D.S. (Dirkje), Boezen, H.M. (Marike), Plaat, D.A.D., Vonk, J.M. (Judith), Lahousse, L. (Lies), de Jong, K., Faiz, A., Nedeljkovic, I., Amin, N. (Najaf), Diemen, C.C. (Cleo) van, Brusselle, G.G. (Guy), Bossé, Y. (Yohan), Brandsma, CA, Hao, K. (Ke), Pare, P.D., Duijn, C.M., Postma, D.S. (Dirkje), and Boezen, H.M. (Marike)
Abstract: Background: Airflow obstruction is a hallmark of chronic obstructive pulmonary disease (COPD), and is defined as either the ratio between forced expiratory volume in one second and forced vital capacity (FEV1/FVC) < 70% or < lower limit of normal (LLN). This study aimed to assess the overlap between genome-wide association studies (GWAS) on airflow obstruction using these two definitions in the same population stratified by smoking. Methods: GWASes were performed in the LifeLines Cohort Study for both airflow obstruction definitions in never-smokers (NS = 5071) and ever-smokers (ES = 4855). The FEV1/FVC < 70% models were adjusted for sex, age, and height; FEV1/FVC < LLN models were not adjusted. Ever-smokers models were additionally adjusted for pack-years and current-smoking. The overlap in significantly associated SNPs between the two definitions and never/ever-smokers was assessed using several p-value thresholds. To quantify the agreement, the Pearson correlation coefficient was calculated between the p-values and ORs. Replication was performed in the Vlagtwedde-Vlaardingen study (NS = 432, ES = 823). The overlapping SNPs with p < 10− 4 were validated in the Vlagtwedde-Vlaardingen and Rotterdam Study cohorts (NS = 1966, ES = 3134) and analysed for expression quantitative trait loci (eQTL) in lung tissue (n = 1087). Results: In the LifeLines cohort, 96% and 93% of the never- and ever-smokers were classified concordantly based on the two definitions. 26 and 29% of the investigated SNPs were overlapping at p < 0.05 in never- and eversmokers, respectively. At p < 10− 4 the overlap was 4% and 6% respectively, which could be change findings as shown by simulation studies. The effect estimates of the SNPs of the two definitions correlated strongly, but the p-values showed more variation and correlated only moderately. Similar observations were made in the Vlagtwedde-Vlaardingen study. Two overlapping SNPs in never-smokers (NFYC and FABP7) had the same direction of effe
Published: 2019
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5. Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

Author: Kilpeläinen, T.O. (Tuomas), Bentley, A.R. (Amy), Noordam, R., Sung, YJ, Schwander, K., Winkler, T.W. (Thomas), Jakupovic, H., Chasman, D.I. (Daniel), Manning, A., Ntalla, I. (Ioanna), Aschard, H. (Hugues), Brown, M.R., de Las Fuentes, L., Franceschini, N. (Nora), Guo, X. (Xiuqing), Vojinovic, D., Aslibekyan, S, Feitosa, M.F. (Mary Furlan), Kho, M., Musani, SK, Richard, M., Wang, H.M., Wang, Z. (Zhen), Bartz, TM, Bielak, L.F. (Lawrence F.), Campbell, A. (Archie), Dorajoo, R. (Rajkumar), Fisher, V., Hartwig, F.P., Horimoto, A., Li, C.W., Lohman, K. (Kurt), Marten, J, Sim, XL, Smith, A.V. (Davey), Tajuddin, S. M., Alver, M, Amini, M., Boissel, M., Chai, J.F., Chen, X. (Xishu), Divers, J, Evangelou, E. (Evangelos), Gao, C. (Cheng), Graff, M.J. (Maud J.L.), Harris, S.E. (Sarah), He, M. (Meian), Hsu, F.-C. (Fang-Chi), Jackson, A.U. (Anne), Zhao, J.H. (Jing Hua), Kraja, A. (Aldi), Kuhnel, B. (Brigitte), Laguzzi, F., Lyytikäinen, L.-P. (Leo-Pekka), Nolte, IM, Rauramaa, R. (Rainer), Riaz, M. (Muhammad), Robino, A. (Antonietta), Rueedi, R, Stringham, H.M. (Heather), Takeuchi, F, Most, P.J. (Peter) van der, Varga, T.V. (Tibor), Verweij, N. (Niek), Ware, EB, Wen, WQ, Li, X. Y., Yanek, L.R. (Lisa), Amin, N. (Najaf), Arnett, D.K. (Donna), Boerwinkle, E.A. (Eric), Brumat, M., Cade, B, Canouil, M., Chen, Y.D.I. (Yii-Der Ida), Concas, MP, Connell, J. (John), Mutsert, R. (Reneé) de, de Silva, H.J., de Vries, PS, Demirkan, A. (Ayşe), Ding, J. (Jingzhong), Eaton, CB, Faul, J.D. (Jessica), Friedlander, Y. (Yechiel), Gabriel, K.P., Ghanbari, M., Giulianini, F. (Franco), Gu, C.C., Gu, DF, Harris, T.B. (Tamara), He, J. (Jing), Heikkinen, S., Heng, C.K. (Chew-Kiat), Hunt, S.C. (Steven), Ikram, M.A. (Arfan), Jonas, J.B., Koh, WP, Komulainen, P. (Pirjo), Krieger, J.E. (José), Kritchevsky, S.B. (Stephen), Kutalik, Z. (Zoltán), Kuusisto, J. (Johanna), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Launer, LJ, Leander, K. (Karin), Lemaitre, R.N. (Rozenn ), Lewis, CE, Liang, J.J., Alizadeh, BZ, Boezen, H.M. (Marike), Franke, L. (Lude), Navis, G. (Gerjan), Rots, M., Swertz, M. (Morris), Wolffenbuttel, B.H.R. (Bruce), Wijmenga, C. (Cisca), Liu, J. (Jianjun), Maagi, R., Manichaikul, A. (Ani), Meitinger, T. (Thomas), Metspalu, A. (Andres), Milaneschi, Y. (Yuri), Mohlke, K.L. (Karen), Mosley, T.H. (Thomas), Murray, A.D., Nalls, M.A. (Michael), Nang, EEK, Nelson, C.P. (Christopher), Nona, S., Norris, JM, Nwuba, C.V., O´Connell, J.R., Palmer, N.D. (Nicholette), Papanicolau, GJ, Pazoki, R. (Raha), Pedersen, N.L. (Nancy), Peters, A. (Annette), Peyser, P.A. (Patricia A.), Polasek, O. (Ozren), Porteous, D.J. (David J.), Poveda, A. (Andrés), Raitakari, OT, Rich, S.S. (Stephen), Risch, N., Robinson, JG, Rose, L.M. (Lynda), Rudan, I. (Igor), Schreiner, PJ, Scott, L.J. (Laura), Sidney, SS, Sims, M, Smith, J.A. (Jennifer A), Snieder, H. (Harold), Sofer, T., Starr, J.M. (John), Sternfeld, B., Strauch, K. (Konstantin), Tang, H. (Hui), Taylor, K.D. (Kent), Tsai, M.Y. (Michael), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), van der Ende, M.Y., Heemst, D. van, Voortman, R.G. (Trudy), Waldenberger, M. (Melanie), Wennberg, P. (Patrik), Wilson, G, Xiang, YB, Yao, J, Yu, C.Z., Yuan, JM, Zhao, W. (Wei), Zonderman, A.B. (Alan), Becker, D.M. (Diane), Boehnke, M. (Michael), Bowden, DW, Faire, U. (Ulf) de, Deary, I.J. (Ian), Elliott, P.M. (Perry), Esko, T. (Tõnu), Freedman, B.I. (Barry), Froguel, P. (Philippe), Gasparini, P. (Paolo), Gieger, C. (Christian), Kato, N, Laakso, M. (Markku), Lakka, T.A. (Timo), Lehtimaki, T, Magnusson, P.K. (Patrik), Oldenhinkel, A.J. (A.), Penninx, B.W.J.H. (Brenda), Samani, N.J. (Nilesh), Shu, X.-O. (Xiao-Ou), Harst, P. (Pim) van der, Vliet-Ostaptchouk, J.V. (Jana) van, Vollenweider, P. (Peter), Wagenknecht, L.E. (Lynne), Wang, Y. (Ying), Wareham, N.J. (Nick), Weir, D.R. (David), Wu, TC, Zheng, W. (Wei), Zhu, X. (Xiaofeng), Evans, MK, Franks, P.W. (Paul), Guonason, V. (Vilmundur), Hayward, C. (Caroline), Horta, BL, Kelly, TN, Liu, Y. (YongMei), North, K.E. (Kari), Pereira, AC, Ridker, P.M. (Paul), Tai, E.S. (Shyong), Dam, R.M. (Rob) van, Fox, E.R. (Ervin), Kardia, S.L.R. (Sharon), Liu, C.-T. (Ching-Ti), Mook-Kanamori, D.O. (Dennis), Province, M.A. (Mike), Redline, S. (Susan), Duijn, C.M., Rotter, J.I. (Jerome), Kooperberg, C.B., Gauderman, W.J. (W James), Psaty, B.M. (Bruce), Rice, K, Munroe, P. (Patricia), Fornage, M. (Myriam), Cupples, L.A. (Adrienne), Rotimi, CN, Morrison, A.C. (Alanna), Rao, D.C. (Dabeeru C.), Loos, R.J.F. (Ruth), Kilpeläinen, T.O. (Tuomas), Bentley, A.R. (Amy), Noordam, R., Sung, YJ, Schwander, K., Winkler, T.W. (Thomas), Jakupovic, H., Chasman, D.I. (Daniel), Manning, A., Ntalla, I. (Ioanna), Aschard, H. (Hugues), Brown, M.R., de Las Fuentes, L., Franceschini, N. (Nora), Guo, X. (Xiuqing), Vojinovic, D., Aslibekyan, S, Feitosa, M.F. (Mary Furlan), Kho, M., Musani, SK, Richard, M., Wang, H.M., Wang, Z. (Zhen), Bartz, TM, Bielak, L.F. (Lawrence F.), Campbell, A. (Archie), Dorajoo, R. (Rajkumar), Fisher, V., Hartwig, F.P., Horimoto, A., Li, C.W., Lohman, K. (Kurt), Marten, J, Sim, XL, Smith, A.V. (Davey), Tajuddin, S. M., Alver, M, Amini, M., Boissel, M., Chai, J.F., Chen, X. (Xishu), Divers, J, Evangelou, E. (Evangelos), Gao, C. (Cheng), Graff, M.J. (Maud J.L.), Harris, S.E. (Sarah), He, M. (Meian), Hsu, F.-C. (Fang-Chi), Jackson, A.U. (Anne), Zhao, J.H. (Jing Hua), Kraja, A. (Aldi), Kuhnel, B. (Brigitte), Laguzzi, F., Lyytikäinen, L.-P. (Leo-Pekka), Nolte, IM, Rauramaa, R. (Rainer), Riaz, M. (Muhammad), Robino, A. (Antonietta), Rueedi, R, Stringham, H.M. (Heather), Takeuchi, F, Most, P.J. (Peter) van der, Varga, T.V. (Tibor), Verweij, N. (Niek), Ware, EB, Wen, WQ, Li, X. Y., Yanek, L.R. (Lisa), Amin, N. (Najaf), Arnett, D.K. (Donna), Boerwinkle, E.A. (Eric), Brumat, M., Cade, B, Canouil, M., Chen, Y.D.I. (Yii-Der Ida), Concas, MP, Connell, J. (John), Mutsert, R. (Reneé) de, de Silva, H.J., de Vries, PS, Demirkan, A. (Ayşe), Ding, J. (Jingzhong), Eaton, CB, Faul, J.D. (Jessica), Friedlander, Y. (Yechiel), Gabriel, K.P., Ghanbari, M., Giulianini, F. (Franco), Gu, C.C., Gu, DF, Harris, T.B. (Tamara), He, J. (Jing), Heikkinen, S., Heng, C.K. (Chew-Kiat), Hunt, S.C. (Steven), Ikram, M.A. (Arfan), Jonas, J.B., Koh, WP, Komulainen, P. (Pirjo), Krieger, J.E. (José), Kritchevsky, S.B. (Stephen), Kutalik, Z. (Zoltán), Kuusisto, J. (Johanna), Langefeld, C.D. (Carl), Langenberg, C. (Claudia), Launer, LJ, Leander, K. (Karin), Lemaitre, R.N. (Rozenn ), Lewis, CE, Liang, J.J., Alizadeh, BZ, Boezen, H.M. (Marike), Franke, L. (Lude), Navis, G. (Gerjan), Rots, M., Swertz, M. (Morris), Wolffenbuttel, B.H.R. (Bruce), Wijmenga, C. (Cisca), Liu, J. (Jianjun), Maagi, R., Manichaikul, A. (Ani), Meitinger, T. (Thomas), Metspalu, A. (Andres), Milaneschi, Y. (Yuri), Mohlke, K.L. (Karen), Mosley, T.H. (Thomas), Murray, A.D., Nalls, M.A. (Michael), Nang, EEK, Nelson, C.P. (Christopher), Nona, S., Norris, JM, Nwuba, C.V., O´Connell, J.R., Palmer, N.D. (Nicholette), Papanicolau, GJ, Pazoki, R. (Raha), Pedersen, N.L. (Nancy), Peters, A. (Annette), Peyser, P.A. (Patricia A.), Polasek, O. (Ozren), Porteous, D.J. (David J.), Poveda, A. (Andrés), Raitakari, OT, Rich, S.S. (Stephen), Risch, N., Robinson, JG, Rose, L.M. (Lynda), Rudan, I. (Igor), Schreiner, PJ, Scott, L.J. (Laura), Sidney, SS, Sims, M, Smith, J.A. (Jennifer A), Snieder, H. (Harold), Sofer, T., Starr, J.M. (John), Sternfeld, B., Strauch, K. (Konstantin), Tang, H. (Hui), Taylor, K.D. (Kent), Tsai, M.Y. (Michael), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), van der Ende, M.Y., Heemst, D. van, Voortman, R.G. (Trudy), Waldenberger, M. (Melanie), Wennberg, P. (Patrik), Wilson, G, Xiang, YB, Yao, J, Yu, C.Z., Yuan, JM, Zhao, W. (Wei), Zonderman, A.B. (Alan), Becker, D.M. (Diane), Boehnke, M. (Michael), Bowden, DW, Faire, U. (Ulf) de, Deary, I.J. (Ian), Elliott, P.M. (Perry), Esko, T. (Tõnu), Freedman, B.I. (Barry), Froguel, P. (Philippe), Gasparini, P. (Paolo), Gieger, C. (Christian), Kato, N, Laakso, M. (Markku), Lakka, T.A. (Timo), Lehtimaki, T, Magnusson, P.K. (Patrik), Oldenhinkel, A.J. (A.), Penninx, B.W.J.H. (Brenda), Samani, N.J. (Nilesh), Shu, X.-O. (Xiao-Ou), Harst, P. (Pim) van der, Vliet-Ostaptchouk, J.V. (Jana) van, Vollenweider, P. (Peter), Wagenknecht, L.E. (Lynne), Wang, Y. (Ying), Wareham, N.J. (Nick), Weir, D.R. (David), Wu, TC, Zheng, W. (Wei), Zhu, X. (Xiaofeng), Evans, MK, Franks, P.W. (Paul), Guonason, V. (Vilmundur), Hayward, C. (Caroline), Horta, BL, Kelly, TN, Liu, Y. (YongMei), North, K.E. (Kari), Pereira, AC, Ridker, P.M. (Paul), Tai, E.S. (Shyong), Dam, R.M. (Rob) van, Fox, E.R. (Ervin), Kardia, S.L.R. (Sharon), Liu, C.-T. (Ching-Ti), Mook-Kanamori, D.O. (Dennis), Province, M.A. (Mike), Redline, S. (Susan), Duijn, C.M., Rotter, J.I. (Jerome), Kooperberg, C.B., Gauderman, W.J. (W James), Psaty, B.M. (Bruce), Rice, K, Munroe, P. (Patricia), Fornage, M. (Myriam), Cupples, L.A. (Adrienne), Rotimi, CN, Morrison, A.C. (Alanna), Rao, D.C. (Dabeeru C.), and Loos, R.J.F. (Ruth)
Abstract: Many genetic loci affect circulating lipid levels, but it remains unknown whether lifestyle factors, such as physical activity, modify these genetic effects. To identify lipid loci interacting with physical activity, we performed genome-wide analyses of circulating HDL cholesterol, LDL cholesterol, and triglyceride levels in up to 120,979 individuals of European, African, Asian, Hispanic, and Brazilian ancestry, with follow-up of suggestive associations in an additional 131,012 individuals. We find four loci, in/near CLASP1, LHX1, SNTA1, and CNTNAP2, that are associated with circulating lipid levels through interaction with physical activity; higher levels of physical activity enhance the HDL cholesterol-increasing effects of the CLASP1, LHX1, and SNTA1 loci and attenuate the LDL cholesterol-increasing effect of the CNTNAP2 l
Published: 2019
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6. Occupational exposure to pesticides is associated with differential DNA methylation

Author: Plaat, D.A. (Diana) van der, Jong, K. (Kim) de, Vries, M. (Maaike) de, Diemen, C.C. (Cleo) van, Prokić, I. (Ivana), Amin, N. (Najaf), Kromhout, H. (Hans), Vermeulen, R. (Roel), Postma, D.S. (Dirkje), Duijn, C.M. (Cornelia) van, Boezen, H.M. (Marike), Vonk, J.M. (Judith), Plaat, D.A. (Diana) van der, Jong, K. (Kim) de, Vries, M. (Maaike) de, Diemen, C.C. (Cleo) van, Prokić, I. (Ivana), Amin, N. (Najaf), Kromhout, H. (Hans), Vermeulen, R. (Roel), Postma, D.S. (Dirkje), Duijn, C.M. (Cornelia) van, Boezen, H.M. (Marike), and Vonk, J.M. (Judith)
Abstract: Objectives Occupational pesticide exposure is associated with a wide range of diseases, including lung diseases, but it is largely unknown how pesticides influence airway disease pathogenesis. A potential mechanism might be through epigenetic mechanisms, like DNA methylation. Therefore, we assessed associations between occupational exposure to pesticides and genome-wide DNA methylation sites. Methods 1561 subjects of LifeLines were included with either no (n=1392), low (n=108) or high (n=61) exposure to any type of pesticides (estimated based on current or last held job). Blood DNA methylation levels were measured using Illumina 450K arrays. Associations between pesticide exposure and 420 938 methylation sites (CpGs) were assessed using robust linear regression adjusted for appropriate confounders. In addition, we performed genome-wide stratified and interaction analyses by gender, smoking and airway obstruction status, and assessed associations between gene expression and methylation for genome-wide significant CpGs (n=2802). Results In total for all analyses, high p
Published: 2018
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7. From blood to lung tissue: Effect of cigarette smoke on DNA methylation and lung function 06 Biological Sciences 0604 Genetics 11 Medical and Health Sciences 1102 Cardiorespiratory Medicine and Haematology

Author: De Vries, M. (Maaike), Van Der Plaat, D.A. (Diana A), Prokić, I. (Ivana), Verkaik-Schakel, R.N. (Rikst Nynke), Kooistra, W. (Wierd), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Brandsma, C.-A. (Corry-Anke), Diemen, C.C. (Cleo) van, Vonk, J.M. (Judith), Boezen, H.M. (Marike), De Vries, M. (Maaike), Van Der Plaat, D.A. (Diana A), Prokić, I. (Ivana), Verkaik-Schakel, R.N. (Rikst Nynke), Kooistra, W. (Wierd), Amin, N. (Najaf), Duijn, C.M. (Cornelia) van, Brandsma, C.-A. (Corry-Anke), Diemen, C.C. (Cleo) van, Vonk, J.M. (Judith), and Boezen, H.M. (Marike)
Abstract: Background: Genetic and environmental factors play a role in the development of COPD. The epigenome, and more specifically DNA methylation, is recognized as important link between these factors. We postulate that DNA methylation is one of the routes by which cigarette smoke influences the development of COPD. In this study, we aim to identify CpG-sites that are associated with cigarette smoke exposure and lung function levels in whole blood and validate these CpG-sites in lung tissue. Methods: The association between pack years and DNA methylation was studied genome-wide in 658 current smokers with >5 pack years using robust linear regression analysis. Using mediation analysis, we subsequently selected the CpG-sites that were also associated with lung function levels. Significant CpG-sites were validated in lung tissue with pyrosequencing and expression quantitative trait methylation (eQTM) analysis was performed to investigate the association between DNA methylation and gene expression. Results: 15 CpG-sites were significantly associated with pack years and 10 of these were additionally associated with lung function levels. We validated 5 CpG-sites in lung tissue and found several associations between DNA methylation and gene expression. Conclusion: This study is the first to validate a panel of CpG-sites that are associated with cigarette smoking and lung function levels in whole blood in the tissue of interest: lung tissue.
Published: 2018
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8. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

Author: Teumer, A. (Alexander), Chaker, L. (Layal), Groeneweg, S. (Stefan), Li, Y. (Yong), Di Munno, C. (Celia), Barbieri, C. (Caterina), Schultheiss, U.T. (Ulla T.), Traglia, M. (Michela), Ahluwalia, T.S. (Tarunveer Singh), Akiyama, M. (Masato), Appel, E.V.R. (Emil Vincent R.), Arking, D.E. (Dan), Arnold, A.M. (Alice), Astrup, A. (Arne), Beekman, M. (Marian), Beilby, J.P. (John), Bekaert, S. (Sofie), Boerwinkle, E. (Eric), Brown, S.J. (Stephen), Buyzere, M. (Marc) de, Campbell, P.J. (Purdey J.), Ceresini, G. (Graziano), Cerqueira, C. (Charlotte), Cucca, F. (Francesco), Deary, I.J. (Ian), Deelen, J. (Joris), Eckardt, K.-U. (Kai-Uwe), Ekici, A.B. (Arif B.), Hagen, K. (Knut), Ferrrucci, L. (Luigi), Fiers, T. (Tom), Fiorillo, E. (Edoardo), Ford, I. (Ian), Fox, C.S. (Caroline), Fuchsberger, C. (Christian), Galesloot, T.E. (Tessel), Gieger, C. (Christian), Gögele, M. (Martin), Grandi, A. (Alessandro) de, Grarup, N. (Niels), Greiser, K.H. (Karin Halina), Haljas, K. (Kadri), Hansen, T. (Torben), Harris, S.E. (Sarah), Heemst, D. (Diana) van, Heijer, M. (Martin) den, Hicks, A.A. (Andrew A.), Hollander, W. (Wouter) den, Homuth, G. (Georg), Hui, J. (Jennie), Ikram, M.A. (Arfan), Ittermann, T. (Till), Jensen, R.A. (Richard A.), Jing, J. (Jiaojiao), Jukema, J.W. (Jan Wouter), Kajantie, E. (Eero), Kamatani, Y. (Yoichiro), Kasbohm, E. (Elisa), Kaufman, J.-M. (Jean-Marc), Kiemeney, L.A. (Lambertus A.), Kloppenburg, M. (Margreet), Kronenberg, F. (Florian), Kubo, M. (Michiaki), Lahti, J. (Jari), Lapauw, B. (Bruno), Li, S. (Shuo), Liewald, D.C.M. (David C. M.), Alizadeh, B.Z. (Behrooz), Boezen, H.M. (Marike), Franke, L. (Lude), van der Harst, P. (Pim), Navis, G. (Gerjan), Rots, M.G. (M.), Snieder, H. (Harold), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Lim, E.M. (Ee Mun), Linneberg, A. (Allan), Marina, M. (Michela), Mascalzoni, D. (Deborah), Matsuda, K. (Koichi), Medenwald, D. (Daniel), Meisinger, C. (Christa), Meulenbelt, I. (Ingrid), Meyer, T. (Thorsten), Meyer zu Schwabedissen, H.E. (Henriette E.), Mikolajczyk, R. (Rafael), Moed, H. (Heleen), Netea-Maier, R.T. (Romana), Nolte, I.M. (Ilja), Okada, Y. (Yukinori), Pala, M. (Mauro), Penninx, B.W.J.H., Pedersen, O. (Oluf), Petersmann, A. (Astrid), Porcu, E. (Eleonora), Postmus, D. (Douwe), Pramstaller, P.P. (Peter Paul), Psaty, B.M. (Bruce), Ramos, Y.F.M. (Yolande F. M.), Rawal, R. (Rajesh), Redmond, P. (Paul), Richards, J.B. (Brent), Rietzschel, E.R. (Ernst), Rivadeneira Ramirez, F. (Fernando), Roef, G.L. (Greet), Rotter, J.I. (Jerome I.), Sala, C. (Cinzia), Schlessinger, D. (David), Selvin, E. (Elizabeth), Slagboom, P.E. (Eline), Soranzo, N. (Nicole), Sørensen, T.I.A. (Thorkild), Spector, T.D. (Timothy), Starr, J.M. (John), Stott, D.J. (David. J.), Taes, Y.E. (Youri), Taliun, D. (Daniel), Tanaka, T. (Toshiko), Thuesen, L. (Leif), Tiller, D. (Daniel), Toniolo, D. (Daniela), Uitterlinden, A.G. (Andre G.), Visser, W.E. (Edward), Walsh, J.P. (John P.), Wilson, S.G. (Scott), Wolffenbuttel, B.H.R. (Bruce), Yang, Q. (Qiong Fang), Zheng, H.-F. (Hou-Feng), Cappola, A.R. (Anne), Peeters, R.P. (Robin), Naitza, S. (Silvia), Völzke, H. (Henry), Sanna, S. (Serena), Köttgen, A. (Anna), Visser, T.J. (Theo), Medici, M. (Marco), Teumer, A. (Alexander), Chaker, L. (Layal), Groeneweg, S. (Stefan), Li, Y. (Yong), Di Munno, C. (Celia), Barbieri, C. (Caterina), Schultheiss, U.T. (Ulla T.), Traglia, M. (Michela), Ahluwalia, T.S. (Tarunveer Singh), Akiyama, M. (Masato), Appel, E.V.R. (Emil Vincent R.), Arking, D.E. (Dan), Arnold, A.M. (Alice), Astrup, A. (Arne), Beekman, M. (Marian), Beilby, J.P. (John), Bekaert, S. (Sofie), Boerwinkle, E. (Eric), Brown, S.J. (Stephen), Buyzere, M. (Marc) de, Campbell, P.J. (Purdey J.), Ceresini, G. (Graziano), Cerqueira, C. (Charlotte), Cucca, F. (Francesco), Deary, I.J. (Ian), Deelen, J. (Joris), Eckardt, K.-U. (Kai-Uwe), Ekici, A.B. (Arif B.), Hagen, K. (Knut), Ferrrucci, L. (Luigi), Fiers, T. (Tom), Fiorillo, E. (Edoardo), Ford, I. (Ian), Fox, C.S. (Caroline), Fuchsberger, C. (Christian), Galesloot, T.E. (Tessel), Gieger, C. (Christian), Gögele, M. (Martin), Grandi, A. (Alessandro) de, Grarup, N. (Niels), Greiser, K.H. (Karin Halina), Haljas, K. (Kadri), Hansen, T. (Torben), Harris, S.E. (Sarah), Heemst, D. (Diana) van, Heijer, M. (Martin) den, Hicks, A.A. (Andrew A.), Hollander, W. (Wouter) den, Homuth, G. (Georg), Hui, J. (Jennie), Ikram, M.A. (Arfan), Ittermann, T. (Till), Jensen, R.A. (Richard A.), Jing, J. (Jiaojiao), Jukema, J.W. (Jan Wouter), Kajantie, E. (Eero), Kamatani, Y. (Yoichiro), Kasbohm, E. (Elisa), Kaufman, J.-M. (Jean-Marc), Kiemeney, L.A. (Lambertus A.), Kloppenburg, M. (Margreet), Kronenberg, F. (Florian), Kubo, M. (Michiaki), Lahti, J. (Jari), Lapauw, B. (Bruno), Li, S. (Shuo), Liewald, D.C.M. (David C. M.), Alizadeh, B.Z. (Behrooz), Boezen, H.M. (Marike), Franke, L. (Lude), van der Harst, P. (Pim), Navis, G. (Gerjan), Rots, M.G. (M.), Snieder, H. (Harold), Swertz, M.A. (Morris A.), Wijmenga, C. (Cisca), Lim, E.M. (Ee Mun), Linneberg, A. (Allan), Marina, M. (Michela), Mascalzoni, D. (Deborah), Matsuda, K. (Koichi), Medenwald, D. (Daniel), Meisinger, C. (Christa), Meulenbelt, I. (Ingrid), Meyer, T. (Thorsten), Meyer zu Schwabedissen, H.E. (Henriette E.), Mikolajczyk, R. (Rafael), Moed, H. (Heleen), Netea-Maier, R.T. (Romana), Nolte, I.M. (Ilja), Okada, Y. (Yukinori), Pala, M. (Mauro), Penninx, B.W.J.H., Pedersen, O. (Oluf), Petersmann, A. (Astrid), Porcu, E. (Eleonora), Postmus, D. (Douwe), Pramstaller, P.P. (Peter Paul), Psaty, B.M. (Bruce), Ramos, Y.F.M. (Yolande F. M.), Rawal, R. (Rajesh), Redmond, P. (Paul), Richards, J.B. (Brent), Rietzschel, E.R. (Ernst), Rivadeneira Ramirez, F. (Fernando), Roef, G.L. (Greet), Rotter, J.I. (Jerome I.), Sala, C. (Cinzia), Schlessinger, D. (David), Selvin, E. (Elizabeth), Slagboom, P.E. (Eline), Soranzo, N. (Nicole), Sørensen, T.I.A. (Thorkild), Spector, T.D. (Timothy), Starr, J.M. (John), Stott, D.J. (David. J.), Taes, Y.E. (Youri), Taliun, D. (Daniel), Tanaka, T. (Toshiko), Thuesen, L. (Leif), Tiller, D. (Daniel), Toniolo, D. (Daniela), Uitterlinden, A.G. (Andre G.), Visser, W.E. (Edward), Walsh, J.P. (John P.), Wilson, S.G. (Scott), Wolffenbuttel, B.H.R. (Bruce), Yang, Q. (Qiong Fang), Zheng, H.-F. (Hou-Feng), Cappola, A.R. (Anne), Peeters, R.P. (Robin), Naitza, S. (Silvia), Völzke, H. (Henry), Sanna, S. (Serena), Köttgen, A. (Anna), Visser, T.J. (Theo), and Medici, M. (Marco)
Abstract: Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves’ disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.
Published: 2018
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9. Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

Author: Wyss, A.B. (Annah B.), Sofer, T. (Tamar), Lee, M.K. (Mi Kyeong), Terzikhan, N. (Natalie), Nguyen, J.N. (Jennifer N.), Lahousse, L. (Lies), Latourelle, J.C. (Jeanne), Smith, A.V. (Albert), Bartz, T.M. (Traci M.), Feitosa, M.F. (Mary Furlan), Gao, W. (Wei), Ahluwalia, T.S. (Tarunveer Singh), Tang, W. (Wenbo), Oldmeadow, C. (Christopher), Duan, Q. (Qing), Jong, K. (Kim) de, Wojczynski, M.K. (Mary ), Wang, X.-Q. (Xin-Qun), Noordam, R. (Raymond), Hartwig, F.P. (Fernando Pires), Jackson, V.E. (Victoria E.), Wang, T. (Tianyuan), Obeidat, M. (Ma’en), Hobbs, B.D. (Brian D.), Huan, T. (Tianxiao), Gui, H. (Hongsheng), Parker, M.M. (Margaret M.), Hu, D. (Donglei), Mogil, L.S. (Lauren S.), Kichaev, G. (Gleb), Jin, J. (Jianping), Graff, M.J. (Maud J.L.), Harris, T.B. (Tamara), Kalhan, R. (Ravi), Heckbert, S.R. (Susan), Paternoster, L. (Lavinia), Burkart, K.M. (Kristin), Liu, Y. (YongMei), Holliday, E.G. (Elizabeth), Wilson, J.F. (James), Vonk, J.M. (Judith), Sanders, J.L. (Jason L.), Barr, R.G. (Graham), Mutsert, R. (Reneé) de, Menezes, A.M.B. (Ana Maria Baptista), Adams, H.H.H. (Hieab), Van Den Berge, M. (Maarten), Joehanes, R. (Roby), Levin, A.M. (Albert M.), Liberto, J. (Jennifer), Launer, L.J. (Lenore), Morrison, A.C. (Alanna), Sitlani, C.M. (Colleen), Celedón, J.C. (Juan C.), Kritchevsky, S.B. (Stephen), Scott, R.J. (Rodney J.), Christensen, K. (Kaare), Rotter, J.I. (Jerome I.), Bonten, T.N. (Tobias N.), Wehrmeister, F.C. (Fernando C.), Bossé, Y. (Yohan), Xiao, S. (Shujie), Oh, S. (Sam), Franceschini, N. (Nora), Brody, J.A. (Jennifer A.), Kaplan, R.C. (Robert), Lohman, K. (Kurt), McEvoy, M. (Mark), Province, M.A. (Mike), Rosendaal, F.R. (Frits), Taylor, K.D. (Kent), Nickle, D.C. (David C.), Williams, L.K. (L. Keoki), Burchard, E.G. (Esteban), Wheeler, H.E. (Heather), Sin, D.D. (Don D.), Gudnason, V. (Vilmundur), North, K.E. (Kari), Fornage, M. (Myriam), Psaty, B.M. (Bruce M.), Myers, R.H. (Richard), O’Connor, G. (George), Hansen, T. (Torben), Laurie, C.C. (Cathy C.), Cassano, P.A. (Patricia), Sung, J. (Joohon), Kim, W.J. (Woo Jin), Attia, J. (John), Lange, L.A. (Leslie), Boezen, H.M. (Marike), Thyagarajan, B. (Bharat), Rich, S.S. (Stephen), Mook-Kanamori, D.O. (Dennis O.), Horta, B.L. (Bernardo Lessa), Uitterlinden, A.G. (André), Im, H.K. (Hae Kyung), Cho, M.H. (Michael H.), Brusselle, G.G. (Guy), Gharib, S.A. (Sina), Dupuis, J. (Josée), Manichaikul, A. (Ani), London, S.J. (Stephanie J.), Wyss, A.B. (Annah B.), Sofer, T. (Tamar), Lee, M.K. (Mi Kyeong), Terzikhan, N. (Natalie), Nguyen, J.N. (Jennifer N.), Lahousse, L. (Lies), Latourelle, J.C. (Jeanne), Smith, A.V. (Albert), Bartz, T.M. (Traci M.), Feitosa, M.F. (Mary Furlan), Gao, W. (Wei), Ahluwalia, T.S. (Tarunveer Singh), Tang, W. (Wenbo), Oldmeadow, C. (Christopher), Duan, Q. (Qing), Jong, K. (Kim) de, Wojczynski, M.K. (Mary ), Wang, X.-Q. (Xin-Qun), Noordam, R. (Raymond), Hartwig, F.P. (Fernando Pires), Jackson, V.E. (Victoria E.), Wang, T. (Tianyuan), Obeidat, M. (Ma’en), Hobbs, B.D. (Brian D.), Huan, T. (Tianxiao), Gui, H. (Hongsheng), Parker, M.M. (Margaret M.), Hu, D. (Donglei), Mogil, L.S. (Lauren S.), Kichaev, G. (Gleb), Jin, J. (Jianping), Graff, M.J. (Maud J.L.), Harris, T.B. (Tamara), Kalhan, R. (Ravi), Heckbert, S.R. (Susan), Paternoster, L. (Lavinia), Burkart, K.M. (Kristin), Liu, Y. (YongMei), Holliday, E.G. (Elizabeth), Wilson, J.F. (James), Vonk, J.M. (Judith), Sanders, J.L. (Jason L.), Barr, R.G. (Graham), Mutsert, R. (Reneé) de, Menezes, A.M.B. (Ana Maria Baptista), Adams, H.H.H. (Hieab), Van Den Berge, M. (Maarten), Joehanes, R. (Roby), Levin, A.M. (Albert M.), Liberto, J. (Jennifer), Launer, L.J. (Lenore), Morrison, A.C. (Alanna), Sitlani, C.M. (Colleen), Celedón, J.C. (Juan C.), Kritchevsky, S.B. (Stephen), Scott, R.J. (Rodney J.), Christensen, K. (Kaare), Rotter, J.I. (Jerome I.), Bonten, T.N. (Tobias N.), Wehrmeister, F.C. (Fernando C.), Bossé, Y. (Yohan), Xiao, S. (Shujie), Oh, S. (Sam), Franceschini, N. (Nora), Brody, J.A. (Jennifer A.), Kaplan, R.C. (Robert), Lohman, K. (Kurt), McEvoy, M. (Mark), Province, M.A. (Mike), Rosendaal, F.R. (Frits), Taylor, K.D. (Kent), Nickle, D.C. (David C.), Williams, L.K. (L. Keoki), Burchard, E.G. (Esteban), Wheeler, H.E. (Heather), Sin, D.D. (Don D.), Gudnason, V. (Vilmundur), North, K.E. (Kari), Fornage, M. (Myriam), Psaty, B.M. (Bruce M.), Myers, R.H. (Richard), O’Connor, G. (George), Hansen, T. (Torben), Laurie, C.C. (Cathy C.), Cassano, P.A. (Patricia), Sung, J. (Joohon), Kim, W.J. (Woo Jin), Attia, J. (John), Lange, L.A. (Leslie), Boezen, H.M. (Marike), Thyagarajan, B. (Bharat), Rich, S.S. (Stephen), Mook-Kanamori, D.O. (Dennis O.), Horta, B.L. (Bernardo Lessa), Uitterlinden, A.G. (André), Im, H.K. (Hae Kyung), Cho, M.H. (Michael H.), Brusselle, G.G. (Guy), Gharib, S.A. (Sina), Dupuis, J. (Josée), Manichaikul, A. (Ani), and London, S.J. (Stephanie J.)
Abstract: 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 lu
Published: 2018
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10. Long-term air pollution exposure, genome-wide DNA methylation and lung function in the lifelines cohort study

Author: Lichtenfels, A.J.F.C. (Ana Julia De F. C.), Van Der Plaat, D.A. (Diana A.), Jong, K. (Kim) de, Diemen, C.C. (Cleo) van, Postma, D.S. (Dirkje S.), Prokić, I. (Ivana), Duijn, C.M. (Cornelia) van, Amin, N. (Najaf), La Bastide-van Gemert, S. (Sacha), De Vries, M. (Maaike), Ward-Caviness, C.K. (Cavin K.), Wolf, K. (Kathrin), Waldenberger, M. (Melanie), Peters, A. (Annette), Stolk, R.P. (Ronald), Brunekreef, B. (Bert), Boezen, H.M. (Marike), Vonk, J.M. (Judith), Lichtenfels, A.J.F.C. (Ana Julia De F. C.), Van Der Plaat, D.A. (Diana A.), Jong, K. (Kim) de, Diemen, C.C. (Cleo) van, Postma, D.S. (Dirkje S.), Prokić, I. (Ivana), Duijn, C.M. (Cornelia) van, Amin, N. (Najaf), La Bastide-van Gemert, S. (Sacha), De Vries, M. (Maaike), Ward-Caviness, C.K. (Cavin K.), Wolf, K. (Kathrin), Waldenberger, M. (Melanie), Peters, A. (Annette), Stolk, R.P. (Ronald), Brunekreef, B. (Bert), Boezen, H.M. (Marike), and Vonk, J.M. (Judith)
Abstract: BACKGROUND: Long-term air pollution exposure is negatively associated with lung function, yet the mechanisms underlying this association are not fully clear. Differential DNA methylation may explain this association. OBJECTIVES: Our main aim was to study the association between long-term air pollution exposure and DNA methylation. METHODS: We performed a genome-wide methylation study using robust linear regression models in 1,017 subjects from the LifeLines cohort study to analyze the association between exposure to nitrogen dioxide (NO2) and particulate matter (PM2.5, fine particulate mat
Published: 2018
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11. A Genome-wide linkage study for chronic obstructive pulmonary disease in a dutch genetic isolate identifies novel rare candidate variants

Author: Prokić, I. (Ivana), Terzikhan, N. (Natalie), Vonk, J.M. (Judith), van der Plaat, D.A. (Diana A.), Lahousse, L. (Lies), Diemen, C.C. (Cleo) van, Hobbs, B.D. (Brian D.), Qiao, D. (Dandi), Cho, M.H. (Michael), Brusselle, G.G. (Guy), Postma, D.S. (Dirkje S.), Boezen, H.M. (Marike), Duijn, C.M. (Cornelia) van, Amin, N. (Najaf), Prokić, I. (Ivana), Terzikhan, N. (Natalie), Vonk, J.M. (Judith), van der Plaat, D.A. (Diana A.), Lahousse, L. (Lies), Diemen, C.C. (Cleo) van, Hobbs, B.D. (Brian D.), Qiao, D. (Dandi), Cho, M.H. (Michael), Brusselle, G.G. (Guy), Postma, D.S. (Dirkje S.), Boezen, H.M. (Marike), Duijn, C.M. (Cornelia) van, and Amin, N. (Najaf)
Abstract: Chronic obstructive pulmonary disease (COPD) is a complex and heritable disease, associated with multiple genetic variants. Specific familial types of COPD may be explained by rare variants, which have not been widely studied. We aimed to discover rare genetic variants underlying COPD through a genome-wide linkage scan. Affected-only analysis was performed using the 6K Illumina Linkage IV Panel in 142 cases clustered in 27 families from a genetic isolate, the Erasmus Rucphen Family (ERF) study. Potential causal variants were identified by searching for shared rare variants in the exome-sequence data of the affected members of the families contributing most to the linkage peak. The identified rare variants were then tested for association with COPD in a large meta-analysis of several cohorts. Significant evidence for linkage was observed on chromosomes 15q14-15q25 [logarithm of the odds (LOD) score = 5.52], 11p15.4-11q14.1 (LOD = 3.71) and 5q14.3-5q33.2 (LOD = 3.49). In the chromosome 15 peak, that harbors the known COPD locus for nicotinic receptors, and in the chromosome 5 peak we could not identify shared variants. In the chromosome 11 locus, we identified four rare (minor allele frequency (MAF) < 0.02), predicted pathogenic, missense variants. These were shared among the affected family members. The identified variants localize to genes including neuroblast differentiation-associated protein (AHNAK), previously associated with blood biomarkers in COPD, phospholipase C Beta 3 (PLCB3), shown to increase airway hyper-responsiveness, solute carrier family 22-A11 (SLC22A11), involved in amino acid metabolism and ion transport, and metallothionein-like protein 5 (MTL5), involved in nicotinate and nicotinamide metabolism. Association of SLC22A11 and MTL5 variants were confirmed in the meta-analysis of 9,888 cases and 27,060 controls. In conclusion, we have identified novel rare variants in plausible genes related to COPD. Further studies utilizing large sample whole-gen
Published: 2018
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12. COPD GWAS variant at 19q13.2 in relation with DNA methylation and gene expression

Author: Prokić, I. (Ivana), Lahousse, L. (Lies), Carnero-Montoro, E. (Elena), Faiz, A. (Alen), Vonk, J.M. (Judith), Jong, K. (Kim) de, van der Plaat, D.A. (Diana A.), Diemen, C.C. (Cleo) van, Van Den Berge, M. (Maarten), Obeidat, M. (Ma'en), Bossé, Y. (Yohan), Nickle, D.C. (David C.), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Postma, D.S. (Dirkje S.), Boezen, H.M. (Marike), Duijn, C.M. (Cornelia) van, Amin, N. (Najaf), Prokić, I. (Ivana), Lahousse, L. (Lies), Carnero-Montoro, E. (Elena), Faiz, A. (Alen), Vonk, J.M. (Judith), Jong, K. (Kim) de, van der Plaat, D.A. (Diana A.), Diemen, C.C. (Cleo) van, Van Den Berge, M. (Maarten), Obeidat, M. (Ma'en), Bossé, Y. (Yohan), Nickle, D.C. (David C.), Uitterlinden, A.G. (André), Meurs, J.B.J. (Joyce) van, Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Postma, D.S. (Dirkje S.), Boezen, H.M. (Marike), Duijn, C.M. (Cornelia) van, and Amin, N. (Najaf)
Abstract: Chronic obstructive pulmonary disease (COPD) is among the major health burdens in adults. While cigarette smoking is the leading risk factor, a growing number of genetic variations have been discovered to influence disease susceptibility. Epigenetic modifications may mediate the response of the genome to smoking and regulate gene expression. Chromosome 19q13.2 region is associated with both smoking and COPD, yet its functional role is unclear. Our study aimed to determine whether rs7937 (RAB4B, EGLN2), a top genetic variant in 19q13.2 region identified in genome-wide association studies of COPD, is associated with differential DNA methylation in blood (N=1490) and gene expression in blood (N=721) and lungs (N=1087). We combined genetic and epigenetic data from the Rotterdam Study (RS) to perform the epigenome-wide association analysis of rs7937. Further, we used genetic and transcriptomic data from blood (RS) and from lung tissue (Lung expression quantitative trait loci mapping study), to perform the transcriptome-wide association study of rs7937. Rs7937 was significantly (FDR < 0.05) and consistently associated with differential DNA methylation in blood at 4 CpG sites in cis, independent of smoking. One methylation site (cg11298343-EGLN2) was also associated with COPD (P=0.001). Additionally, rs7937 was associated with gene expression levels in blood in cis (EGLN2), 42% mediated through cg11298343, and in lung tissue, in cis and trans (NUMBL, EGLN2, DNMT3A, LOC101929709 and PAK2). Our results suggest that changes of DNA methylation and gene expression may be intermediate steps between genetic variants and COPD, but further causal studies in lung tissue should confirm this hypothesis.
Published: 2018
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13. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

Author: Hobbs, B.D. (Brian D.), Jong, K. (Kim) de, Lamontagne, M. (Maxime), Bossé, Y. (Yohan), Shrine, N.R.G. (Nick), Artigas, M.S., Wain, L.V. (Louise V), Hall, I.P. (Ian), Jackson, V.E. (Victoria E.), Wyss, A.B. (Annah B.), London, S.J. (Stephanie J), North, K.E. (Kari), Franceschini, N. (Nora), Strachan, D.P. (David), Beaty, T.H. (Terri), Hokanson, J.E. (John E.), Crapo, R.O. (Robert), Castaldi, P.J. (Peter J.), Chase, R.P. (Robert P.), Bartz, T.M. (Traci M.), Heckbert, S.R. (Susan), Psaty, B.M. (Bruce M.), Gharib, S.A. (Sina), Zanen, P. (Pieter), Lammers, J.-W.J. (Jan-Willem), Oudkerk, M. (Matthijs), Groen, H.J.M. (Henk), Locantore, N. (Nicholas), Tal-Singer, R. (Ruth), Rennard, S.I., Vestbo, J. (Jorgen), Timens, W. (Wim), Paré, P.D. (Peter), Latourelle, J.C. (Jeanne), Dupuis, J. (Josée), O'Connor, G.T. (George), Wilk, J.B. (Jemma), Kim, W.J. (Woo Jin), Lee, M.K. (Mi Kyeong), Oh, Y.-M. (Yeon-Mok), Vonk, J.M. (Judith), Koning, H.J. (Harry) de, Leng, S. (Shuguang), Belinsky, S.A. (Steven A.), Tesfaigzi, Y. (Yohannes), Manichaikul, A. (Ani), Wang, X.-Q. (Xin-Qun), Rich, S.S. (Stephen), Barr, R.G. (Graham), Sparrow, D. (David), Litonjua, A.A. (Augusto), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Lahousse, L. (Lies), Brusselle, G.G. (Guy), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Ampleford, E.J. (Elizabeth J.), Bleecker, E.R. (E.), Woodruff, P.G. (Prescott G.), Meyers, D.A. (Deborah A.), Qiao, D. (Dandi), Lomas, D.A. (David A.), Yim, J.-J. (Jae-Joon), Kim, D.K. (Deog Kyeom), Hawrylkiewicz, I. (Iwona), Sliwinski, P. (Pawel), Hardin, M. (Megan), Fingerlin, T.E. (Tasha E.), Schwartz, D.A. (David A.), Postma, D.S. (Dirkje S.), MacNee, W., Tobin, M.D. (Martin), Silverman, E. (Edwin), Boezen, H.M. (Marike), Cho, M.H. (Michael), Hobbs, B.D. (Brian D.), Jong, K. (Kim) de, Lamontagne, M. (Maxime), Bossé, Y. (Yohan), Shrine, N.R.G. (Nick), Artigas, M.S., Wain, L.V. (Louise V), Hall, I.P. (Ian), Jackson, V.E. (Victoria E.), Wyss, A.B. (Annah B.), London, S.J. (Stephanie J), North, K.E. (Kari), Franceschini, N. (Nora), Strachan, D.P. (David), Beaty, T.H. (Terri), Hokanson, J.E. (John E.), Crapo, R.O. (Robert), Castaldi, P.J. (Peter J.), Chase, R.P. (Robert P.), Bartz, T.M. (Traci M.), Heckbert, S.R. (Susan), Psaty, B.M. (Bruce M.), Gharib, S.A. (Sina), Zanen, P. (Pieter), Lammers, J.-W.J. (Jan-Willem), Oudkerk, M. (Matthijs), Groen, H.J.M. (Henk), Locantore, N. (Nicholas), Tal-Singer, R. (Ruth), Rennard, S.I., Vestbo, J. (Jorgen), Timens, W. (Wim), Paré, P.D. (Peter), Latourelle, J.C. (Jeanne), Dupuis, J. (Josée), O'Connor, G.T. (George), Wilk, J.B. (Jemma), Kim, W.J. (Woo Jin), Lee, M.K. (Mi Kyeong), Oh, Y.-M. (Yeon-Mok), Vonk, J.M. (Judith), Koning, H.J. (Harry) de, Leng, S. (Shuguang), Belinsky, S.A. (Steven A.), Tesfaigzi, Y. (Yohannes), Manichaikul, A. (Ani), Wang, X.-Q. (Xin-Qun), Rich, S.S. (Stephen), Barr, R.G. (Graham), Sparrow, D. (David), Litonjua, A.A. (Augusto), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Lahousse, L. (Lies), Brusselle, G.G. (Guy), Stricker, B.H.Ch. (Bruno), Uitterlinden, A.G. (André), Ampleford, E.J. (Elizabeth J.), Bleecker, E.R. (E.), Woodruff, P.G. (Prescott G.), Meyers, D.A. (Deborah A.), Qiao, D. (Dandi), Lomas, D.A. (David A.), Yim, J.-J. (Jae-Joon), Kim, D.K. (Deog Kyeom), Hawrylkiewicz, I. (Iwona), Sliwinski, P. (Pawel), Hardin, M. (Megan), Fingerlin, T.E. (Tasha E.), Schwartz, D.A. (David A.), Postma, D.S. (Dirkje S.), MacNee, W., Tobin, M.D. (Martin), Silverman, E. (Edwin), Boezen, H.M. (Marike), and Cho, M.H. (Michael)
Abstract: Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality worldwide. We performed a genetic association study in 15,256 cases and 47,936 controls, with replication of select top results (P < 5 × 10-6) in 9,498 cases and 9,748 controls. In the combined meta-analysis, we identified 22 loci associated at genome-wide significance, including 13 new associations with COPD. Nine of these 13 loci have been associated with lung function in general population samples, while 4 (EEFSEC, DSP, MTCL1, and SFTPD) are new. We noted two loci shared with pulmonary fibrosis (FAM13A and DSP) but that had opposite risk alleles for COPD. None of our loci overlapped with genome-wide associations for asthma, although one locus has been implicated in joint susceptibility to asthma and obesity. We also identified genetic correlation between COPD and asthma. Our findings highlight new loci associated with COPD, demonstrate the importance of specific loci associated with lung function to COPD, and identify potential regions of genetic overlap between COPD and other respiratory diseases.
Published: 2017
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14. Genes and pathways underlying susceptibility to impaired lung function in the context of environmental tobacco smoke exposure

Author: Jong, K. (Kim) de, Vonk, J.M. (Judith), Imboden, M. (Medea), Lahousse, L. (Lies), Hofman, A. (Albert), Brusselle, G.G. (Guy), Probst-Hensch, N.M. (Nicole M.), Postma, D.S. (Dirkje), Boezen, H.M. (Marike), Jong, K. (Kim) de, Vonk, J.M. (Judith), Imboden, M. (Medea), Lahousse, L. (Lies), Hofman, A. (Albert), Brusselle, G.G. (Guy), Probst-Hensch, N.M. (Nicole M.), Postma, D.S. (Dirkje), and Boezen, H.M. (Marike)
Abstract: Background: Studies aiming to assess genetic susceptibility for impaired lung function levels upon exposure to environmental tobacco smoke (ETS) have thus far focused on candidate-genes selected based on a-priori knowledge of potentially relevant biological pathways, such as glutathione S-transferases and ADAM33. By using a hypothesis-free approach, we aimed to identify novel susceptibility loci, and additionally explored biological pathways potentially underlying this susceptibility to impaired lung function in the context of ETS exposure. Methods: Genome-wide interactions of single nucleotide polymorphism (SNP) by ETS exposure (0 versus ≥1 h/day) in relation to the level of forced expiratory volume in one second (FEV1) were investigated in 10,817 subjects from the Dutch LifeLines cohort study, and verified in subjects from the Swiss SAPALDIA study (n = 1276) and the Dutch Rotterdam Study (n = 1156). SNP-by-ETS exposure p-values obtained from the identification analysis were used to perform a pathway analysis. Results: Fourty Five SNP-by-ETS exposure interactions with p-values <10-4 were identified in the LifeLines study, two being replicated with nominally significant p-values (<0.05) in at least one of the replication cohorts. Three pathways were enriched in the pathway-level analysis performed in the identification cohort LifeLines, i.E. the apoptosis, p38 MAPK and TNF pathways. Conclusion: This unique, first genome-wide gene-by-ETS interaction study on the level of FEV1 showed that pathways previously implicated in chronic obstructive pulmonary disease (COPD), a disease characterized by airflow obstruction, may also underlie susceptibility to impaired lung function in the context of ETS exposure.
Published: 2017
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15. Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma

Author: Nieuwenhuis, M.A., Siedlinski, M., van den Berge, M., Granell, R. (Raquel), Li, X., Niens, M., Vlies, P. (P.) van der, Altmüller, J. (Janine), Nürnberg, P. (Peter), Kerkhof, M. (Marjan), Schayck, O.C.P. (Onno), Riemersma, R.A. (Roland), Molen, T. (Thys) van der, Monchy, J.G. de, Bossé, Y., Sandford, A. (Andrew), Bruijnzeel-Koomen, C.A., Gerth van Wijk, R., ten Hacken, N.H., Timens, W. (Wim), Boezen, H.M. (Marike), Henderson, J., Kabesch, M. (Michael), Vonk, J.M. (Judith), Postma, D.S. (Dirkje), Koppelman, G.H. (Gerard), Nieuwenhuis, M.A., Siedlinski, M., van den Berge, M., Granell, R. (Raquel), Li, X., Niens, M., Vlies, P. (P.) van der, Altmüller, J. (Janine), Nürnberg, P. (Peter), Kerkhof, M. (Marjan), Schayck, O.C.P. (Onno), Riemersma, R.A. (Roland), Molen, T. (Thys) van der, Monchy, J.G. de, Bossé, Y., Sandford, A. (Andrew), Bruijnzeel-Koomen, C.A., Gerth van Wijk, R., ten Hacken, N.H., Timens, W. (Wim), Boezen, H.M. (Marike), Henderson, J., Kabesch, M. (Michael), Vonk, J.M. (Judith), Postma, D.S. (Dirkje), and Koppelman, G.H. (Gerard)
Abstract: Background: Genomewide association studies (GWASs) of asthma have identified single-nucleotide polymorphisms (SNPs) that modestly increase the risk for asthma. This could be due to phenotypic heterogeneity of asthma. Bronchial hyperresponsiveness (BHR) is a phenotypic hallmark of asthma. We aim to identify susceptibility genes for asthma combined with BHR and analyse the presence of cis-eQTLs among replicated SNPs. Secondly, we compare the genetic association of SNPs previously associated with (doctor's diagnosed) asthma to our GWAS of asthma with BHR. Methods: A GWAS was performed in 920 asthmatics with BHR and 980 controls. Top SNPs of our GWAS were analysed in four replication cohorts, and lung cis-eQTL analysis was performed on replicated SNPs. We investigated association of SNPs previously associated with asthma in our data. Results: A total of 368 SNPs were followed up for replication. Six SNPs in genes encoding ABI3BP, NAF1, MICA and the 17q21 locus replicated in one or more cohorts, with one locus (17q21) achieving genomewide significance after meta-analysis. Five of 6 replicated SNPs regulated 35 gene transcripts in whole lung. Eight of 20 asthma-associated SNPs from previous GWAS were significantly associated with asthma and BHR. Three SNPs, in IL-33 and GSDMB, showed larger effect sizes in our data compared to p
Published: 2016
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16. Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram

Author: Verweij, N. (Niek), Leach, I.M. (Irene Mateo), Isaacs, A.J. (Aaron), Arking, D.E. (Dan), Bis, J.C. (Joshua), Pers, T.H. (Tune), Berg, M.E. (Marten) van den, Lyytikäinen, L.-P. (Leo-Pekka), Barnett, P. (Phil), Wang, X. (Xinchen), Soliman, E.Z. (Elsayed Z.), Duijn, C.M. (Cornelia) van, Kähönen, M. (Mika), Van Veldhuisen, D.J. (Dirk J.), Kors, J.A. (Jan), Raitakari, O.T. (Olli T.), Silva Aldana, C.T. (Claudia), Lehtimäki, T. (Terho), Hillege, H.L. (Hans), Hirschhorn, J.N. (Joel), Boyer, L.A. (Laurie A.), Gilst, W.H. (Wiek) van, Alonso, A. (Alvaro), Sotoodehnia, N. (Nona), Eijgelsheim, M. (Mark), Boer, R.A. (Rudolf) de, Bakker, P.I.W. (Paul) de, Franke, L. (Lude), Harst, P. (Pim) van der, Klauw, M. (Melanie van der), Navis, G. (Gerjan), Ormel, H. (Hans), Postma, D.S. (Dirkje), Rosmalen, J.G.M. (Judith), Slaets, J.P.J. (Joris), Stolk, R.P., Wolffenbuttel, B.H.R. (Bruce H. R.), Alizadeh, B.Z. (Behrooz), Boezen, H.M. (Marike), Bruinenberg, M. (M.), Festen, N. (Noortje), Snieder, H. (Harold), Wijmenga, C. (Cisca), Verweij, N. (Niek), Leach, I.M. (Irene Mateo), Isaacs, A.J. (Aaron), Arking, D.E. (Dan), Bis, J.C. (Joshua), Pers, T.H. (Tune), Berg, M.E. (Marten) van den, Lyytikäinen, L.-P. (Leo-Pekka), Barnett, P. (Phil), Wang, X. (Xinchen), Soliman, E.Z. (Elsayed Z.), Duijn, C.M. (Cornelia) van, Kähönen, M. (Mika), Van Veldhuisen, D.J. (Dirk J.), Kors, J.A. (Jan), Raitakari, O.T. (Olli T.), Silva Aldana, C.T. (Claudia), Lehtimäki, T. (Terho), Hillege, H.L. (Hans), Hirschhorn, J.N. (Joel), Boyer, L.A. (Laurie A.), Gilst, W.H. (Wiek) van, Alonso, A. (Alvaro), Sotoodehnia, N. (Nona), Eijgelsheim, M. (Mark), Boer, R.A. (Rudolf) de, Bakker, P.I.W. (Paul) de, Franke, L. (Lude), Harst, P. (Pim) van der, Klauw, M. (Melanie van der), Navis, G. (Gerjan), Ormel, H. (Hans), Postma, D.S. (Dirkje), Rosmalen, J.G.M. (Judith), Slaets, J.P.J. (Joris), Stolk, R.P., Wolffenbuttel, B.H.R. (Bruce H. R.), Alizadeh, B.Z. (Behrooz), Boezen, H.M. (Marike), Bruinenberg, M. (M.), Festen, N. (Noortje), Snieder, H. (Harold), and Wijmenga, C. (Cisca)
Abstract: The ST-segment and adjacent T-wave (ST-T wave) amplitudes of the electrocardiogram are quantitative characteristics of cardiac repolarization. Repolarization abnormalities have been linked to ventricular arrhythmias and sudden cardiac death. We performed the first genome-wide association meta-analysis of ST-T-wave amplitudes in up to 37 977 individuals identifying 71 robust genotype-phenotype associations clustered within 28 independent loci. Fifty-four genes were prioritized as candidates underlying the phenotypes, including genes with established roles in the cardiac repolarization phase (SCN5A/SCN10A, KCND3, KCNB1, NOS1AP and HEY2) and others with as yet undefined cardiac function. These associations may provide insights in the spatiotemporal contribution of genetic variation influencing cardiac repolarization and provide novel leads for future functional follow-up.
Published: 2016
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17. Association of Forced Vital Capacity with the Developmental Gene NCOR2

Author: Minelli, C. (Cosetta), Dean, C.H. (Charlotte H.), Hind, M. (Matthew), Alves, A.C. (Alexessander Couto), Amaral, A.F.S. (André), Siroux, V. (V.), Huikari, V. (Ville), Artigas, M.S., Evans, D.M. (David M.), Loth, D.W. (Daan), Bossé, Y. (Yohan), Postma, D.S. (Dirkje), Sin, D.D., Thompson, J.R. (John), Demenais, F. (Florence), Henderson, J. (John), Bouzigon, E. (Emmanuelle), Jarvis, D.L. (Deborah), Jarvelin, M.-R. (Marjo-Riitta), Burney, P.G., Gharib, S.A. (Sina), Wain, L.V. (Louise), Franceschini, N. (Nora), Koch, B. (Beate), Pottinger, T.D. (Tess), Smith, A.V. (Albert), Duan, Q. (Qing), Oldmeadow, C. (Christopher), Lee, M.K. (Mi Kyeong), Strachan, D.P. (David P.), James, A.L. (Alan L.), Huffman, J.E. (Jennifer), Vitart, V. (Veronique), Ramasamy, A. (Adaikalavan), Wareham, N.J. (Nicholas J.), Kaprio, J. (Jaakko), Wang, X.-Q. (Xin-Qun), Trochet, H. (Holly), Kähönen, M. (Mika), Flexeder, C. (Claudia), Albrecht, E. (Eva), Lopez, L.M. (Lorna M.), Jong, K. (Kim) de, Thyagarajan, B. (Bharat), Enroth, S. (Stefan), Omenaas, E. (Ernst), Joshi, P.K. (Peter), Fall, M. (Magnus), Viñuela, A. (Ana), Launer, L.J. (Lenore), Loehr, L.R. (Laura), Fornage, M. (Myriam), Li, G. (Guo), Wilk, J.B. (Jemma), Tang, W. (Wenbo), Manichaikul, A. (Ani), Lahousse, L. (Lies), Harris, T.B. (Tamara), North, K.E. (Kari E.), Rudnicka, A.R. (Alicja), Hui, J. (Jennie), Gu, X. (Xiangjun), Lumley, T. (Thomas), Wright, A.F. (Alan F.), Hastie, N. (Nick), Campbell, S. (Susan), Kumar, R. (Rajesh), Pin, I. (Isabelle), Scott, R.A. (Robert), Pietilainen, K.H. (Kirsi Hannele), Surakka, I. (Ida), Liu, Y. (YongMei), Holliday, E.G. (Elizabeth), Schulz, H. (Holger), Heinrich, J. (Joachim), Davies, G. (Gail), MVonk, J. (Judith), Wojczynski, M.K. (Mary ), Pouta, A. (Anneli), Johansson, A. (Åsa), Wild, S. (Sarah), Ingelsson, E. (Erik), Rivadeneira Ramirez, F. (Fernando), Völzke, H. (Henry), Hysi, P.G. (Pirro), Eiriksdottir, G. (Gudny), Morrison, A.C. (Alanna), Rotter, J.I. (Jerome I.), Gao, W. (Wei), White, W.B. (Wendy), Rich, S.S. (Stephen S.), Hofman, A. (Albert), Aspelund, T. (Thor), Couper, D.J. (David), Smith, L.J. (Lewis J.), Psaty, B.M. (Bruce), Lohman, K. (Kurt), Burchard, E.G. (Esteban), Uitterlinden, A.G. (André), Garcia, M. (Melissa), Joubert, B.R. (Bonnie), McArdle, W.L. (Wendy), Musk, A.B. (A Bill), Hansel, C.R.W. (Christian), Heckbert, S.R. (Susan), Zgaga, L. (Lina), Meurs, J.B.J. (Joyce) van, Navarro, P. (Pau), Rudan, I. (Igor), Oh, Y.-M. (Yeon-Mok), Redline, S. (Susan), Jarvis, D.L. (Deborah L.), Zhao, J.H. (Jing Hua), Rantanen, T. (Taina), Connor, G.T. (George) O', Ripatti, S. (Samuli), Scott, R.J. (Rodney), Karrasch, S. (Stefan), Grallert, H. (Harald), Gaddis, N.C. (Nathan C.), MStarr, J. (John), Wijmenga, C. (Cisca), Minster, R.L. (Ryan), Lederer, C.W. (Carsten), Pekkanen, J. (Juha), Gyllensten, U. (Ulf), Campbell, H. (Harry), Morris, A.P. (Andrew), Gläser, S. (Sven), Hammond, C.J. (Christopher J.), MBurkart, K. (Kristin), Beilby, J. (John), Kritchevsky, S.B. (Stephen B.), Gudnason, V. (Vilmundur), Hancock, D.B. (Dana), Williams, O. (O'Dale), Polasek, O. (Ozren), Zemunik, T. (Tatijana), Kolcic, I. (Ivana), Petrini, M.F. (Marcy), Wjst, M. (Matthias), Kim, W.J. (Woo Jin), Porteous, D.J. (David J.), Scotland, G. (Generation), Smith, B.H. (Blair), Viljanen, A. (Anne), Heliovaara, M. (Markku), Attia, J. (John), Sayers, I. (Ian), Hampel, R. (Regina), Gieger, C. (Christian), Deary, I.J. (Ian), Boezen, H.M. (Marike), Newman, A.B. (Anne B.), Wilson, J.F. (James F), Lind, L. (Lars), Stricker, B.H.Ch. (Bruno), Teumer, A. (Alexander), Spector, T.D. (Timothy), Melén, E. (Erik), Peters, M.J. (Marjolein), Lange, L.A. (Leslie), Barr, R.G. (Graham), Bracke, K.R. (Ken), MVerhamme, F. (Fien), Sung, J. (Joohon), Hiemstra, P.S. (Pieter), Cassano, P.A. (Patricia), Sood, A. (Akshay), Hayward, C. (Caroline), Dupuis, J. (Josée), Hall, I.P. (Ian), Brusselle, G.G. (Guy), Tobin, M.D. (Martin), London, S.J. (Stephanie J), Minelli, C. (Cosetta), Dean, C.H. (Charlotte H.), Hind, M. (Matthew), Alves, A.C. (Alexessander Couto), Amaral, A.F.S. (André), Siroux, V. (V.), Huikari, V. (Ville), Artigas, M.S., Evans, D.M. (David M.), Loth, D.W. (Daan), Bossé, Y. (Yohan), Postma, D.S. (Dirkje), Sin, D.D., Thompson, J.R. (John), Demenais, F. (Florence), Henderson, J. (John), Bouzigon, E. (Emmanuelle), Jarvis, D.L. (Deborah), Jarvelin, M.-R. (Marjo-Riitta), Burney, P.G., Gharib, S.A. (Sina), Wain, L.V. (Louise), Franceschini, N. (Nora), Koch, B. (Beate), Pottinger, T.D. (Tess), Smith, A.V. (Albert), Duan, Q. (Qing), Oldmeadow, C. (Christopher), Lee, M.K. (Mi Kyeong), Strachan, D.P. (David P.), James, A.L. (Alan L.), Huffman, J.E. (Jennifer), Vitart, V. (Veronique), Ramasamy, A. (Adaikalavan), Wareham, N.J. (Nicholas J.), Kaprio, J. (Jaakko), Wang, X.-Q. (Xin-Qun), Trochet, H. (Holly), Kähönen, M. (Mika), Flexeder, C. (Claudia), Albrecht, E. (Eva), Lopez, L.M. (Lorna M.), Jong, K. (Kim) de, Thyagarajan, B. (Bharat), Enroth, S. (Stefan), Omenaas, E. (Ernst), Joshi, P.K. (Peter), Fall, M. (Magnus), Viñuela, A. (Ana), Launer, L.J. (Lenore), Loehr, L.R. (Laura), Fornage, M. (Myriam), Li, G. (Guo), Wilk, J.B. (Jemma), Tang, W. (Wenbo), Manichaikul, A. (Ani), Lahousse, L. (Lies), Harris, T.B. (Tamara), North, K.E. (Kari E.), Rudnicka, A.R. (Alicja), Hui, J. (Jennie), Gu, X. (Xiangjun), Lumley, T. (Thomas), Wright, A.F. (Alan F.), Hastie, N. (Nick), Campbell, S. (Susan), Kumar, R. (Rajesh), Pin, I. (Isabelle), Scott, R.A. (Robert), Pietilainen, K.H. (Kirsi Hannele), Surakka, I. (Ida), Liu, Y. (YongMei), Holliday, E.G. (Elizabeth), Schulz, H. (Holger), Heinrich, J. (Joachim), Davies, G. (Gail), MVonk, J. (Judith), Wojczynski, M.K. (Mary ), Pouta, A. (Anneli), Johansson, A. (Åsa), Wild, S. (Sarah), Ingelsson, E. (Erik), Rivadeneira Ramirez, F. (Fernando), Völzke, H. (Henry), Hysi, P.G. (Pirro), Eiriksdottir, G. (Gudny), Morrison, A.C. (Alanna), Rotter, J.I. (Jerome I.), Gao, W. (Wei), White, W.B. (Wendy), Rich, S.S. (Stephen S.), Hofman, A. (Albert), Aspelund, T. (Thor), Couper, D.J. (David), Smith, L.J. (Lewis J.), Psaty, B.M. (Bruce), Lohman, K. (Kurt), Burchard, E.G. (Esteban), Uitterlinden, A.G. (André), Garcia, M. (Melissa), Joubert, B.R. (Bonnie), McArdle, W.L. (Wendy), Musk, A.B. (A Bill), Hansel, C.R.W. (Christian), Heckbert, S.R. (Susan), Zgaga, L. (Lina), Meurs, J.B.J. (Joyce) van, Navarro, P. (Pau), Rudan, I. (Igor), Oh, Y.-M. (Yeon-Mok), Redline, S. (Susan), Jarvis, D.L. (Deborah L.), Zhao, J.H. (Jing Hua), Rantanen, T. (Taina), Connor, G.T. (George) O', Ripatti, S. (Samuli), Scott, R.J. (Rodney), Karrasch, S. (Stefan), Grallert, H. (Harald), Gaddis, N.C. (Nathan C.), MStarr, J. (John), Wijmenga, C. (Cisca), Minster, R.L. (Ryan), Lederer, C.W. (Carsten), Pekkanen, J. (Juha), Gyllensten, U. (Ulf), Campbell, H. (Harry), Morris, A.P. (Andrew), Gläser, S. (Sven), Hammond, C.J. (Christopher J.), MBurkart, K. (Kristin), Beilby, J. (John), Kritchevsky, S.B. (Stephen B.), Gudnason, V. (Vilmundur), Hancock, D.B. (Dana), Williams, O. (O'Dale), Polasek, O. (Ozren), Zemunik, T. (Tatijana), Kolcic, I. (Ivana), Petrini, M.F. (Marcy), Wjst, M. (Matthias), Kim, W.J. (Woo Jin), Porteous, D.J. (David J.), Scotland, G. (Generation), Smith, B.H. (Blair), Viljanen, A. (Anne), Heliovaara, M. (Markku), Attia, J. (John), Sayers, I. (Ian), Hampel, R. (Regina), Gieger, C. (Christian), Deary, I.J. (Ian), Boezen, H.M. (Marike), Newman, A.B. (Anne B.), Wilson, J.F. (James F), Lind, L. (Lars), Stricker, B.H.Ch. (Bruno), Teumer, A. (Alexander), Spector, T.D. (Timothy), Melén, E. (Erik), Peters, M.J. (Marjolein), Lange, L.A. (Leslie), Barr, R.G. (Graham), Bracke, K.R. (Ken), MVerhamme, F. (Fien), Sung, J. (Joohon), Hiemstra, P.S. (Pieter), Cassano, P.A. (Patricia), Sood, A. (Akshay), Hayward, C. (Caroline), Dupuis, J. (Josée), Hall, I.P. (Ian), Brusselle, G.G. (Guy), Tobin, M.D. (Martin), and London, S.J. (Stephanie J)
Abstract: Background Forced Vital Capacity (FVC) is an important predictor of all-cause mortality in the absence of chronic respiratory conditions. Epidemiological evidence highlights the role of early life factors on adult FVC, pointing to environmental exposures and genes affecting lung development as risk factors for low FVC later in life. Although highly heritable, a small number of genes have been found associated with FVC, and we aimed at identifying further genetic variants by focusing on lung development genes. Methods Per-allele effects of 24,728 SNPs in 403 genes involved in lung development were tested in 7,749 adults from three studies (NFBC1966, ECRHS, EGEA). The most significant SNP for the top 25 genes was followed-up in 46,103 adults (CHARGE and SpiroMeta consortia) and 5,062 chil
Published: 2016
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18. Genome-wide association analysis identifies six new loci associated with forced vital capacity

Author: Loth, D.W. (Daan), Artigas, M.S., Gharib, S.A. (Sina), Wain, L.V. (Louise), Franceschini, N. (Nora), Koch, B. (Beate), Pottinger, T.D. (Tess), Smith, A.V. (Davey), Duan, Q. (Qing), Oldmeadow, C. (Christopher), Lee, M.K. (Mi Kyeong), Strachan, D.P. (David), James, A.L. (Alan), Huffman, J.E. (Jennifer), Vitart, V. (Veronique), Ramasamy, A. (Adaikalavan), Wareham, N.J. (Nick), Kaprio, J. (Jaakko), Wang, X.-Q. (Xin-Qun), Trochet, H. (Holly), Kähönen, M. (Mika), Flexeder, C. (Claudia), Albrecht, E. (Eva), Lopez, L.M. (Lorna), Thyagarajan, B. (Bharat), Alves, A.C. (Alexessander Couto), Enroth, S. (Stefan), Omenaas, E. (Ernst), Joshi, P.K. (Peter), Fall, M. (Magnus), Viñuela, A. (Ana), Launer, L.J. (Lenore), Loehr, L.R. (Laura), Fornage, M. (Myriam), Li, G. (Guo), Wilk, J.B. (Jemma), Tang, W. (Wenbo), Manichaikul, A. (Ani), Lahousse, L. (Lies), Harris, T.B. (Tamara), North, K.E. (Kari), Rudnicka, A.R. (Alicja), Hui, J. (Jennie), Gu, X. (Xiangjun), Lumley, T. (Thomas), Wright, A.F. (Alan), Hastie, N. (Nick), Campbell, S. (Susan), Kumar, R. (Rajesh), Pin, I. (Isabelle), Scott, R.A. (Robert), Pietilainen, K.H. (Kirsi Hannele), Surakka, I. (Ida), Liu, Y. (YongMei), Holliday, E.G. (Elizabeth), Schulz, H. (Holger), Heinrich, J. (Joachim), Davies, G. (Gail), Vonk, J.M. (Judith), Wojczynski, M.K. (Mary ), Pouta, A. (Anneli), Johansson, A. (Åsa), Wild, S.H. (Sarah), Ingelsson, E. (Erik), Rivadeneira Ramirez, F. (Fernando), Völzke, H. (Henry), Hysi, P.G. (Pirro), Eiriksdottir, G. (Gudny), Morrison, A.C. (Alanna), Rotter, J.I. (Jerome), Gao, W. (Wei), Postma, D.S. (Dirkje), White, W.B. (Wendy), Rich, S.S. (Stephen), Hofman, A. (Albert), Aspelund, T. (Thor), Couper, D. (David), Smith, L.J. (Lewis), Psaty, B.M. (Bruce), Lohman, K. (Kurt), Burchard, E.G. (Esteban), Uitterlinden, A.G. (André), Garcia, M. (Melissa), Joubert, B.R. (Bonnie), McArdle, W.L. (Wendy), Musk, A.W. (Arthur), Hansel, C.R.W. (Christian), Heckbert, S.R. (Susan), Zgaga, L. (Lina), Meurs, J.B.J. (Joyce) van, Navarro, P. (Pau), Rudan, I. (Igor), Oh, Y.-M. (Yeon-Mok), Redline, S. (Susan), Jarvis, D.L. (Deborah), Zhao, J.H. (Jing Hua), Rantanen, T. (Taina), O'Connor, G.T. (George), Ripatti, S. (Samuli), Scott, R.J. (Rodney), Karrasch, S. (Stefan), Grallert, H. (Harald), Gaddis, N.C. (Nathan), Starr, J.M. (John), Wijmenga, C. (Cisca), Minster, R.L. (Ryan), Lederer, C.W. (Carsten), Pekkanen, J. (Juha), Gyllensten, U. (Ulf), Campbell, H. (Harry), Morris, A.P. (Andrew), Gläser, S. (Sven), Hammond, C.J. (Christopher), Burkart, K.M. (Kristin), Beilby, J.P. (John), Kritchevsky, S.B. (Stephen), Gudnason, V. (Vilmundur), Hancock, D.B. (Dana), Williams, O.D. (Dale), Polasek, O. (Ozren), Zemunik, T. (Tatijana), Kolcic, I. (Ivana), Petrini, M.F. (Marcy), Jong, K.T. (Kim) de, Wjst, M. (Matthias), Kim, W.H. (Woo), Porteous, D.J. (David J.), Scotland, G. (Generation), Smith, B.H. (Blair), Viljanen, A. (Anne), Heliovaara, M. (Markku), Attia, J. (John), Sayers, I. (Ian), Hampel, R. (Regina), Gieger, C. (Christian), Deary, I.J. (Ian), Boezen, H.M. (Marike), Newman, A.B. (Anne), Jarvelin, M.-R. (Marjo-Riitta), Wilson, J.F. (James), Lind, L. (Lars), Stricker, B.H.Ch. (Bruno), Teumer, A. (Alexander), Spector, T.D. (Timothy), Melén, E. (Erik), Peters, M.J. (Marjolein), Lange, L.A. (Leslie), Barr, R.G. (Graham), Bracke, K.R. (Ken), Verhamme, F.M. (Fien), Sung, J. (Joohon), Hiemstra, P.S. (Pieter), Cassano, P.A. (Patricia), Sood, A. (Akshay), Hayward, C. (Caroline), Dupuis, J. (Josée), Hall, I.P. (Ian), Brusselle, G.G. (Guy), Tobin, M.D. (Martin), London, S.J. (Stephanie), Loth, D.W. (Daan), Artigas, M.S., Gharib, S.A. (Sina), Wain, L.V. (Louise), Franceschini, N. (Nora), Koch, B. (Beate), Pottinger, T.D. (Tess), Smith, A.V. (Davey), Duan, Q. (Qing), Oldmeadow, C. (Christopher), Lee, M.K. (Mi Kyeong), Strachan, D.P. (David), James, A.L. (Alan), Huffman, J.E. (Jennifer), Vitart, V. (Veronique), Ramasamy, A. (Adaikalavan), Wareham, N.J. (Nick), Kaprio, J. (Jaakko), Wang, X.-Q. (Xin-Qun), Trochet, H. (Holly), Kähönen, M. (Mika), Flexeder, C. (Claudia), Albrecht, E. (Eva), Lopez, L.M. (Lorna), Thyagarajan, B. (Bharat), Alves, A.C. (Alexessander Couto), Enroth, S. (Stefan), Omenaas, E. (Ernst), Joshi, P.K. (Peter), Fall, M. (Magnus), Viñuela, A. (Ana), Launer, L.J. (Lenore), Loehr, L.R. (Laura), Fornage, M. (Myriam), Li, G. (Guo), Wilk, J.B. (Jemma), Tang, W. (Wenbo), Manichaikul, A. (Ani), Lahousse, L. (Lies), Harris, T.B. (Tamara), North, K.E. (Kari), Rudnicka, A.R. (Alicja), Hui, J. (Jennie), Gu, X. (Xiangjun), Lumley, T. (Thomas), Wright, A.F. (Alan), Hastie, N. (Nick), Campbell, S. (Susan), Kumar, R. (Rajesh), Pin, I. (Isabelle), Scott, R.A. (Robert), Pietilainen, K.H. (Kirsi Hannele), Surakka, I. (Ida), Liu, Y. (YongMei), Holliday, E.G. (Elizabeth), Schulz, H. (Holger), Heinrich, J. (Joachim), Davies, G. (Gail), Vonk, J.M. (Judith), Wojczynski, M.K. (Mary ), Pouta, A. (Anneli), Johansson, A. (Åsa), Wild, S.H. (Sarah), Ingelsson, E. (Erik), Rivadeneira Ramirez, F. (Fernando), Völzke, H. (Henry), Hysi, P.G. (Pirro), Eiriksdottir, G. (Gudny), Morrison, A.C. (Alanna), Rotter, J.I. (Jerome), Gao, W. (Wei), Postma, D.S. (Dirkje), White, W.B. (Wendy), Rich, S.S. (Stephen), Hofman, A. (Albert), Aspelund, T. (Thor), Couper, D. (David), Smith, L.J. (Lewis), Psaty, B.M. (Bruce), Lohman, K. (Kurt), Burchard, E.G. (Esteban), Uitterlinden, A.G. (André), Garcia, M. (Melissa), Joubert, B.R. (Bonnie), McArdle, W.L. (Wendy), Musk, A.W. (Arthur), Hansel, C.R.W. (Christian), Heckbert, S.R. (Susan), Zgaga, L. (Lina), Meurs, J.B.J. (Joyce) van, Navarro, P. (Pau), Rudan, I. (Igor), Oh, Y.-M. (Yeon-Mok), Redline, S. (Susan), Jarvis, D.L. (Deborah), Zhao, J.H. (Jing Hua), Rantanen, T. (Taina), O'Connor, G.T. (George), Ripatti, S. (Samuli), Scott, R.J. (Rodney), Karrasch, S. (Stefan), Grallert, H. (Harald), Gaddis, N.C. (Nathan), Starr, J.M. (John), Wijmenga, C. (Cisca), Minster, R.L. (Ryan), Lederer, C.W. (Carsten), Pekkanen, J. (Juha), Gyllensten, U. (Ulf), Campbell, H. (Harry), Morris, A.P. (Andrew), Gläser, S. (Sven), Hammond, C.J. (Christopher), Burkart, K.M. (Kristin), Beilby, J.P. (John), Kritchevsky, S.B. (Stephen), Gudnason, V. (Vilmundur), Hancock, D.B. (Dana), Williams, O.D. (Dale), Polasek, O. (Ozren), Zemunik, T. (Tatijana), Kolcic, I. (Ivana), Petrini, M.F. (Marcy), Jong, K.T. (Kim) de, Wjst, M. (Matthias), Kim, W.H. (Woo), Porteous, D.J. (David J.), Scotland, G. (Generation), Smith, B.H. (Blair), Viljanen, A. (Anne), Heliovaara, M. (Markku), Attia, J. (John), Sayers, I. (Ian), Hampel, R. (Regina), Gieger, C. (Christian), Deary, I.J. (Ian), Boezen, H.M. (Marike), Newman, A.B. (Anne), Jarvelin, M.-R. (Marjo-Riitta), Wilson, J.F. (James), Lind, L. (Lars), Stricker, B.H.Ch. (Bruno), Teumer, A. (Alexander), Spector, T.D. (Timothy), Melén, E. (Erik), Peters, M.J. (Marjolein), Lange, L.A. (Leslie), Barr, R.G. (Graham), Bracke, K.R. (Ken), Verhamme, F.M. (Fien), Sung, J. (Joohon), Hiemstra, P.S. (Pieter), Cassano, P.A. (Patricia), Sood, A. (Akshay), Hayward, C. (Caroline), Dupuis, J. (Josée), Hall, I.P. (Ian), Brusselle, G.G. (Guy), Tobin, M.D. (Martin), and London, S.J. (Stephanie)
Abstract: 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.
Published: 2014
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19. Genome-wide association analysis identifies six new loci associated with forced vital capacity

Author: Loth, D.W. (Daan), Artigas, M.S., Gharib, S.A. (Sina), Wain, L.V. (Louise), Franceschini, N. (Nora), Koch, B. (Beate), Pottinger, T.D. (Tess), Smith, A.V. (Davey), Duan, Q. (Qing), Oldmeadow, C. (Christopher), Lee, M.K. (Mi Kyeong), Strachan, D.P. (David), James, A.L. (Alan), Huffman, J.E. (Jennifer), Vitart, V. (Veronique), Ramasamy, A. (Adaikalavan), Wareham, N.J. (Nick), Kaprio, J. (Jaakko), Wang, X.-Q. (Xin-Qun), Trochet, H. (Holly), Kähönen, M. (Mika), Flexeder, C. (Claudia), Albrecht, E. (Eva), Lopez, L.M. (Lorna), Thyagarajan, B. (Bharat), Alves, A.C. (Alexessander Couto), Enroth, S. (Stefan), Omenaas, E. (Ernst), Joshi, P.K. (Peter), Fall, M. (Magnus), Viñuela, A. (Ana), Launer, L.J. (Lenore), Loehr, L.R. (Laura), Fornage, M. (Myriam), Li, G. (Guo), Wilk, J.B. (Jemma), Tang, W. (Wenbo), Manichaikul, A. (Ani), Lahousse, L. (Lies), Harris, T.B. (Tamara), North, K.E. (Kari), Rudnicka, A.R. (Alicja), Hui, J. (Jennie), Gu, X. (Xiangjun), Lumley, T. (Thomas), Wright, A.F. (Alan), Hastie, N. (Nick), Campbell, S. (Susan), Kumar, R. (Rajesh), Pin, I. (Isabelle), Scott, R.A. (Robert), Pietilainen, K.H. (Kirsi Hannele), Surakka, I. (Ida), Liu, Y. (YongMei), Holliday, E.G. (Elizabeth), Schulz, H. (Holger), Heinrich, J. (Joachim), Davies, G. (Gail), Vonk, J.M. (Judith), Wojczynski, M.K. (Mary ), Pouta, A. (Anneli), Johansson, A. (Åsa), Wild, S.H. (Sarah), Ingelsson, E. (Erik), Rivadeneira Ramirez, F. (Fernando), Völzke, H. (Henry), Hysi, P.G. (Pirro), Eiriksdottir, G. (Gudny), Morrison, A.C. (Alanna), Rotter, J.I. (Jerome), Gao, W. (Wei), Postma, D.S. (Dirkje), White, W.B. (Wendy), Rich, S.S. (Stephen), Hofman, A. (Albert), Aspelund, T. (Thor), Couper, D. (David), Smith, L.J. (Lewis), Psaty, B.M. (Bruce), Lohman, K. (Kurt), Burchard, E.G. (Esteban), Uitterlinden, A.G. (André), Garcia, M. (Melissa), Joubert, B.R. (Bonnie), McArdle, W.L. (Wendy), Musk, A.W. (Arthur), Hansel, C.R.W. (Christian), Heckbert, S.R. (Susan), Zgaga, L. (Lina), Meurs, J.B.J. (Joyce) van, Navarro, P. (Pau), Rudan, I. (Igor), Oh, Y.-M. (Yeon-Mok), Redline, S. (Susan), Jarvis, D.L. (Deborah), Zhao, J.H. (Jing Hua), Rantanen, T. (Taina), O'Connor, G.T. (George), Ripatti, S. (Samuli), Scott, R.J. (Rodney), Karrasch, S. (Stefan), Grallert, H. (Harald), Gaddis, N.C. (Nathan), Starr, J.M. (John), Wijmenga, C. (Cisca), Minster, R.L. (Ryan), Lederer, C.W. (Carsten), Pekkanen, J. (Juha), Gyllensten, U. (Ulf), Campbell, H. (Harry), Morris, A.P. (Andrew), Gläser, S. (Sven), Hammond, C.J. (Christopher), Burkart, K.M. (Kristin), Beilby, J.P. (John), Kritchevsky, S.B. (Stephen), Gudnason, V. (Vilmundur), Hancock, D.B. (Dana), Williams, O.D. (Dale), Polasek, O. (Ozren), Zemunik, T. (Tatijana), Kolcic, I. (Ivana), Petrini, M.F. (Marcy), Jong, K.T. (Kim) de, Wjst, M. (Matthias), Kim, W.H. (Woo), Porteous, D.J. (David J.), Scotland, G. (Generation), Smith, B.H. (Blair), Viljanen, A. (Anne), Heliovaara, M. (Markku), Attia, J. (John), Sayers, I. (Ian), Hampel, R. (Regina), Gieger, C. (Christian), Deary, I.J. (Ian), Boezen, H.M. (Marike), Newman, A.B. (Anne), Jarvelin, M.-R. (Marjo-Riitta), Wilson, J.F. (James), Lind, L. (Lars), Stricker, B.H.Ch. (Bruno), Teumer, A. (Alexander), Spector, T.D. (Timothy), Melén, E. (Erik), Peters, M.J. (Marjolein), Lange, L.A. (Leslie), Barr, R.G. (Graham), Bracke, K.R. (Ken), Verhamme, F.M. (Fien), Sung, J. (Joohon), Hiemstra, P.S. (Pieter), Cassano, P.A. (Patricia), Sood, A. (Akshay), Hayward, C. (Caroline), Dupuis, J. (Josée), Hall, I.P. (Ian), Brusselle, G.G. (Guy), Tobin, M.D. (Martin), London, S.J. (Stephanie), Loth, D.W. (Daan), Artigas, M.S., Gharib, S.A. (Sina), Wain, L.V. (Louise), Franceschini, N. (Nora), Koch, B. (Beate), Pottinger, T.D. (Tess), Smith, A.V. (Davey), Duan, Q. (Qing), Oldmeadow, C. (Christopher), Lee, M.K. (Mi Kyeong), Strachan, D.P. (David), James, A.L. (Alan), Huffman, J.E. (Jennifer), Vitart, V. (Veronique), Ramasamy, A. (Adaikalavan), Wareham, N.J. (Nick), Kaprio, J. (Jaakko), Wang, X.-Q. (Xin-Qun), Trochet, H. (Holly), Kähönen, M. (Mika), Flexeder, C. (Claudia), Albrecht, E. (Eva), Lopez, L.M. (Lorna), Thyagarajan, B. (Bharat), Alves, A.C. (Alexessander Couto), Enroth, S. (Stefan), Omenaas, E. (Ernst), Joshi, P.K. (Peter), Fall, M. (Magnus), Viñuela, A. (Ana), Launer, L.J. (Lenore), Loehr, L.R. (Laura), Fornage, M. (Myriam), Li, G. (Guo), Wilk, J.B. (Jemma), Tang, W. (Wenbo), Manichaikul, A. (Ani), Lahousse, L. (Lies), Harris, T.B. (Tamara), North, K.E. (Kari), Rudnicka, A.R. (Alicja), Hui, J. (Jennie), Gu, X. (Xiangjun), Lumley, T. (Thomas), Wright, A.F. (Alan), Hastie, N. (Nick), Campbell, S. (Susan), Kumar, R. (Rajesh), Pin, I. (Isabelle), Scott, R.A. (Robert), Pietilainen, K.H. (Kirsi Hannele), Surakka, I. (Ida), Liu, Y. (YongMei), Holliday, E.G. (Elizabeth), Schulz, H. (Holger), Heinrich, J. (Joachim), Davies, G. (Gail), Vonk, J.M. (Judith), Wojczynski, M.K. (Mary ), Pouta, A. (Anneli), Johansson, A. (Åsa), Wild, S.H. (Sarah), Ingelsson, E. (Erik), Rivadeneira Ramirez, F. (Fernando), Völzke, H. (Henry), Hysi, P.G. (Pirro), Eiriksdottir, G. (Gudny), Morrison, A.C. (Alanna), Rotter, J.I. (Jerome), Gao, W. (Wei), Postma, D.S. (Dirkje), White, W.B. (Wendy), Rich, S.S. (Stephen), Hofman, A. (Albert), Aspelund, T. (Thor), Couper, D. (David), Smith, L.J. (Lewis), Psaty, B.M. (Bruce), Lohman, K. (Kurt), Burchard, E.G. (Esteban), Uitterlinden, A.G. (André), Garcia, M. (Melissa), Joubert, B.R. (Bonnie), McArdle, W.L. (Wendy), Musk, A.W. (Arthur), Hansel, C.R.W. (Christian), Heckbert, S.R. (Susan), Zgaga, L. (Lina), Meurs, J.B.J. (Joyce) van, Navarro, P. (Pau), Rudan, I. (Igor), Oh, Y.-M. (Yeon-Mok), Redline, S. (Susan), Jarvis, D.L. (Deborah), Zhao, J.H. (Jing Hua), Rantanen, T. (Taina), O'Connor, G.T. (George), Ripatti, S. (Samuli), Scott, R.J. (Rodney), Karrasch, S. (Stefan), Grallert, H. (Harald), Gaddis, N.C. (Nathan), Starr, J.M. (John), Wijmenga, C. (Cisca), Minster, R.L. (Ryan), Lederer, C.W. (Carsten), Pekkanen, J. (Juha), Gyllensten, U. (Ulf), Campbell, H. (Harry), Morris, A.P. (Andrew), Gläser, S. (Sven), Hammond, C.J. (Christopher), Burkart, K.M. (Kristin), Beilby, J.P. (John), Kritchevsky, S.B. (Stephen), Gudnason, V. (Vilmundur), Hancock, D.B. (Dana), Williams, O.D. (Dale), Polasek, O. (Ozren), Zemunik, T. (Tatijana), Kolcic, I. (Ivana), Petrini, M.F. (Marcy), Jong, K.T. (Kim) de, Wjst, M. (Matthias), Kim, W.H. (Woo), Porteous, D.J. (David J.), Scotland, G. (Generation), Smith, B.H. (Blair), Viljanen, A. (Anne), Heliovaara, M. (Markku), Attia, J. (John), Sayers, I. (Ian), Hampel, R. (Regina), Gieger, C. (Christian), Deary, I.J. (Ian), Boezen, H.M. (Marike), Newman, A.B. (Anne), Jarvelin, M.-R. (Marjo-Riitta), Wilson, J.F. (James), Lind, L. (Lars), Stricker, B.H.Ch. (Bruno), Teumer, A. (Alexander), Spector, T.D. (Timothy), Melén, E. (Erik), Peters, M.J. (Marjolein), Lange, L.A. (Leslie), Barr, R.G. (Graham), Bracke, K.R. (Ken), Verhamme, F.M. (Fien), Sung, J. (Joohon), Hiemstra, P.S. (Pieter), Cassano, P.A. (Patricia), Sood, A. (Akshay), Hayward, C. (Caroline), Dupuis, J. (Josée), Hall, I.P. (Ian), Brusselle, G.G. (Guy), Tobin, M.D. (Martin), and London, S.J. (Stephanie)
Abstract: 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.
Published: 2014
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20. Transient early wheeze and lung function in early childhood associated with chronic obstructive pulmonary disease genes

Author: Kerkhof, M. (Marjan), Boezen, H.M. (Marike), Granell, R. (Raquel), Wijga, A.H. (Alet), Brunekreef, B. (Bert), Smit, H.A. (Henriëtte), Jongste, J.C. (Johan) de, Thijs, C. (Carel), Mommers, M. (Monique), Penders, J. (John), Henderson, J. (John), Koppelman, G.H. (Gerard), Postma, D.S. (Dirkje), Kerkhof, M. (Marjan), Boezen, H.M. (Marike), Granell, R. (Raquel), Wijga, A.H. (Alet), Brunekreef, B. (Bert), Smit, H.A. (Henriëtte), Jongste, J.C. (Johan) de, Thijs, C. (Carel), Mommers, M. (Monique), Penders, J. (John), Henderson, J. (John), Koppelman, G.H. (Gerard), and Postma, D.S. (Dirkje)
Abstract: Background It has been hypothesized that a disturbed early lung development underlies the susceptibility to chronic obstructive pulmonary disease (COPD). Little is known about whether subjects genetically predisposed to COPD show their first symptoms or reduced lung function in ch
Published: 2014
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21. Susceptibility to chronic mucus hypersecretion, a genome wide association study

Author: Dijkstra, A.E. (Akkelies), Smolonska, J. (Joanna), Berge, M. (Maarten) van den, Wijmenga, C. (Ciska), Zanen, P. (Pieter), Luinge, M.A. (Marjan), Platteel, I. (Inge), Lammers, J.-W.J. (Jan-Willem), Dahlback, M. (Magnus), Tosh, K. (Kerrie), Hiemstra, P.S. (Pieter), Sterk, P.J. (Peter), Spira, M.E. (Micha), Vestbo, J. (Jorgen), Nordestgaard, B.G. (Børge), Benn, M. (Marianne), Nielsen, S.F. (Sune), Dahl, M. (Morten), Verschuren, W.M.M. (W. M. Monique), Picavet, H.S.J. (Susan), Smit, H.A. (Henriëtte), Owsijewitsch, M. (Michael), Kauczor, H.U. (Hans), Koning, H.J. (Harry) de, Nizankowska-Mogilnicka, E. (Eva), Mejza, F. (Filip), Nastalek, P. (Pawel), Diemen, C.C. (Cleo) van, Cho, M.H. (Michael), Silverman, E.K. (Edwin), Crapo, R.O. (Robert), Beaty, T.H. (Terri), Lomas, D.J. (David John), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Bossé, Y. (Yohan), Obeidat, M. (Ma'en), Loth, D.W. (Daan), Lahousse, L. (Lies), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Hofman, A. (Albert), Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Duijn, C.M. (Cornelia) van, Brouwer, U. (Uilke), Koppelman, G.H. (Gerard), Vonk, J.M. (Judith), Nawijn, M.C. (Martijn), Groen, H.J.M. (Henk), Timens, W. (Wim), Boezen, H.M. (Marike), Postma, D.S. (Dirkje), Alizadeh, B.Z. (Behrooz), Boer, R.A. (Rudolf) de, Bruinenberg, M. (M.), Franke, L. (Lude), Harst, P. (Pim) van der, Hillege, H.L. (Hans), Klauw, M.M. (Melanie) van der, Navis, G. (Gerjan), Ormel, J. (Johan), Rosmalen, J.G.M. (Judith), Slaets, J.P.J. (Joris), Snieder, H. (Harold), Stolk, R.P. (Ronald), Wolffenbuttel, B. (Bhr), Dijkstra, A.E. (Akkelies), Smolonska, J. (Joanna), Berge, M. (Maarten) van den, Wijmenga, C. (Ciska), Zanen, P. (Pieter), Luinge, M.A. (Marjan), Platteel, I. (Inge), Lammers, J.-W.J. (Jan-Willem), Dahlback, M. (Magnus), Tosh, K. (Kerrie), Hiemstra, P.S. (Pieter), Sterk, P.J. (Peter), Spira, M.E. (Micha), Vestbo, J. (Jorgen), Nordestgaard, B.G. (Børge), Benn, M. (Marianne), Nielsen, S.F. (Sune), Dahl, M. (Morten), Verschuren, W.M.M. (W. M. Monique), Picavet, H.S.J. (Susan), Smit, H.A. (Henriëtte), Owsijewitsch, M. (Michael), Kauczor, H.U. (Hans), Koning, H.J. (Harry) de, Nizankowska-Mogilnicka, E. (Eva), Mejza, F. (Filip), Nastalek, P. (Pawel), Diemen, C.C. (Cleo) van, Cho, M.H. (Michael), Silverman, E.K. (Edwin), Crapo, R.O. (Robert), Beaty, T.H. (Terri), Lomas, D.J. (David John), Bakke, A.B. (Arnold B.), Gulsvik, A. (Amund), Bossé, Y. (Yohan), Obeidat, M. (Ma'en), Loth, D.W. (Daan), Lahousse, L. (Lies), Rivadeneira Ramirez, F. (Fernando), Uitterlinden, A.G. (André), Hofman, A. (Albert), Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Duijn, C.M. (Cornelia) van, Brouwer, U. (Uilke), Koppelman, G.H. (Gerard), Vonk, J.M. (Judith), Nawijn, M.C. (Martijn), Groen, H.J.M. (Henk), Timens, W. (Wim), Boezen, H.M. (Marike), Postma, D.S. (Dirkje), Alizadeh, B.Z. (Behrooz), Boer, R.A. (Rudolf) de, Bruinenberg, M. (M.), Franke, L. (Lude), Harst, P. (Pim) van der, Hillege, H.L. (Hans), Klauw, M.M. (Melanie) van der, Navis, G. (Gerjan), Ormel, J. (Johan), Rosmalen, J.G.M. (Judith), Slaets, J.P.J. (Joris), Snieder, H. (Harold), Stolk, R.P. (Ronald), and Wolffenbuttel, B. (Bhr)
Abstract: Background: Chronic mucus hypersecretion (CMH) is associated with an increased frequency of respiratory infections, excess lung function decline, and increased hospitalisation and mortality rates in the general population. It is associated with smoking, but it is unknown why only a minority of smokers develops CMH. A plausible explanation for this phenomenon is a predisposing genetic constitution. Therefore, we performed a genome wide association (GWA) study of CMH in Caucasian populations. Methods: GWA analysis was performed in the NELSON-study using the Illumina 610 array, followed by replication and meta-analysis in 11 additional cohorts. In total 2,704 subjects with, and 7,624 subjects without CMH were included, all current or former heavy smokers (≥20 pack-years). Additional studies were performed to test the functional relevance of the most significant single nucleotide polymorphism (SNP). Results: A strong association with CMH, consistent across all cohorts, was observed with rs6577641 (p = 4.25x10-6, OR = 1.17), located in intron 9 of the special AT-rich sequence-binding protein 1 locus (SATB1) on chromosome 3. The risk allele (G) was associated with higher mRNA expression of SATB1 (4.3x10 -9) in lung tissue. Presence of CMH was associated with increased SATB1 mRNA expression in bronchial biopsies from COPD patients. SATB1 expression was induced during differentiation of primary human bronchial epithelial cells in culture. Conclusions: Our findings, that SNP rs6577641 is associated with CMH in multiple cohorts and is a cis-eQTL for SATB1, together with our additional observation that SATB1 expression increases during epithelial differentiation provide suggestive evidence that SATB1 is a gene that affects CMH.
Published: 2014
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22. Rate of progression of CT-quantified emphysema in male current and ex-smokers: A follow-up study

Author: Mohamed Hoesein, F.A.A. (Firdaus), Zanen, P. (Pieter), Jong, P.A. (Pim) de, Ginneken, B.T.J. (Berbke) van, Boezen, H.M. (Marike), Groen, H.J.M. (Henk), Oudkerk, M. (Matthijs), Koning, H.J. (Harry) de, Postma, D.S. (Dirkje), Lammers, J.-W.J. (Jan-Willem), Mohamed Hoesein, F.A.A. (Firdaus), Zanen, P. (Pieter), Jong, P.A. (Pim) de, Ginneken, B.T.J. (Berbke) van, Boezen, H.M. (Marike), Groen, H.J.M. (Henk), Oudkerk, M. (Matthijs), Koning, H.J. (Harry) de, Postma, D.S. (Dirkje), and Lammers, J.-W.J. (Jan-Willem)
Abstract: Background: Little is known about the factors associated with CT-quantified emphysema progression in heavy smokers. The objective of this study was to investigate the effect of length of smoking cessation and clinical / demographical factors on the rate of emphysema progression and FEV1-decline in male heavy smokers.Methods: 3,670 male smokers with mean (SD) 40.8 (17.9) packyears underwent chest CT scans and pulmonary function tests at baseline and after 1 and 3 years follow-up. Smoking status (quitted ≥5, ≥1-<5, <1 years or current smoker) was noted. Rate of progression of emphysema and FEV1-decline after follow-up were assessed by analysis of variance adjusting for age, height, baseline pulmonary function and emphysema severity, packyears, years in study and respiratory symptoms. The quitted ≥5 group was used as reference.Results: Median (Q1-Q3) emphysema severity,<-950 HU, was 8.8 (5.1 - 14.1) and mean (SD) FEV1 was 3.4 (0.73) L or 98.5 (18.5) % of predicted. The group quitted '>5 years' showed significantly lower rates of progression of emphysema compared to current smokers, 1.07% and 1.12% per year, respectively (p<0.001). Current smokers had a yearly FEV1-decline of 69 ml, while subjects quit smoking >5 years had a yearly decline of 57.5 ml (p<0.001).Conclusion: Quit smoking >5 years significantly slows the rate of emphysema progression and lung function decline.Trial registration: Registered at http://www.trialregister.nl with trial number ISRCTN63545820.
Published: 2013
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23. Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function

Author: Hancock, D.B. (Dana), Artigas, M.S., Gharib, S.A. (Sina), Henry, A. (Amanda), Manichaikul, A. (Ani), Ramasamy, A. (Adaikalavan), Loth, D.W. (Daan), Imboden, M. (Medea), Koch, B. (Beate), McArdle, W.L. (Wendy), Smith, A.V. (Davey), Smolonska, J. (Joanna), Sood, A. (Akshay), Tang, W. (Wenbo), Wilk, J.B. (Jemma), Zhai, G. (Guangju), Zhao, J.H. (Jing Hua), Aschard, H. (Hugues), Burkart, K.M. (Kristin), Curjuric, I. (Ivan), Eijgelsheim, M. (Mark), Elliott, P. (Paul), Gu, X. (Xiangjun), Harris, T.B. (Tamara), Janson, C. (Christer), Homuth, G. (Georg), Hysi, P.G. (Pirro), Liu, J. (Jason), Loehr, L.R. (Laura), Lohman, K. (Kurt), Loos, R.J.F. (Ruth), Manning, A.K. (Alisa), Marciante, K. (Kristin), Obeidat, M. (Ma'en), Postma, D.S. (Dirkje), Aldrich, M.C. (Melinda), Brusselle, G.G. (Guy), Chen, T.H., Eiriksdottir, G. (Gudny), Franceschini, N. (Nora), Heinrich, J. (Joachim), Rotter, J.I. (Jerome), Wijmenga, C. (Cisca), Williams, O.D. (Dale), Hofman, A. (Albert), Laurie, C.C. (Cathy), Lumley, T. (Thomas), Morrison, A.C. (Alanna), Joubert, B.R. (Bonnie), Rivadeneira Ramirez, F. (Fernando), Couper, D.J. (David), Kritchevsky, S.B. (Stephen), Liu, Y. (YongMei), Wjst, M. (Matthias), Wain, L.V. (Louise), Vonk, J.M. (Judith), Uitterlinden, A.G. (André), Rochat, T. (Thierry), Rich, S.S. (Stephen), Psaty, B.M. (Bruce), O'Connor, G.T. (George), North, K.E. (Kari), Mirel, D. (Daniel), Meibohm, B. (Bernd), Launer, L.J. (Lenore), Khaw, K-T. (Kay-Tee), Hartikainen, A.L., Hammond, C.J. (Christopher), Gläser, S. (Sven), Marchini, J. (Jonathan), Kraft, P. (Peter), Wareham, N.J. (Nick), Völzke, H. (Henry), Stricker, B.H.Ch. (Bruno), Spector, T.D. (Timothy), Probst-Hensch, N.M. (Nicole M.), Jarvis, D.L. (Deborah), Jarvelin, M.-R. (Marjo-Riitta), Heckbert, S.R. (Susan), Gudnason, V. (Vilmundur), Boezen, H.M. (Marike), Barr, R.G. (Graham), Cassano, P.A. (Patricia), Strachan, D.P. (David), Fornage, M. (Myriam), Hall, I.P. (Ian), Dupuis, J. (Josée), Tobin, M.D. (Martin), London, S.J. (Stephanie), Bentley, A.R. (Amy), Hancock, D.B. (Dana), Artigas, M.S., Gharib, S.A. (Sina), Henry, A. (Amanda), Manichaikul, A. (Ani), Ramasamy, A. (Adaikalavan), Loth, D.W. (Daan), Imboden, M. (Medea), Koch, B. (Beate), McArdle, W.L. (Wendy), Smith, A.V. (Davey), Smolonska, J. (Joanna), Sood, A. (Akshay), Tang, W. (Wenbo), Wilk, J.B. (Jemma), Zhai, G. (Guangju), Zhao, J.H. (Jing Hua), Aschard, H. (Hugues), Burkart, K.M. (Kristin), Curjuric, I. (Ivan), Eijgelsheim, M. (Mark), Elliott, P. (Paul), Gu, X. (Xiangjun), Harris, T.B. (Tamara), Janson, C. (Christer), Homuth, G. (Georg), Hysi, P.G. (Pirro), Liu, J. (Jason), Loehr, L.R. (Laura), Lohman, K. (Kurt), Loos, R.J.F. (Ruth), Manning, A.K. (Alisa), Marciante, K. (Kristin), Obeidat, M. (Ma'en), Postma, D.S. (Dirkje), Aldrich, M.C. (Melinda), Brusselle, G.G. (Guy), Chen, T.H., Eiriksdottir, G. (Gudny), Franceschini, N. (Nora), Heinrich, J. (Joachim), Rotter, J.I. (Jerome), Wijmenga, C. (Cisca), Williams, O.D. (Dale), Hofman, A. (Albert), Laurie, C.C. (Cathy), Lumley, T. (Thomas), Morrison, A.C. (Alanna), Joubert, B.R. (Bonnie), Rivadeneira Ramirez, F. (Fernando), Couper, D.J. (David), Kritchevsky, S.B. (Stephen), Liu, Y. (YongMei), Wjst, M. (Matthias), Wain, L.V. (Louise), Vonk, J.M. (Judith), Uitterlinden, A.G. (André), Rochat, T. (Thierry), Rich, S.S. (Stephen), Psaty, B.M. (Bruce), O'Connor, G.T. (George), North, K.E. (Kari), Mirel, D. (Daniel), Meibohm, B. (Bernd), Launer, L.J. (Lenore), Khaw, K-T. (Kay-Tee), Hartikainen, A.L., Hammond, C.J. (Christopher), Gläser, S. (Sven), Marchini, J. (Jonathan), Kraft, P. (Peter), Wareham, N.J. (Nick), Völzke, H. (Henry), Stricker, B.H.Ch. (Bruno), Spector, T.D. (Timothy), Probst-Hensch, N.M. (Nicole M.), Jarvis, D.L. (Deborah), Jarvelin, M.-R. (Marjo-Riitta), Heckbert, S.R. (Susan), Gudnason, V. (Vilmundur), Boezen, H.M. (Marike), Barr, R.G. (Graham), Cassano, P.A. (Patricia), Strachan, D.P. (David), Fornage, M. (Myriam), Hall, I.P. (Ian), Dupuis, J. (Josée), Tobin, M.D. (Martin), London, S.J. (Stephanie), and Bentley, A.R. (Amy)
Published: 2012
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24. Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction

Author: Wilk, J.B. (Jemma), Shrine, N.R.G. (Nick), Loehr, L.R. (Laura), Zhao, J.H. (Jing Hua), Manichaikul, A. (Ani), Lopez, L.M. (Lorna), Smith, A.V. (Davey), Heckbert, S.R. (Susan), Smolonska, J. (Joanna), Tang, W. (Wenbo), Loth, D.W. (Daan), Curjuric, I. (Ivan), Hui, J. (Jennie), Cho, M.H. (Michael), Latourelle, J.C. (Jeanne), Henry, A. (Amanda), Aldrich, M.C. (Melinda), Bakke, A.B. (Arnold B.), Beaty, T.H. (Terri), Bentley, A.R. (Amy), Borecki, I.B. (Ingrid), Brusselle, G.G. (Guy), Burkart, K.M. (Kristin), Chen, T.H., Couper, D.J. (David), Crapo, R.O. (Robert), Davies, G. (Gail), Dupuis, J. (Josée), Franceschini, N. (Nora), Gulsvik, A. (Amund), Hancock, D.B. (Dana), Harris, T.B. (Tamara), Hofman, A. (Albert), Imboden, M. (Medea), James, A.L. (Alan), Khaw, K-T. (Kay-Tee), Lahousse, L. (Lies), Launer, L.J. (Lenore), Litonjua, A.A. (Augusto), Liu, Y. (YongMei), Lohman, K. (Kurt), Lomas, D.J. (David John), Lumley, T. (Thomas), Marciante, K. (Kristin), McArdle, W.L. (Wendy), Meibohm, B. (Bernd), Morrison, A.C. (Alanna), Musk, A.W. (Arthur), Myers, R.H. (Richard), North, K.E. (Kari), Postma, D.S. (Dirkje), Psaty, B.M. (Bruce), Rich, S.S. (Stephen), Rivadeneira Ramirez, F. (Fernando), Rochat, T. (Thierry), Rotter, J.I. (Jerome), Soler Artigas, M. (Maria), Starr, J.M. (John), Uitterlinden, A.G. (André), Wareham, N.J. (Nick), Wijmenga, C. (Cisca), Zanen, P. (Pieter), Province, M.A. (Mike), Silverman, E. (Edwin), Deary, I.J. (Ian), Palmer, C. (Cameron), Cassano, P.A. (Patricia), Gudnason, V. (Vilmundur), Barr, R.G. (Graham), Loos, R.J.F. (Ruth), Strachan, D.P. (David), London, S.J. (Stephanie), Boezen, H.M. (Marike), Probst-Hensch, N. (Nicole), Gharib, S.A. (Sina), Hall, I.P. (Ian), O'Connor, G.T. (George), Tobin, M.D. (Martin), Stricker, B.H.Ch. (Bruno), Wilk, J.B. (Jemma), Shrine, N.R.G. (Nick), Loehr, L.R. (Laura), Zhao, J.H. (Jing Hua), Manichaikul, A. (Ani), Lopez, L.M. (Lorna), Smith, A.V. (Davey), Heckbert, S.R. (Susan), Smolonska, J. (Joanna), Tang, W. (Wenbo), Loth, D.W. (Daan), Curjuric, I. (Ivan), Hui, J. (Jennie), Cho, M.H. (Michael), Latourelle, J.C. (Jeanne), Henry, A. (Amanda), Aldrich, M.C. (Melinda), Bakke, A.B. (Arnold B.), Beaty, T.H. (Terri), Bentley, A.R. (Amy), Borecki, I.B. (Ingrid), Brusselle, G.G. (Guy), Burkart, K.M. (Kristin), Chen, T.H., Couper, D.J. (David), Crapo, R.O. (Robert), Davies, G. (Gail), Dupuis, J. (Josée), Franceschini, N. (Nora), Gulsvik, A. (Amund), Hancock, D.B. (Dana), Harris, T.B. (Tamara), Hofman, A. (Albert), Imboden, M. (Medea), James, A.L. (Alan), Khaw, K-T. (Kay-Tee), Lahousse, L. (Lies), Launer, L.J. (Lenore), Litonjua, A.A. (Augusto), Liu, Y. (YongMei), Lohman, K. (Kurt), Lomas, D.J. (David John), Lumley, T. (Thomas), Marciante, K. (Kristin), McArdle, W.L. (Wendy), Meibohm, B. (Bernd), Morrison, A.C. (Alanna), Musk, A.W. (Arthur), Myers, R.H. (Richard), North, K.E. (Kari), Postma, D.S. (Dirkje), Psaty, B.M. (Bruce), Rich, S.S. (Stephen), Rivadeneira Ramirez, F. (Fernando), Rochat, T. (Thierry), Rotter, J.I. (Jerome), Soler Artigas, M. (Maria), Starr, J.M. (John), Uitterlinden, A.G. (André), Wareham, N.J. (Nick), Wijmenga, C. (Cisca), Zanen, P. (Pieter), Province, M.A. (Mike), Silverman, E. (Edwin), Deary, I.J. (Ian), Palmer, C. (Cameron), Cassano, P.A. (Patricia), Gudnason, V. (Vilmundur), Barr, R.G. (Graham), Loos, R.J.F. (Ruth), Strachan, D.P. (David), London, S.J. (Stephanie), Boezen, H.M. (Marike), Probst-Hensch, N. (Nicole), Gharib, S.A. (Sina), Hall, I.P. (Ian), O'Connor, G.T. (George), Tobin, M.D. (Martin), and Stricker, B.H.Ch. (Bruno)
Abstract: 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 ofCOPD assessedby spirometry, in population-based cohorts examining all participants, ever smokers, never smokers, asthma-free participants, and more severe cases. Methods: Fif
Published: 2012
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25. Gender differences in respiratory symptoms in 19-year-old adults born preterm

Author: Vrijlandt, E.J.L.E., Gerritsen, J. (Jorrit), Boezen, H.M. (Marike), Duiverman, E.J. (Eric), Hille, E.T. (Elysee), Groot, C.H. (C.) de, Kloosterboer-Boerrigter, H. (H.), Ouden, A.L. (A.) den, Rijpstra, A. (A.), Verloove-Vanhorick, S.P., Vogelaar, J.A. (J.), Kok, J.H. (Joke), Ilsen, A. (Adri), Lans, M. (M.) van der, Boelen-van der Loo, W.J.C. (W. J C), Lundqvist, T. (T.), Heymans, H.S.A. (Hugo), Geven, W.B. (Wil), Duiverman, M.L. (M.), Geven, L.I. (L.), Mulder, A.L.M., Gerver, W.J., Kollee, L.A., Reijmers, R.M. (Rogier), Sonnemans, R. (R.), Wit, J.M. (Jan), Dekker, F.W. (Friedo), Finken, M.J. (Martijn), Weisglas-Kuperus, N. (Nynke), Keijzer-Veen, M.G. (Mandy), Heijden, A.J. (Bert) van der, Goudoever, J.B. (Hans) van, Weissenbruch, M.M. (Mirjam) van, Cranendonk, A. (Anneke), Delemarre-van de Waal, H.A. (Henriette), Groot, L. (Laila) de, Samsom, J.F. (J.), Vries, L.S. (Linda) de, Rademaker, K.J. (K.), Moerman, E. (E.), Voogsgeerd, M. (M.), Kleine, M.J.K. (Martin) de, Andriessen, P. (Peter), Dielissen-van Helvoirt, C.C.M. (C. C M), Mohamed, I. (I.), Straaten, H.L.M. (Henrica) van, Baerts, W. (Wim), Veneklaas Slots-Kloosterboer, G.W. (G.), Tuller-Pikkemaat, E.M.J. (E. M J), Ens-Dokkum, M.H. (Martina), Steenbrugge, G.J. (G.) van, Vrijlandt, E.J.L.E., Gerritsen, J. (Jorrit), Boezen, H.M. (Marike), Duiverman, E.J. (Eric), Hille, E.T. (Elysee), Groot, C.H. (C.) de, Kloosterboer-Boerrigter, H. (H.), Ouden, A.L. (A.) den, Rijpstra, A. (A.), Verloove-Vanhorick, S.P., Vogelaar, J.A. (J.), Kok, J.H. (Joke), Ilsen, A. (Adri), Lans, M. (M.) van der, Boelen-van der Loo, W.J.C. (W. J C), Lundqvist, T. (T.), Heymans, H.S.A. (Hugo), Geven, W.B. (Wil), Duiverman, M.L. (M.), Geven, L.I. (L.), Mulder, A.L.M., Gerver, W.J., Kollee, L.A., Reijmers, R.M. (Rogier), Sonnemans, R. (R.), Wit, J.M. (Jan), Dekker, F.W. (Friedo), Finken, M.J. (Martijn), Weisglas-Kuperus, N. (Nynke), Keijzer-Veen, M.G. (Mandy), Heijden, A.J. (Bert) van der, Goudoever, J.B. (Hans) van, Weissenbruch, M.M. (Mirjam) van, Cranendonk, A. (Anneke), Delemarre-van de Waal, H.A. (Henriette), Groot, L. (Laila) de, Samsom, J.F. (J.), Vries, L.S. (Linda) de, Rademaker, K.J. (K.), Moerman, E. (E.), Voogsgeerd, M. (M.), Kleine, M.J.K. (Martin) de, Andriessen, P. (Peter), Dielissen-van Helvoirt, C.C.M. (C. C M), Mohamed, I. (I.), Straaten, H.L.M. (Henrica) van, Baerts, W. (Wim), Veneklaas Slots-Kloosterboer, G.W. (G.), Tuller-Pikkemaat, E.M.J. (E. M J), Ens-Dokkum, M.H. (Martina), and Steenbrugge, G.J. (G.) van
Abstract: Objective: To study the prevalence of respiratory and atopic symptoms in (young) adults born prematurely, differences between those who did and did not develop Bronchopulmonary Disease (BPD) at neonatal age and differences in respiratory health between males and females. Methods: Design: Prospective cohort study. Setting: Nation wide follow-up study, the Netherlands. Participants: 690 adults (19 year old) born with a gestational age below 32 completed weeks and/or with a birth weight less than 1500g. Controls were Dutch participants of the European Community Respiratory Health Survey (ECRHS). Main outcome measures: Presence of wheeze, shortness of breath, asthma, hay fever and eczema using the ECRHS-questionnaire R
Published: 2005
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25 results on '"Boezen, H.M. (Marike)"'

1. Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression

2. Occupational exposure to gases/fumes and mineral dust affect DNA methylation levels of genes regulating expression

3. DNA methylation is associated with lung function in never smokers

4. Limited overlap in significant hits between genome-wide association studies on two airflow obstruction definitions in the same population

5. Multi-ancestry study of blood lipid levels identifies four loci interacting with physical activity

6. Occupational exposure to pesticides is associated with differential DNA methylation

7. From blood to lung tissue: Effect of cigarette smoke on DNA methylation and lung function 06 Biological Sciences 0604 Genetics 11 Medical and Health Sciences 1102 Cardiorespiratory Medicine and Haematology

8. Genome-wide analyses identify a role for SLC17A4 and AADAT in thyroid hormone regulation

9. Multiethnic meta-analysis identifies ancestry-specific and cross-ancestry loci for pulmonary function

10. Long-term air pollution exposure, genome-wide DNA methylation and lung function in the lifelines cohort study

11. A Genome-wide linkage study for chronic obstructive pulmonary disease in a dutch genetic isolate identifies novel rare candidate variants

12. COPD GWAS variant at 19q13.2 in relation with DNA methylation and gene expression

13. Genetic loci associated with chronic obstructive pulmonary disease overlap with loci for lung function and pulmonary fibrosis

14. Genes and pathways underlying susceptibility to impaired lung function in the context of environmental tobacco smoke exposure

15. Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma

16. Twenty-eight genetic loci associated with ST-T-wave amplitudes of the electrocardiogram

17. Association of Forced Vital Capacity with the Developmental Gene NCOR2

18. Genome-wide association analysis identifies six new loci associated with forced vital capacity

19. Genome-wide association analysis identifies six new loci associated with forced vital capacity

20. Transient early wheeze and lung function in early childhood associated with chronic obstructive pulmonary disease genes

21. Susceptibility to chronic mucus hypersecretion, a genome wide association study

22. Rate of progression of CT-quantified emphysema in male current and ex-smokers: A follow-up study

23. Genome-Wide Joint Meta-Analysis of SNP and SNP-by-Smoking Interaction Identifies Novel Loci for Pulmonary Function

24. Genome-wide association studies identify CHRNA5/3 and HTR4 in the development of airflow obstruction

25. Gender differences in respiratory symptoms in 19-year-old adults born preterm

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25 results on '"Boezen, H.M. (Marike)"'

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