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60 results on '"Vonk, J.M."'

4. Ultrafine particles, particle components and lung function at age 16 years: The PIAMA birth cohort study

Author

Yu, Z., Koppelman, G.H., Hoek, G., Kerckhoffs, J., Vonk, J.M., Vermeulen, R., Gehring, U., Yu, Z., Koppelman, G.H., Hoek, G., Kerckhoffs, J., Vonk, J.M., Vermeulen, R., and Gehring, U.

Abstract

Background Particulate matter (PM) air pollution exposure has been linked to lung function in adolescents, but little is known about the relevance of specific PM components and ultrafine particles (UFP). Objectives To investigate the associations of long-term exposure to PM elemental composition and UFP with lung function at age 16 years. Methods For 706 participants of a prospective Dutch birth cohort, we assessed associations of forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC) at age 16 with average exposure to eight elemental components (copper, iron, potassium, nickel, sulfur, silicon, vanadium and zinc) in PM2.5 and PM10, as well as UFP during the preceding years (age 13–16 years) estimated by land-use regression models. After assessing associations for each pollutant individually using linear regression models with adjustment for potential confounders, independence of associations with different pollutants was assessed in two-pollutant models with PM mass and NO2, for which associations with lung function have been reported previously. Results We observed that for most PM elemental components higher exposure was associated with lower FEV1, especially PM10 sulfur [e.g. adjusted difference −2.23% (95% confidence interval (CI) −3.70 to −0.74%) per interquartile range (IQR) increase in PM10 sulfur]. The association with PM10 sulfur remained after adjusting for PM10 mass. Negative associations of exposure to UFP with both FEV1 and FVC were observed [-1.06% (95% CI: −2.08 to −0.03%) and −0.65% (95% CI: −1.53 to 0.23%), respectively per IQR increase in UFP], but did not persist in two-pollutant models with NO2 or PM2.5. Conclusions Long-term exposure to sulfur in PM10 may result in lower FEV1 at age 16. There is no evidence for an independent effect of UFP exposure.

Published
2021

5. Shared DNA methylation signatures in childhood allergy: The MeDALL study

Author

Xu, C., Gruzieva, O., Qi, C., Esplugues, A., Gehring, U., Bergström, A., Mason, D., Chatzi, L., Porta, D., Carlsen, K.C.L., Baïz, N., Madore, A.M., Alenius, H., Rijkom, B. van, Jankipersadsing, S.A., Vlies, P., Kull, I., Hage, M., Bustamante, M, Lertxundi, A., Torrent, M., Santorelli, G., Fantini, M.P., Hovland, V., Pesce, G., Fyhrquist, N., Laatikainen, T., Nawijn, M.C., Li, Y., Wijmenga, C., Netea, M.G., Bousquet, J., Anto, J.M., Laprise, C., Haahtela, T., Annesi-Maesano, I., Carlsen, K.H., Gori, D., Kogevinas, M., Wright, J., Söderhäll, C., Vonk, J.M., Sunyer, J., Melén, E., Koppelman, G.H., Xu, C., Gruzieva, O., Qi, C., Esplugues, A., Gehring, U., Bergström, A., Mason, D., Chatzi, L., Porta, D., Carlsen, K.C.L., Baïz, N., Madore, A.M., Alenius, H., Rijkom, B. van, Jankipersadsing, S.A., Vlies, P., Kull, I., Hage, M., Bustamante, M, Lertxundi, A., Torrent, M., Santorelli, G., Fantini, M.P., Hovland, V., Pesce, G., Fyhrquist, N., Laatikainen, T., Nawijn, M.C., Li, Y., Wijmenga, C., Netea, M.G., Bousquet, J., Anto, J.M., Laprise, C., Haahtela, T., Annesi-Maesano, I., Carlsen, K.H., Gori, D., Kogevinas, M., Wright, J., Söderhäll, C., Vonk, J.M., Sunyer, J., Melén, E., and Koppelman, G.H.

Abstract

Contains fulltext : 232514.pdf (Publisher’s version ) (Open Access), BACKGROUND: Differential DNA methylation associated with allergy might provide novel insights into the shared or unique etiology of asthma, rhinitis, and eczema. OBJECTIVE: We sought to identify DNA methylation profiles associated with childhood allergy. METHODS: Within the European Mechanisms of the Development of Allergy (MeDALL) consortium, we performed an epigenome-wide association study of whole blood DNA methylation by using a cross-sectional design. Allergy was defined as having symptoms from at least 1 allergic disease (asthma, rhinitis, or eczema) and positive serum-specific IgE to common aeroallergens. The discovery study included 219 case patients and 417 controls at age 4 years and 228 case patients and 593 controls at age 8 years from 3 birth cohorts, with replication analyses in 325 case patients and 1111 controls. We performed additional analyses on 21 replicated sites in 785 case patients and 2124 controls by allergic symptoms only from 8 cohorts, 3 of which were not previously included in analyses. RESULTS: We identified 80 differentially methylated CpG sites that showed a 1% to 3% methylation difference in the discovery phase, of which 21 (including 5 novel CpG sites) passed genome-wide significance after meta-analysis. All 21 CpG sites were also significantly differentially methylated with allergic symptoms and shared between asthma, rhinitis, and eczema. The 21 CpG sites mapped to relevant genes, including ACOT7, LMAN3, and CLDN23. All 21 CpG sties were differently methylated in asthma in isolated eosinophils, and 10 were replicated in respiratory epithelium. CONCLUSION: Reduced whole blood DNA methylation at 21 CpG sites was significantly associated with childhood allergy. The findings provide novel insights into the shared molecular mechanisms underlying asthma, rhinitis, and eczema.

Published
2021

8. Shared DNA methylation signatures in childhood allergy: The MeDALL study

Author

Xu, C., Gruzieva, O., Qi, C., Esplugues, A., Gehring, U., Bergström, A., Mason, D., Chatzi, L., Porta, D., Carlsen, K.C.L., Baïz, N., Madore, A.M., Alenius, H., Rijkom, B. van, Jankipersadsing, S.A., Vlies, P., Kull, I., Hage, M., Bustamante, M, Lertxundi, A., Torrent, M., Santorelli, G., Fantini, M.P., Hovland, V., Pesce, G., Fyhrquist, N., Laatikainen, T., Nawijn, M.C., Li, Y., Wijmenga, C., Netea, M.G., Bousquet, J., Anto, J.M., Laprise, C., Haahtela, T., Annesi-Maesano, I., Carlsen, K.H., Gori, D., Kogevinas, M., Wright, J., Söderhäll, C., Vonk, J.M., Sunyer, J., Melén, E., Koppelman, G.H., Xu, C., Gruzieva, O., Qi, C., Esplugues, A., Gehring, U., Bergström, A., Mason, D., Chatzi, L., Porta, D., Carlsen, K.C.L., Baïz, N., Madore, A.M., Alenius, H., Rijkom, B. van, Jankipersadsing, S.A., Vlies, P., Kull, I., Hage, M., Bustamante, M, Lertxundi, A., Torrent, M., Santorelli, G., Fantini, M.P., Hovland, V., Pesce, G., Fyhrquist, N., Laatikainen, T., Nawijn, M.C., Li, Y., Wijmenga, C., Netea, M.G., Bousquet, J., Anto, J.M., Laprise, C., Haahtela, T., Annesi-Maesano, I., Carlsen, K.H., Gori, D., Kogevinas, M., Wright, J., Söderhäll, C., Vonk, J.M., Sunyer, J., Melén, E., and Koppelman, G.H.

Abstract

Contains fulltext : 232514.pdf (Publisher’s version ) (Open Access), BACKGROUND: Differential DNA methylation associated with allergy might provide novel insights into the shared or unique etiology of asthma, rhinitis, and eczema. OBJECTIVE: We sought to identify DNA methylation profiles associated with childhood allergy. METHODS: Within the European Mechanisms of the Development of Allergy (MeDALL) consortium, we performed an epigenome-wide association study of whole blood DNA methylation by using a cross-sectional design. Allergy was defined as having symptoms from at least 1 allergic disease (asthma, rhinitis, or eczema) and positive serum-specific IgE to common aeroallergens. The discovery study included 219 case patients and 417 controls at age 4 years and 228 case patients and 593 controls at age 8 years from 3 birth cohorts, with replication analyses in 325 case patients and 1111 controls. We performed additional analyses on 21 replicated sites in 785 case patients and 2124 controls by allergic symptoms only from 8 cohorts, 3 of which were not previously included in analyses. RESULTS: We identified 80 differentially methylated CpG sites that showed a 1% to 3% methylation difference in the discovery phase, of which 21 (including 5 novel CpG sites) passed genome-wide significance after meta-analysis. All 21 CpG sites were also significantly differentially methylated with allergic symptoms and shared between asthma, rhinitis, and eczema. The 21 CpG sites mapped to relevant genes, including ACOT7, LMAN3, and CLDN23. All 21 CpG sties were differently methylated in asthma in isolated eosinophils, and 10 were replicated in respiratory epithelium. CONCLUSION: Reduced whole blood DNA methylation at 21 CpG sites was significantly associated with childhood allergy. The findings provide novel insights into the shared molecular mechanisms underlying asthma, rhinitis, and eczema.

Published
2021

13. DNA methylation and body mass index from birth to adolescence: meta-analyses of epigenome-wide association studies

Author

Vehmeijer, F.O.L. (Florianne O.L.), Küpers, A.M. (Marlijn), Sharp, G.C. (Gemma C.), Salas, L.A. (Lucas A.), Lent, S. (Samantha), Jima, D.D. (Dereje D.), Tindula, G. (Gwen), Reese, S.E. (Sarah E.), Qi, C. (Cancan), Gruzieva, O. (Olena), Page, C. (Christian), Rezwan, F.I. (Faisal I.), Melton, P.E. (Philip E.), Nohr, C. (Christian), Escaramís, G. (Geòrgia), Rzehak, P. (Peter), Heiskala, A. (Anni), Gong, T. (Tong), Tuominen, S.T. (Samuli T.), Gao, L. (Lu), Ross, J.P. (Jason P.), Starling, A.P. (Anne P.), Holloway, J.W. (John W.), Yousefi, P. (Paul), Aasvang, G.M. (Gunn Marit), Beilin, L.J. (Lawrence), Bergström, A. (Anna), Binder, E.B. (Elisabeth), Chatzi, L. (Leda), Corpeleijn, E. (Eva), Czamara, D. (Darina), Eskenazi, B. (B.), Ewart, S. (Susan), Ferre, N. (Natalia), Grote, V. (Veit), Gruszfeld, D. (Dariusz), Håberg, S.E. (Siri E), Hoyo, C. (Cathrine), Huen, K. (Karen), Karlsson, R. (Robert), Kull, C.A. (Christian), Langhendries, J.P. (Jean Paul), Lepeule, J. (Johanna), Magnus, M.C. (Maria C.), Maguire, R.L. (Rachel L.), Molloy, P.L. (Peter L.), Poppelaars-Monnereau, C. (Claire), Mori, T.A. (Trevor A.), Oken, E. (Emily), Räikkönen, K. (Katri), Rifas-Shiman, S.L. (Sheryl), Ruiz-Arenas, C. (Carlos), Sebert, S. (Sylvain), Ullemar, V. (Vilhelmina), Verduci, E. (Elvira), Vonk, J.M. (Judith), Xu, C.-J. (Cheng-Jian), Yang, I.V. (Ivana V.), Zhang, H. (Hongmei), Zhang, W. (Weiming), Karmaus, W. (Wilfried), Dabelea, D. (Dana), Muhlhausler, B.S. (Beverly S.), Breton, C. (Carrie), Lahti, J. (Jari), Almqvist, C. (Catarina), Jarvelin, M.-R. (Marjo-Riitta), Koletzko, B. (Berthold), Vrijheid, M. (Martine), Sørensen, T.I.A. (Thorkild), Huang, R.-C. (Rae-Chi), Arshad, S.H. (Syed), Nystad, W. (Wenche), Melén, E. (Erik), Koppelman, G.H. (Gerard), London, S.J. (Stephanie J.), Holland, N. (Nina), Bustamante, M. (Mariona), Murphy, S.K. (Susan K.), Hivert, M.-F. (Marie-France), Baccarelli, A.A. (Andrea), Relton, C.L. (Caroline), Snieder, H. (Harold), Jaddoe, V.W.V. (Vincent), Felix, J.F. (Janine), Vehmeijer, F.O.L. (Florianne O.L.), Küpers, A.M. (Marlijn), Sharp, G.C. (Gemma C.), Salas, L.A. (Lucas A.), Lent, S. (Samantha), Jima, D.D. (Dereje D.), Tindula, G. (Gwen), Reese, S.E. (Sarah E.), Qi, C. (Cancan), Gruzieva, O. (Olena), Page, C. (Christian), Rezwan, F.I. (Faisal I.), Melton, P.E. (Philip E.), Nohr, C. (Christian), Escaramís, G. (Geòrgia), Rzehak, P. (Peter), Heiskala, A. (Anni), Gong, T. (Tong), Tuominen, S.T. (Samuli T.), Gao, L. (Lu), Ross, J.P. (Jason P.), Starling, A.P. (Anne P.), Holloway, J.W. (John W.), Yousefi, P. (Paul), Aasvang, G.M. (Gunn Marit), Beilin, L.J. (Lawrence), Bergström, A. (Anna), Binder, E.B. (Elisabeth), Chatzi, L. (Leda), Corpeleijn, E. (Eva), Czamara, D. (Darina), Eskenazi, B. (B.), Ewart, S. (Susan), Ferre, N. (Natalia), Grote, V. (Veit), Gruszfeld, D. (Dariusz), Håberg, S.E. (Siri E), Hoyo, C. (Cathrine), Huen, K. (Karen), Karlsson, R. (Robert), Kull, C.A. (Christian), Langhendries, J.P. (Jean Paul), Lepeule, J. (Johanna), Magnus, M.C. (Maria C.), Maguire, R.L. (Rachel L.), Molloy, P.L. (Peter L.), Poppelaars-Monnereau, C. (Claire), Mori, T.A. (Trevor A.), Oken, E. (Emily), Räikkönen, K. (Katri), Rifas-Shiman, S.L. (Sheryl), Ruiz-Arenas, C. (Carlos), Sebert, S. (Sylvain), Ullemar, V. (Vilhelmina), Verduci, E. (Elvira), Vonk, J.M. (Judith), Xu, C.-J. (Cheng-Jian), Yang, I.V. (Ivana V.), Zhang, H. (Hongmei), Zhang, W. (Weiming), Karmaus, W. (Wilfried), Dabelea, D. (Dana), Muhlhausler, B.S. (Beverly S.), Breton, C. (Carrie), Lahti, J. (Jari), Almqvist, C. (Catarina), Jarvelin, M.-R. (Marjo-Riitta), Koletzko, B. (Berthold), Vrijheid, M. (Martine), Sørensen, T.I.A. (Thorkild), Huang, R.-C. (Rae-Chi), Arshad, S.H. (Syed), Nystad, W. (Wenche), Melén, E. (Erik), Koppelman, G.H. (Gerard), London, S.J. (Stephanie J.), Holland, N. (Nina), Bustamante, M. (Mariona), Murphy, S.K. (Susan K.), Hivert, M.-F. (Marie-France), Baccarelli, A.A. (Andrea), Relton, C.L. (Caroline), Snieder, H. (Harold), Jaddoe, V.W.V. (Vincent), and Felix, J.F. (Janine)

Abstract

Background: DNA methylation has been shown to be associated with adiposity in adulthood. However, whether similar DNA methylation patterns are associated with childhood and adolescent body mass index (BMI) is largely unknown. More insight into this relationship at younger ages may have implications for future prevention of obesity and its related traits. Methods: We examined whether DNA methylation in cord blood and whole blood in childhood and adolescence was associated with BMI in the age range from 2 to 18 years using both cross-sectional and longitudinal models. We performed meta-analyses of epigenome-wide association studies including up to 4133 children from 23 studies. We examined the overlap of findings reported in previous studies in children and adults with those in our analyses and calculated enrichment. Results: DNA methylation at three CpGs (cg05937453, cg25212453, and cg10040131), each in a different age range, was associated with BMI at Bonferroni significance, P < 1.06 × 10−7, with a 0.96 standard deviation score (SDS) (standard error (SE) 0.17), 0.32 SDS (SE 0.06), and 0.32 BMI SDS (SE 0.06) higher BMI per 10% increase in methylation, respectively. DNA methylation at nine additional CpGs in the cross-sectional childhood model was associated with BMI at false discovery rate significance. The strength of the associations of DNA methylation at the 187 CpGs previously identified to be associated with adult BMI, increased with advancing age across childhood and adolescence in our analyses. In addition, correlation coefficients between effect estimates for those CpGs in adults and in children and adolescents also increased. Among the top findings for each age range, we observed increasing enrichment for the CpGs that were previously identified in adults (birth Penrichment = 1; childhood Penrichment = 2.00 × 10−4; adolescence Penrichment = 2.10 × 10−7). Conclusions: There were only minimal associations of DNA methylation with childhood and adolescent BMI.

Published
2020
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14. A cross-omics integrative study of metabolic signatures of chronic obstructive pulmonary disease

Author

Prokić, I. (Ivana), Lahousse, L. (Lies), de Vries, M. (Maaike), Liu, J. (Jun), Kalaoja, M. (Marita), Vonk, J.M. (Judith), van der Plaat, D.A. (Diana A.), van Diemen, C.C. (Cleo C.), Spek, A. (Ashley) van der, Zhernakova, A. (Alexandra), Fu, J. (Jingyuan), Ghanbari, M. (Mohsen), Ala-Korpela, M. (Mika), Kettunen, J. (Johannes), Havulinna, A.S. (Aki), Perola, M. (Markus), Salomaa, V. (Veikko), Kao, W.H.L. (Wen), Ärnlöv, J. (Johan), Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Boezen, H.M. (H Marike), Duijn, C.M. (Cornelia) van, Amin, N. (Najaf), Prokić, I. (Ivana), Lahousse, L. (Lies), de Vries, M. (Maaike), Liu, J. (Jun), Kalaoja, M. (Marita), Vonk, J.M. (Judith), van der Plaat, D.A. (Diana A.), van Diemen, C.C. (Cleo C.), Spek, A. (Ashley) van der, Zhernakova, A. (Alexandra), Fu, J. (Jingyuan), Ghanbari, M. (Mohsen), Ala-Korpela, M. (Mika), Kettunen, J. (Johannes), Havulinna, A.S. (Aki), Perola, M. (Markus), Salomaa, V. (Veikko), Kao, W.H.L. (Wen), Ärnlöv, J. (Johan), Stricker, B.H.Ch. (Bruno), Brusselle, G.G. (Guy), Boezen, H.M. (H Marike), Duijn, C.M. (Cornelia) van, and Amin, N. (Najaf)

Abstract

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a common lung disorder characterized by persistent and progressive airflow limitation as well as systemic changes. Metabolic changes in blood may help detect COPD in an earlier stage and predict prognosis. METHODS: We conducted a comprehensive study of circulating metabolites, measured by proton Nuclear Magnetic Resonance Spectroscopy, in relation with COPD and lung function. The discovery sample consisted of 5557 individuals from two large population-based studies in the Netherlands, the Rotterdam Study and the Erasmus Rucphen Family study. Significant findings were replicated in 12,205 individuals from the Lifelines-DEEP study, FINRISK and the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) studies. For replicated metabolites further investigation of causality was performed, utilizing genetics in the Mendelian randomization approach. RESULTS: There were 602 cases of COPD and 4955 controls used in the discovery meta-analysis. Our logistic regression results showed that higher levels of plasma Glycoprotein acetyls (GlycA) are significantly associated with COPD (OR = 1.16, P = 5.6 × 10- 4 in the discovery and OR = 1.30, P = 1.8 × 10- 6 in the replication sample). A bi-directional two-sample Mendelian randomization analysis suggested that circulating blood GlycA is not causally related to COPD, but that COPD causally i

Published
2020
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15. Epigenome-wide meta-analysis of blood DNA methylation in newborns and children identifies numerous loci related to gestational age

Author

Merid, S.K. (Simon Kebede), Novoloaca, A. (Alexei), Sharp, G.C. (Gemma C.), Küpers, A.M. (Marlijn), Kho, A.T. (Alvin T.), Roy, R. (Ritu), Gao, L. (Lu), Annesi-Maesano, I. (Isabella), Jain, P. (Pooja), Plusquin, M. (Michelle), Kogevinas, M. (Manolis), Allard, C. (Catherine), Vehmeijer, F.O.L. (Florianne O.L.), Kazmi, N. (Nabila), Salas, L.A. (Lucas A.), Rezwan, F.I. (Faisal I.), Zhang, H. (Hongmei), Sebert, S. (Sylvain), Czamara, D. (Darina), Rifas-Shiman, S.L. (Sheryl), Melton, P.E. (Phillip E.), Lawlor, D.A. (Debbie A.), Pershagen, G. (Göran), Breton, C. (Carrie), Huen, K. (Karen), Baïz, N. (Nour), Gagliardi, L. (Luigi), Nawrot, T.S. (Tim S.), Corpeleijn, E. (Eva), Perron, P. (Patrice), Duijts, L. (Liesbeth), Nohr, C. (Christian), Bustamante, M. (Mariona), Ewart, S. (Susan), Karmaus, W. (Wilfried), Zhao, S. (Shanshan), Page, C.M. (Christian M.), Herceg, Z. (Zdenko), Jarvelin, M.-R. (Marjo-Riitta), Lahti, J. (Jari), Baccarelli, A.A. (Andrea), Anderson, D. (Denise), Kachroo, P. (Priyadarshini), Relton, C.L. (Caroline), Bergström, A. (Anna), Eskenazi, B. (B.), Soomro, M.H. (Munawar Hussain), Vineis, P. (Paolo), Snieder, H. (Harold), Bouchard, L. (Luigi), Jaddoe, V.W.V. (Vincent), Sørensen, T.I.A. (Thorkild), Vrijheid, M. (Martine), Arshad, S.H. (Syed), Holloway, J.W. (John W.), Håberg, S.E. (Siri E), Magnus, P. (Per), Dwyer, T. (Terence), Binder, E.B. (Elisabeth), Demeo, D.L. (Dawn), Vonk, J.M. (Judith), Newnham, J.P. (John), Tantisira, K.G. (Kelan G.), Kull, C.A. (Christian), Wiemels, J. (Joseph), Heude, B. (Barbara), Sunyer, J. (Jordi), Nystad, W. (Wenche), Munthe-Kaas, M.C. (Monica Cheng), Räikkönen, K. (Katri), Oken, E. (Emily), Huang, R.-C. (Rae-Chi), Weiss, S.T. (Scott T.), Antó, J.M. (Josep Maria), Bousquet, J. (Jean), Kumar, A. (Ashish), Söderhäll, C. (Cilla), Almqvist, C. (Catarina), Cardenas, A. (Andres), Gruzieva, O. (Olena), Xu, C.-J. (Cheng-Jian), Reese, S.E. (Sarah E.), Kere, J. (Juha), Brodin, P. (Petter), Solomon, O. (Olivia), Wielscher, M. (Matthias), Holland, N. (Nina), Ghantous, A. (Akram), Hivert, M.-F. (Marie-France), Felix, J.F. (Janine), Koppelman, G.H. (Gerard), London, S.J. (Stephanie J.), Melén, E. (Erik), Merid, S.K. (Simon Kebede), Novoloaca, A. (Alexei), Sharp, G.C. (Gemma C.), Küpers, A.M. (Marlijn), Kho, A.T. (Alvin T.), Roy, R. (Ritu), Gao, L. (Lu), Annesi-Maesano, I. (Isabella), Jain, P. (Pooja), Plusquin, M. (Michelle), Kogevinas, M. (Manolis), Allard, C. (Catherine), Vehmeijer, F.O.L. (Florianne O.L.), Kazmi, N. (Nabila), Salas, L.A. (Lucas A.), Rezwan, F.I. (Faisal I.), Zhang, H. (Hongmei), Sebert, S. (Sylvain), Czamara, D. (Darina), Rifas-Shiman, S.L. (Sheryl), Melton, P.E. (Phillip E.), Lawlor, D.A. (Debbie A.), Pershagen, G. (Göran), Breton, C. (Carrie), Huen, K. (Karen), Baïz, N. (Nour), Gagliardi, L. (Luigi), Nawrot, T.S. (Tim S.), Corpeleijn, E. (Eva), Perron, P. (Patrice), Duijts, L. (Liesbeth), Nohr, C. (Christian), Bustamante, M. (Mariona), Ewart, S. (Susan), Karmaus, W. (Wilfried), Zhao, S. (Shanshan), Page, C.M. (Christian M.), Herceg, Z. (Zdenko), Jarvelin, M.-R. (Marjo-Riitta), Lahti, J. (Jari), Baccarelli, A.A. (Andrea), Anderson, D. (Denise), Kachroo, P. (Priyadarshini), Relton, C.L. (Caroline), Bergström, A. (Anna), Eskenazi, B. (B.), Soomro, M.H. (Munawar Hussain), Vineis, P. (Paolo), Snieder, H. (Harold), Bouchard, L. (Luigi), Jaddoe, V.W.V. (Vincent), Sørensen, T.I.A. (Thorkild), Vrijheid, M. (Martine), Arshad, S.H. (Syed), Holloway, J.W. (John W.), Håberg, S.E. (Siri E), Magnus, P. (Per), Dwyer, T. (Terence), Binder, E.B. (Elisabeth), Demeo, D.L. (Dawn), Vonk, J.M. (Judith), Newnham, J.P. (John), Tantisira, K.G. (Kelan G.), Kull, C.A. (Christian), Wiemels, J. (Joseph), Heude, B. (Barbara), Sunyer, J. (Jordi), Nystad, W. (Wenche), Munthe-Kaas, M.C. (Monica Cheng), Räikkönen, K. (Katri), Oken, E. (Emily), Huang, R.-C. (Rae-Chi), Weiss, S.T. (Scott T.), Antó, J.M. (Josep Maria), Bousquet, J. (Jean), Kumar, A. (Ashish), Söderhäll, C. (Cilla), Almqvist, C. (Catarina), Cardenas, A. (Andres), Gruzieva, O. (Olena), Xu, C.-J. (Cheng-Jian), Reese, S.E. (Sarah E.), Kere, J. (Juha), Brodin, P. (Petter), Solomon, O. (Olivia), Wielscher, M. (Matthias), Holland, N. (Nina), Ghantous, A. (Akram), Hivert, M.-F. (Marie-France), Felix, J.F. (Janine), Koppelman, G.H. (Gerard), London, S.J. (Stephanie J.), and Melén, E. (Erik)

Abstract

BACKGROUND: Preterm birth and shorter duration of pregnancy are associated with increased morbidity in neonatal and later life. As the epigenome is known to have an important role during fetal development, we investigated associations between gestational age and blood DNA methylation in children. METHODS: We performed meta-analysis of Illumina's HumanMethylation450-array associations between gestational age and cord blood DNA methylation in 3648 newborns from 17 cohorts without common pregnancy complications, induced delivery or caesarean section. We also explored associations of gestational age with DNA methylation measured at 4-18 years in additional pediatric cohorts. Follow-up analyses of DNA methylation and gene expression correlations were performed in cord blood. DNA methylation profiles were also explored in tissues relevant for gestational age health effects: fetal brain and lung. RESULTS: We identified 8899 CpGs in cord blood that were associated with gestational age (range 27-42 weeks), at Bonferroni significance, P < 1.06 × 10- 7, of which 3343 were novel. These were annotated to 4966 genes. After restricting findings to at least three significant adjacent CpGs, we identified 1276 CpGs annotated to 325 genes. Results were generally consistent when analyses were restricted to term births. Cord blood findings tended not to persist into childhood and adolescence. Pathway analyses identified enrichment for biological processes critical to embryonic development. Follow-up of identified genes showed correlations between gestational age and DNA methylation levels in fetal brain and lung tissue, as well as correlation with expression levels. CONCLUSIONS: We identified numerous CpGs differentially methylated in relation to gestational age at birth that appear to reflect fetal developmental processes across tissues. These findings may contribute to understanding mechanisms linking gestational age to health effects.

Published
2020
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16. The joint effect of maternal smoking during pregnancy and maternal pre-pregnancy overweight on infants' term birth weight

Author

Chattrapiban, T. (Thanin), Smit, H.A. (Henriëtte), Wijga, A.H. (Alet), Brunekreef, B. (Bert), Vonk, J.M. (Judith), Gehring, U. (Ulrike), Rossem, L. (Lenie) van, Chattrapiban, T. (Thanin), Smit, H.A. (Henriëtte), Wijga, A.H. (Alet), Brunekreef, B. (Bert), Vonk, J.M. (Judith), Gehring, U. (Ulrike), and Rossem, L. (Lenie) van

Abstract

Background: It is well known that maternal smoking during pregnancy and maternal pre-pregnancy overweight have opposite effects on the infants' birth weight. We report on the association of the combination between both risk factors and the infants' birth weight. Methods: We studied 3241 infants born at term in the PIAMA birth cohort. Maternal smoking during pregnancy and pre-pregnancy height and weight were self-reported. Multivariable regression analysis was performed to assess the associations between infants of mothers who only smoked during pregnancy, who only had pre-pregnancy overweight and who had both risk factors simultaneously, on term birth weight and the risk of being SGA or LGA. Results: Of 3241 infants, 421 infants (13%) were born to smoking, non-overweight mothers, 514 (15.8%) to non-smoking, overweight mothers, 129 (4%) to smoking and overweight mothers and

Published
2020
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19. 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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20. 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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21. 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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22. 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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23. 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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24. 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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25. 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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26. 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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27. 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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28. 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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29. Cohort profile: Pregnancy and childhood epigenetics (PACE) consortium

Author

Felix, J.F. (Janine F.), Joubert, B.R. (Bonnie), Baccarelli, A.A. (Andrea), Sharp, G.C. (Gemma C.), Almqvist, C. (Catarina), Annesi-Maesano, I. (Isabella), Arshad, H. (Hasan), Baïz, N. (Nour), Bakermans-Kranenburg, M.J. (Marian), Bakulski, K.M. (Kelly M.), Binder, E.B. (Elisabeth), Bouchard, L. (Luigi), Breton, C. (Carrie), Brunekreef, B. (Bert), Brunst, K.J. (Kelly J.), Burchard, E.G. (Esteban), Bustamante, M. (Mariona), Chatzi, L. (Leda), Munthe-Kaas, M.C. (Monica Cheng), Corpeleijn, W.E. (Willemijn), Czamara, D. (Darina), Dabelea, D. (Dana), Smith, G.D. (George Davey), Boever, P. (Patrick) de, Duijts, L. (Liesbeth), Dwyer, T. (Terence), Eng, C. (Celeste), Eskenazi, B. (B.), Everson, T.M. (Todd M.), Falahi, F. (Fahimeh), Fallin, M.D. (M. Daniele), Farchi, S. (Sara), Fernandez, M.F. (Mariana), Gao, L. (Lu), Gaunt, T.R. (Tom), Ghantous, A. (Akram), Gillman, M.W. (Matthew W.), Gonseth, S. (Semira), Grote, V. (Veit), Gruzieva, O. (Olena), Håberg, S.E. (Siri E), Herceg, Z. (Zdenko), Hivert, M.-F. (Marie-France), Holland, N. (Nina), Holloway, J.W. (John W.), Hoyo, C. (Cathrine), Hu, D. (Donglei), Huang, R.-C. (Rae-Chi), Huen, K. (Karen), Järvelin, M.-R. (Marjo-Riitta), Jima, D.D. (Dereje D.), Just, A.C. (Allan C.), Karagas, M.R. (Margaret), Karlsson, R. (Robert), Karmaus, W. (Wilfried), Kechris, K.J. (Katerina J.), Kere, J. (Juha), Kogevinas, M. (Manolis), Koletzko, B. (Berthold), Koppelman, G.H. (Gerard), Küpers, A.M. (Marlijn), Ladd-Acosta, C. (Christine), Lahti, J., Lambrechts, N. (Nathalie), Langie, S.A.S. (Sabine A.S.), Lie, R.T. (Rolv T.), Liu, A.H. (Andrew H.), Magnus, M.C. (Maria C.), Magnus, P. (Per), Maguire, R.L. (Rachel L.), Marsit, C.J. (Carmen J.), McArdle, W.L. (Wendy), Melen, E. (Erik), Melton, P. (Phillip), Murphy, S.K. (Susan K.), Nawrot, T.S. (Tim S.), Nisticò, L. (Lorenza), Nohr, C. (Christian), Nordlund, B. (Björn), Nystad, W. (Wenche), Oh, S.S. (Sam S.), Oken, E. (Emily), Page, C.M. (Christian M.), Perron, P. (Patrice), Pershagen, G. (Göran), Pizzi, C. (Costanza), Plusquin, M. (Michelle), Räikkönen, K. (Katri), Reese, S.E. (Sarah E.), Reischl, G. (Gunilla), Richiardi, L. (Lorenzo), Ring, S.M. (Susan), Roy, R.P. (Ritu P.), Rzehak, P. (Peter), Schoeters, G. (Greet), Schwartz, D.A. (David A.), Sebert, S. (Sylvain), Snieder, H. (Harold), Sørensen, T.I.A. (Thorkild), Starling, A.P. (Anne P.), Sunyer, J. (Jordi), Taylor, J.A. (Jack A), Tiemeier, H.W. (Henning), Ullemar, V. (Vilhelmina), Vafeiadi, M. (Marina), IJzendoorn, M.H. (Rien) van, Vonk, J.M. (Judith), Vriens, A. (Annette), Vrijheid, M. (Martine), Wang, P. (Pei), Wiemels, J. (Joseph), Wilcox, A.J. (Allen), Wright, R.J. (Rosalind J.), Xu, C.-J. (Cheng-Jian), Xu, Z. (Zongli), Yang, I.V. (Ivana V.), Yousefi, P. (Paul), Zhang, H. (Hongmei), Zhang, W. (Weiming), Zhao, S. (Shanshan), Agha, G. (Golareh), Relton, C.L. (Caroline), Jaddoe, V.W.V. (Vincent), London, S.J. (Stephanie J.), Felix, J.F. (Janine F.), Joubert, B.R. (Bonnie), Baccarelli, A.A. (Andrea), Sharp, G.C. (Gemma C.), Almqvist, C. (Catarina), Annesi-Maesano, I. (Isabella), Arshad, H. (Hasan), Baïz, N. (Nour), Bakermans-Kranenburg, M.J. (Marian), Bakulski, K.M. (Kelly M.), Binder, E.B. (Elisabeth), Bouchard, L. (Luigi), Breton, C. (Carrie), Brunekreef, B. (Bert), Brunst, K.J. (Kelly J.), Burchard, E.G. (Esteban), Bustamante, M. (Mariona), Chatzi, L. (Leda), Munthe-Kaas, M.C. (Monica Cheng), Corpeleijn, W.E. (Willemijn), Czamara, D. (Darina), Dabelea, D. (Dana), Smith, G.D. (George Davey), Boever, P. (Patrick) de, Duijts, L. (Liesbeth), Dwyer, T. (Terence), Eng, C. (Celeste), Eskenazi, B. (B.), Everson, T.M. (Todd M.), Falahi, F. (Fahimeh), Fallin, M.D. (M. Daniele), Farchi, S. (Sara), Fernandez, M.F. (Mariana), Gao, L. (Lu), Gaunt, T.R. (Tom), Ghantous, A. (Akram), Gillman, M.W. (Matthew W.), Gonseth, S. (Semira), Grote, V. (Veit), Gruzieva, O. (Olena), Håberg, S.E. (Siri E), Herceg, Z. (Zdenko), Hivert, M.-F. (Marie-France), Holland, N. (Nina), Holloway, J.W. (John W.), Hoyo, C. (Cathrine), Hu, D. (Donglei), Huang, R.-C. (Rae-Chi), Huen, K. (Karen), Järvelin, M.-R. (Marjo-Riitta), Jima, D.D. (Dereje D.), Just, A.C. (Allan C.), Karagas, M.R. (Margaret), Karlsson, R. (Robert), Karmaus, W. (Wilfried), Kechris, K.J. (Katerina J.), Kere, J. (Juha), Kogevinas, M. (Manolis), Koletzko, B. (Berthold), Koppelman, G.H. (Gerard), Küpers, A.M. (Marlijn), Ladd-Acosta, C. (Christine), Lahti, J., Lambrechts, N. (Nathalie), Langie, S.A.S. (Sabine A.S.), Lie, R.T. (Rolv T.), Liu, A.H. (Andrew H.), Magnus, M.C. (Maria C.), Magnus, P. (Per), Maguire, R.L. (Rachel L.), Marsit, C.J. (Carmen J.), McArdle, W.L. (Wendy), Melen, E. (Erik), Melton, P. (Phillip), Murphy, S.K. (Susan K.), Nawrot, T.S. (Tim S.), Nisticò, L. (Lorenza), Nohr, C. (Christian), Nordlund, B. (Björn), Nystad, W. (Wenche), Oh, S.S. (Sam S.), Oken, E. (Emily), Page, C.M. (Christian M.), Perron, P. (Patrice), Pershagen, G. (Göran), Pizzi, C. (Costanza), Plusquin, M. (Michelle), Räikkönen, K. (Katri), Reese, S.E. (Sarah E.), Reischl, G. (Gunilla), Richiardi, L. (Lorenzo), Ring, S.M. (Susan), Roy, R.P. (Ritu P.), Rzehak, P. (Peter), Schoeters, G. (Greet), Schwartz, D.A. (David A.), Sebert, S. (Sylvain), Snieder, H. (Harold), Sørensen, T.I.A. (Thorkild), Starling, A.P. (Anne P.), Sunyer, J. (Jordi), Taylor, J.A. (Jack A), Tiemeier, H.W. (Henning), Ullemar, V. (Vilhelmina), Vafeiadi, M. (Marina), IJzendoorn, M.H. (Rien) van, Vonk, J.M. (Judith), Vriens, A. (Annette), Vrijheid, M. (Martine), Wang, P. (Pei), Wiemels, J. (Joseph), Wilcox, A.J. (Allen), Wright, R.J. (Rosalind J.), Xu, C.-J. (Cheng-Jian), Xu, Z. (Zongli), Yang, I.V. (Ivana V.), Yousefi, P. (Paul), Zhang, H. (Hongmei), Zhang, W. (Weiming), Zhao, S. (Shanshan), Agha, G. (Golareh), Relton, C.L. (Caroline), Jaddoe, V.W.V. (Vincent), and London, S.J. (Stephanie J.)

Published
2018
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30. Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Author

Justice, A.E. (Anne), Winkler, T.W. (Thomas W.), Feitosa, M.F., Graff, M.J. (Maud J.L.), Fisher, V.A. (Virginia A.), Young, K. (Kristin), Barata, L. (Llilda), Deng, X. (Xuan), Czajkowski, J. (Jacek), Hadley, D. (David), Ngwa, J.S. (Julius S.), Ahluwalia, T.S. (Tarunveer Singh), Chu, A.Y. (Audrey Y), Heard-Costa, N.L. (Nancy), Lim, E. (Elise), Perez, J. (Jeremiah), Eicher, J.D. (John D.), Kutalik, Z. (Zoltán), Xue, L. (Luting), Mahajan, A. (Anubha), Renström, F. (Frida), Wu, J.M.W. (Joseph M. W.), Qi, Q., Ahmad, S. (Shafqat), Alfred, T. (Tamuno), Amin, N. (Najaf), Bielak, L.F. (Lawrence F.), Bonnefond, A. (Amélie), Bragg-Gresham, J.L. (Jennifer L.), Cadby, G. (Gemma), Chittani, M. (Martina), Coggeshall, S. (Scott), Corre, T. (Tanguy), Direk, N. (Nese), Eriksson, J. (Joel), Fischer, K. (Krista), Gorski, M. (Mathias), Harder, M.N. (Marie Neergaard), Horikoshi, M. (Momoko), Huang, T. (Tao), Huffman, J.E. (Jennifer), Jackson, A.U. (Anne), Justesen, J.M. (Johanne M.), Kanoni, S. (Stavroula), Kinnunen, L. (Leena), Kleber, M.E. (Marcus), Komulainen, P. (Pirjo), Kumari, M. (Meena), Lim, U. (Unhee), Luan, J., Lyytikäinen, L.-P. (Leo-Pekka), Mangino, M. (Massimo), Manichaikul, A. (Ani), Marten, J. (Jonathan), Middelberg, R.P.S. (Rita), Müller-Nurasyid, M. (Martina), Navarro, P. (Pau), Perusse, L. (Louis), Pervjakova, N. (Natalia), Sarti, C. (Cinzia), Smith, A.V. (Albert), Smith, J.A. (Jennifer A), Stanča'kova, A. (Alena), Strawbridge, R.J. (Rona), Stringham, H.M. (Heather M.), Sung, Y.J. (Yun Ju), Tanaka, T. (Toshiko), Teumer, A. (Alexander), Trompet, S. (Stella), Van Der Laan, S.W. (Sander W.), Most, P.J. (Peter) van der, Vliet-Ostaptchouk, J.V. (Jana) van, Vedantam, S. (Sailaja), Verweij, N. (Niek), Vink, J.M. (Jacqueline), Vitart, V. (Veronique), Wu, Y. (Ying), Yengo, L. (Loic), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Zimmermann, M.E. (Martina E.), Zubair, N. (Niha), Abecasis, G.R. (Gonçalo), Adair, L.S. (Linda S.), Afaq, S. (Saima), Afzal, U. (Uzma), Bakker, S.J.L. (Stephan), Bartz, T.M. (Traci M.), Beilby, J.P. (John), Bergman, R.N. (Richard), Bergmann, S. (Sven), Biffar, R. (Reiner), Blangero, J. (John), Boerwinkle, E.A. (Eric), Bonnycastle, L.L. (Lori), Bottinger, E.P. (Erwin), Braga, D. (Daniele), Buckley, B.M. (Brendan M.), Buyske, S. (Steven), Campbell, H. (Harry), Chambers, J.C. (John C.), Collins, F.S. (Francis), Curran, J.E. (Joanne), Borst, G.J. (Gert) de, Craen, A.J. (Anton) de, Geus, E.J.C. (Eco) de, Dedoussis, G.V. (George), Delgado, G., Ruijter, H.M. (Hester ) den, Eiriksdottir, G. (Gudny), Eriksson, A.L. (Anna L.), Esko, T. (Tõnu), Faul, J.D. (Jessica D.), Ford, I. (Ian), Forrester, T. (Terrence), Gertow, K. (Karl), Gigante, B. (Bruna), Glorioso, N. (Nicola), Gong, J. (Jian), Grallert, H. (Harald), Grammer, T.B. (Tanja), Grarup, N. (Niels), Haitjema, S. (Saskia), Hallmans, G. (Göran), Hamsten, A. (Anders), Hansen, T. (Torben), Harris, T.B. (Tamara), Hartman, C.A. (C.), Hassinen, M. (Maija), Hastie, N. (Nick), Heath, A.C. (Andrew), Hernandez, D.G. (Dena), Hindorff, L.A. (Lucia A), Hocking, L.J., Hollensted, M. (Mette), Holmen, O.L. (Oddgeir L.), Homuth, G. (Georg), Hottenga, J.J. (Jouke Jan), Huang, J. (Jian), Hung, J. (Joseph), Hutri-Kähönen, N. (Nina), Ingelsson, E. (Erik), James, A. (Alan), Jansson, J.-O. (John-Olov), Jarvelin, M.-R. (Marjo-Riitta), Jhun, M.A. (Min A.), Jørgensen, M.E. (Marit E.), Juonala, M. (Markus), Kähönen, M. (Mika), Karlsson, M. (Magnus), Koistinen, H.A. (Heikki A.), Kolcic, I. (Ivana), Kolovou, G. (Genovefa), Kooperberg, C. (Charles), Krämer, B.K. (Bernhard), Kuusisto, J. (Johanna), Kvaløy, K. (Kirsti), Lakka, T.A. (Timo), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Leander, K. (Karin), Lee, N.R. (Nanette R.), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), Linneberg, A. (Allan), Lobbens, S. (Stéphane), Loh, M. (Marie), Lorentzon, M. (Mattias), Luben, R. (Robert), Lubke, G.H. (Gitta), Ludolph-Donislawski, A. (Anja), Lupoli, S. (Sara), Madden, P.A. (Pamela), Männikkö, R. (Reija), Marques-Vidal, P. (Pedro), Martin, N.G. (Nicholas), McKenzie, C.A. (Colin), McKnight, B. (Barbara), Mellström, D. (Dan), Menni, C. (Cristina), Montgomery, G.W. (Grant W.), Musk, A.W. (Arthur), Narisu, N. (Narisu), Nauck, M. (Matthias), Nolte, I.M. (Ilja), Oldehinkel, A.J. (Albertine), Olden, M. (Matthias), Ong, K.K. (Ken K.), Padmanabhan, S. (Sandosh), Peyser, P.A. (Patricia A.), Pisinger, C. (Charlotta), Porteous, D.J. (David J.), Raitakari, O.T. (Olli T.), Rankinen, T. (Tuomo), Rao, D.C. (D. C.), Rasmussen-Torvik, L.J. (Laura), Rawal, R. (Rajesh), Rice, T.K. (Treva K.), Ridker, P.M. (Paul), Rose, L.M. (Lynda M.), Bien, S.A. (Stephanie A.), Rudan, I. (Igor), Sanna, S. (Serena), Sarzynski, M.A. (Mark A.), Sattar, N. (Naveed), Savonen, K. (Kai), Schlessinger, D. (David), Scholtens, S. (Salome), Schurmann, C. (Claudia), Scott, R.A. (Robert), Sennblad, B. (Bengt), Siemelink, M.A. (Marten A.), Silbernagel, G. (Günther), Slagboom, P.E. (Eline), Snieder, H. (Harold), Staessen, J.A. (Jan A.), Stott, D.J. (David. J.), Swertz, M.A. (Morris A.), Swift, A.J. (Amy), Taylor, K.D. (Kent), Tayo, B. (Bamidele), Thorand, B. (Barbara), Thuillier, D. (Dorothee), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Vandenput, L. (Liesbeth), Vohl, M.-C. (Marie-Claude), Völzke, H. (Henry), Vonk, J.M. (Judith), Waeber, G. (Gérard), Waldenberger, M. (Melanie), Westendorp, R.G.J. (Rudi), Wild, S.H. (Sarah), Willemsen, G., Wolffenbuttel, B.H.R. (Bruce), Wong, A. (Andrew), Wright, A.F. (Alan), Zhao, W. (Wei), Zillikens, M.C. (Carola), Baldassarre, D. (Damiano), Balkau, B. (Beverley), Bandinelli, S. (Stefania), Böger, C.A. (Carsten), Boomsma, D.I. (Dorret), Bouchard, C. (Claude), Bruinenberg, M. (M.), Chasman, D.I. (Daniel), Ida Chen, Y.-D. (Yii-Der), Chines, P.S. (Peter), Cooper, R.S. (Richard S.), Cucca, F. (Francesco), Cusi, D. (Daniele), Faire, U. (Ulf) de, Ferrucci, L. (Luigi), Franks, P.W. (Paul), Froguel, P. (Philippe), Gordon-Larsen, P. (Penny), Grabe, H.J. (Hans Jörgen), Gudnason, V. (Vilmundur), Haiman, C.A. (Christopher), Hayward, C. (Caroline), Hveem, K. (Kristian), Johnson, A.D. (Andrew D.), Jukema, J.W. (Jan Wouter), Kardia, S.L.R. (Sharon), Kivimaki, M. (Mika), Kooner, J.S. (Jaspal S.), Kuh, D. (Diana), Laakso, M. (Markku), Lehtimäki, T. (Terho), Le Marchand, L. (Loic), März, W. (Winfried), McCarthy, M.I. (Mark), Metspalu, A. (Andres), Morris, A.P. (Andrew), Ohlsson, C. (Claes), Palmer, L.J. (Lyle J.), Pasterkamp, G. (Gerard), Pedersen, O. (Oluf), Peters, A. (Annette), Peters, U. (Ulrike), Polasek, O. (Ozren), Psaty, B.M. (Bruce M.), Qi, L. (Lu), Rauramaa, R. (Rainer), Smith, B.H. (Blair), Sørensen, T.I.A. (Thorkild), Strauch, K. (Konstantin), Tiemeier, H.W. (Henning), Tremoli, E. (Elena), Van Der Harst, P. (Pim), Vestergaard, H. (Henrik), Vollenweider, P. (Peter), Wareham, N.J. (Nick), Weir, D.R. (David), Whitfield, J. (John), Wilson, J.F. (James F.), Tyrrell, A.W.R., Frayling, T.M. (Timothy M.), Barroso, I.E. (Inês), Boehnke, M. (Michael), Deloukas, P. (Panagiotis), Fox, C.S. (Caroline), Hirschhorn, J.N. (Joel), Hunter, D.J. (David J.), Spector, T.D. (Timothy), Strachan, D.P. (David), Duijn, C.M. (Cornelia) van, Heid, I.M. (Iris), Mohlke, K.L. (Karen), Marchini, J. (Jonathan), Loos, R.J.F. (Ruth), Kilpeläinen, T.O. (Tuomas), Liu, C.-T. (Ching-Ti), Borecki, I.B. (Ingrid), North, K.E. (Kari), Cupples, L.A. (Adrienne), Justice, A.E. (Anne), Winkler, T.W. (Thomas W.), Feitosa, M.F., Graff, M.J. (Maud J.L.), Fisher, V.A. (Virginia A.), Young, K. (Kristin), Barata, L. (Llilda), Deng, X. (Xuan), Czajkowski, J. (Jacek), Hadley, D. (David), Ngwa, J.S. (Julius S.), Ahluwalia, T.S. (Tarunveer Singh), Chu, A.Y. (Audrey Y), Heard-Costa, N.L. (Nancy), Lim, E. (Elise), Perez, J. (Jeremiah), Eicher, J.D. (John D.), Kutalik, Z. (Zoltán), Xue, L. (Luting), Mahajan, A. (Anubha), Renström, F. (Frida), Wu, J.M.W. (Joseph M. W.), Qi, Q., Ahmad, S. (Shafqat), Alfred, T. (Tamuno), Amin, N. (Najaf), Bielak, L.F. (Lawrence F.), Bonnefond, A. (Amélie), Bragg-Gresham, J.L. (Jennifer L.), Cadby, G. (Gemma), Chittani, M. (Martina), Coggeshall, S. (Scott), Corre, T. (Tanguy), Direk, N. (Nese), Eriksson, J. (Joel), Fischer, K. (Krista), Gorski, M. (Mathias), Harder, M.N. (Marie Neergaard), Horikoshi, M. (Momoko), Huang, T. (Tao), Huffman, J.E. (Jennifer), Jackson, A.U. (Anne), Justesen, J.M. (Johanne M.), Kanoni, S. (Stavroula), Kinnunen, L. (Leena), Kleber, M.E. (Marcus), Komulainen, P. (Pirjo), Kumari, M. (Meena), Lim, U. (Unhee), Luan, J., Lyytikäinen, L.-P. (Leo-Pekka), Mangino, M. (Massimo), Manichaikul, A. (Ani), Marten, J. (Jonathan), Middelberg, R.P.S. (Rita), Müller-Nurasyid, M. (Martina), Navarro, P. (Pau), Perusse, L. (Louis), Pervjakova, N. (Natalia), Sarti, C. (Cinzia), Smith, A.V. (Albert), Smith, J.A. (Jennifer A), Stanča'kova, A. (Alena), Strawbridge, R.J. (Rona), Stringham, H.M. (Heather M.), Sung, Y.J. (Yun Ju), Tanaka, T. (Toshiko), Teumer, A. (Alexander), Trompet, S. (Stella), Van Der Laan, S.W. (Sander W.), Most, P.J. (Peter) van der, Vliet-Ostaptchouk, J.V. (Jana) van, Vedantam, S. (Sailaja), Verweij, N. (Niek), Vink, J.M. (Jacqueline), Vitart, V. (Veronique), Wu, Y. (Ying), Yengo, L. (Loic), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Zimmermann, M.E. (Martina E.), Zubair, N. (Niha), Abecasis, G.R. (Gonçalo), Adair, L.S. (Linda S.), Afaq, S. (Saima), Afzal, U. (Uzma), Bakker, S.J.L. (Stephan), Bartz, T.M. (Traci M.), Beilby, J.P. (John), Bergman, R.N. (Richard), Bergmann, S. (Sven), Biffar, R. (Reiner), Blangero, J. (John), Boerwinkle, E.A. (Eric), Bonnycastle, L.L. (Lori), Bottinger, E.P. (Erwin), Braga, D. (Daniele), Buckley, B.M. (Brendan M.), Buyske, S. (Steven), Campbell, H. (Harry), Chambers, J.C. (John C.), Collins, F.S. (Francis), Curran, J.E. (Joanne), Borst, G.J. (Gert) de, Craen, A.J. (Anton) de, Geus, E.J.C. (Eco) de, Dedoussis, G.V. (George), Delgado, G., Ruijter, H.M. (Hester ) den, Eiriksdottir, G. (Gudny), Eriksson, A.L. (Anna L.), Esko, T. (Tõnu), Faul, J.D. (Jessica D.), Ford, I. (Ian), Forrester, T. (Terrence), Gertow, K. (Karl), Gigante, B. (Bruna), Glorioso, N. (Nicola), Gong, J. (Jian), Grallert, H. (Harald), Grammer, T.B. (Tanja), Grarup, N. (Niels), Haitjema, S. (Saskia), Hallmans, G. (Göran), Hamsten, A. (Anders), Hansen, T. (Torben), Harris, T.B. (Tamara), Hartman, C.A. (C.), Hassinen, M. (Maija), Hastie, N. (Nick), Heath, A.C. (Andrew), Hernandez, D.G. (Dena), Hindorff, L.A. (Lucia A), Hocking, L.J., Hollensted, M. (Mette), Holmen, O.L. (Oddgeir L.), Homuth, G. (Georg), Hottenga, J.J. (Jouke Jan), Huang, J. (Jian), Hung, J. (Joseph), Hutri-Kähönen, N. (Nina), Ingelsson, E. (Erik), James, A. (Alan), Jansson, J.-O. (John-Olov), Jarvelin, M.-R. (Marjo-Riitta), Jhun, M.A. (Min A.), Jørgensen, M.E. (Marit E.), Juonala, M. (Markus), Kähönen, M. (Mika), Karlsson, M. (Magnus), Koistinen, H.A. (Heikki A.), Kolcic, I. (Ivana), Kolovou, G. (Genovefa), Kooperberg, C. (Charles), Krämer, B.K. (Bernhard), Kuusisto, J. (Johanna), Kvaløy, K. (Kirsti), Lakka, T.A. (Timo), Langenberg, C. (Claudia), Launer, L.J. (Lenore), Leander, K. (Karin), Lee, N.R. (Nanette R.), Kao, W.H.L. (Wen), Lindgren, C.M. (Cecilia M.), Linneberg, A. (Allan), Lobbens, S. (Stéphane), Loh, M. (Marie), Lorentzon, M. (Mattias), Luben, R. (Robert), Lubke, G.H. (Gitta), Ludolph-Donislawski, A. (Anja), Lupoli, S. (Sara), Madden, P.A. (Pamela), Männikkö, R. (Reija), Marques-Vidal, P. (Pedro), Martin, N.G. (Nicholas), McKenzie, C.A. (Colin), McKnight, B. (Barbara), Mellström, D. (Dan), Menni, C. (Cristina), Montgomery, G.W. (Grant W.), Musk, A.W. (Arthur), Narisu, N. (Narisu), Nauck, M. (Matthias), Nolte, I.M. (Ilja), Oldehinkel, A.J. (Albertine), Olden, M. (Matthias), Ong, K.K. (Ken K.), Padmanabhan, S. (Sandosh), Peyser, P.A. (Patricia A.), Pisinger, C. (Charlotta), Porteous, D.J. (David J.), Raitakari, O.T. (Olli T.), Rankinen, T. (Tuomo), Rao, D.C. (D. C.), Rasmussen-Torvik, L.J. (Laura), Rawal, R. (Rajesh), Rice, T.K. (Treva K.), Ridker, P.M. (Paul), Rose, L.M. (Lynda M.), Bien, S.A. (Stephanie A.), Rudan, I. (Igor), Sanna, S. (Serena), Sarzynski, M.A. (Mark A.), Sattar, N. (Naveed), Savonen, K. (Kai), Schlessinger, D. (David), Scholtens, S. (Salome), Schurmann, C. (Claudia), Scott, R.A. (Robert), Sennblad, B. (Bengt), Siemelink, M.A. (Marten A.), Silbernagel, G. (Günther), Slagboom, P.E. (Eline), Snieder, H. (Harold), Staessen, J.A. (Jan A.), Stott, D.J. (David. J.), Swertz, M.A. (Morris A.), Swift, A.J. (Amy), Taylor, K.D. (Kent), Tayo, B. (Bamidele), Thorand, B. (Barbara), Thuillier, D. (Dorothee), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Vandenput, L. (Liesbeth), Vohl, M.-C. (Marie-Claude), Völzke, H. (Henry), Vonk, J.M. (Judith), Waeber, G. (Gérard), Waldenberger, M. (Melanie), Westendorp, R.G.J. (Rudi), Wild, S.H. (Sarah), Willemsen, G., Wolffenbuttel, B.H.R. (Bruce), Wong, A. (Andrew), Wright, A.F. (Alan), Zhao, W. (Wei), Zillikens, M.C. (Carola), Baldassarre, D. (Damiano), Balkau, B. (Beverley), Bandinelli, S. (Stefania), Böger, C.A. (Carsten), Boomsma, D.I. (Dorret), Bouchard, C. (Claude), Bruinenberg, M. (M.), Chasman, D.I. (Daniel), Ida Chen, Y.-D. (Yii-Der), Chines, P.S. (Peter), Cooper, R.S. (Richard S.), Cucca, F. (Francesco), Cusi, D. (Daniele), Faire, U. (Ulf) de, Ferrucci, L. (Luigi), Franks, P.W. (Paul), Froguel, P. (Philippe), Gordon-Larsen, P. (Penny), Grabe, H.J. (Hans Jörgen), Gudnason, V. (Vilmundur), Haiman, C.A. (Christopher), Hayward, C. (Caroline), Hveem, K. (Kristian), Johnson, A.D. (Andrew D.), Jukema, J.W. (Jan Wouter), Kardia, S.L.R. (Sharon), Kivimaki, M. (Mika), Kooner, J.S. (Jaspal S.), Kuh, D. (Diana), Laakso, M. (Markku), Lehtimäki, T. (Terho), Le Marchand, L. (Loic), März, W. (Winfried), McCarthy, M.I. (Mark), Metspalu, A. (Andres), Morris, A.P. (Andrew), Ohlsson, C. (Claes), Palmer, L.J. (Lyle J.), Pasterkamp, G. (Gerard), Pedersen, O. (Oluf), Peters, A. (Annette), Peters, U. (Ulrike), Polasek, O. (Ozren), Psaty, B.M. (Bruce M.), Qi, L. (Lu), Rauramaa, R. (Rainer), Smith, B.H. (Blair), Sørensen, T.I.A. (Thorkild), Strauch, K. (Konstantin), Tiemeier, H.W. (Henning), Tremoli, E. (Elena), Van Der Harst, P. (Pim), Vestergaard, H. (Henrik), Vollenweider, P. (Peter), Wareham, N.J. (Nick), Weir, D.R. (David), Whitfield, J. (John), Wilson, J.F. (James F.), Tyrrell, A.W.R., Frayling, T.M. (Timothy M.), Barroso, I.E. (Inês), Boehnke, M. (Michael), Deloukas, P. (Panagiotis), Fox, C.S. (Caroline), Hirschhorn, J.N. (Joel), Hunter, D.J. (David J.), Spector, T.D. (Timothy), Strachan, D.P. (David), Duijn, C.M. (Cornelia) van, Heid, I.M. (Iris), Mohlke, K.L. (Karen), Marchini, J. (Jonathan), Loos, R.J.F. (Ruth), Kilpeläinen, T.O. (Tuomas), Liu, C.-T. (Ching-Ti), Borecki, I.B. (Ingrid), North, K.E. (Kari), and Cupples, L.A. (Adrienne)

Abstract

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting

Published
2017
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31. 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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32. Maternal BMI at the start of pregnancy and offspring epigenome-wide DNA methylation: Findings from the pregnancy and childhood epigenetics (PACE) consortium

Author

Sharp, G.C. (Gemma C.), Salas, L.A. (Lucas A.), Poppelaars-Monnereau, C. (Claire), Allard, C. (Catherine), Yousefi, P. (Paul), Everson, T.M. (Todd M.), Bohlin, J. (Jon), Xu, Z. (Zongli), Huang, R.-C. (Rae-Chi), Reese, S.E. (Sarah E.), Xu, C.-J. (Cheng-Jian), Baïz, N. (Nour), Hoyo, C. (Cathrine), Agha, G. (Golareh), Roy, R. (Ritu), Holloway, J. (John), Ghantous, A. (Akram), Merid, S.K. (Simon Kebede), Bakulski, K.M. (Kelly M.), Küpers, A.M. (Marlijn), Zhang, H. (Hongmei), Richmond, R.C. (Rebecca C.), Page, C.M. (Christian M.), Duijts, L. (Liesbeth), Lie, R.T. (Rolv T.), Melton, P.E. (Phillip E.), Vonk, J.M. (Judith), Nohr, C. (Christian), Williams-DeVane, C. (ClarLynda), Huen, K. (Karen), Rifas-Shiman, S.L. (Sheryl), Ruiz-Arenas, C. (Carlos), Gonseth, S. (Semira), Rezwan, F.I. (Faisal I.), Herceg, Z. (Zdenko), Ekström, S. (Sandra), Croen, L. (Lisa), Falahi, F. (Fahimeh), Perron, P. (Patrice), Karagas, M.R. (Margaret), Quraishi, B.M. (Bilal M.), Suderman, M.J. (Matthew J.), Magnus, M.C. (Maria C.), Jaddoe, V.W.V. (Vincent), Taylor, J.A. (Jack A.), Anderson, D. (Denise), Zhao, S. (Shanshan), Smit, H.A. (Henriëtte), Josey, M.J. (Michele J.), Bradman, A. (Asa), Baccarelli, A.A. (Andrea), Bustamante, M. (Mariona), Håberg, S.E. (Siri E), Pershagen, G. (Göran), Hertz-Picciotto, I. (Irva), Newschaffer, C. (Craig), Corpeleijn, W.E. (Willemijn), Bouchard, L. (Luigi), Lawlor, D.A. (Debbie A.), Maguire, R.L. (Rachel L.), Barcellos, L.F. (Lisa), Smith, G.D. (George Davey), Eskenazi, B. (B.), Karmaus, W. (Wilfried), Marsit, C.J. (Carmen J.), Hivert, M.-F. (Marie-France), Snieder, H. (Harold), Fallin, M.D. (M. Daniele), Melén, E. (Erik), Munthe-Kaas, M.C. (Monica Cheng), Arshad, H. (Hasan), Wiemels, J. (Joseph), Annesi-Maesano, I. (Isabella), Vrijheid, M. (Martine), Oken, E. (Emily), Holland, N. (Nina), Murphy, S.K. (Susan K.), Sørensen, T.I.A. (Thorkild), Koppelman, G.H. (Gerard), Newnham, J.P. (John), Wilcox, A.J. (Allen), Nystad, W. (Wenche), London, S.J. (Stephanie J.), Felix, J.F. (Janine), Relton, C.L. (Caroline), Sharp, G.C. (Gemma C.), Salas, L.A. (Lucas A.), Poppelaars-Monnereau, C. (Claire), Allard, C. (Catherine), Yousefi, P. (Paul), Everson, T.M. (Todd M.), Bohlin, J. (Jon), Xu, Z. (Zongli), Huang, R.-C. (Rae-Chi), Reese, S.E. (Sarah E.), Xu, C.-J. (Cheng-Jian), Baïz, N. (Nour), Hoyo, C. (Cathrine), Agha, G. (Golareh), Roy, R. (Ritu), Holloway, J. (John), Ghantous, A. (Akram), Merid, S.K. (Simon Kebede), Bakulski, K.M. (Kelly M.), Küpers, A.M. (Marlijn), Zhang, H. (Hongmei), Richmond, R.C. (Rebecca C.), Page, C.M. (Christian M.), Duijts, L. (Liesbeth), Lie, R.T. (Rolv T.), Melton, P.E. (Phillip E.), Vonk, J.M. (Judith), Nohr, C. (Christian), Williams-DeVane, C. (ClarLynda), Huen, K. (Karen), Rifas-Shiman, S.L. (Sheryl), Ruiz-Arenas, C. (Carlos), Gonseth, S. (Semira), Rezwan, F.I. (Faisal I.), Herceg, Z. (Zdenko), Ekström, S. (Sandra), Croen, L. (Lisa), Falahi, F. (Fahimeh), Perron, P. (Patrice), Karagas, M.R. (Margaret), Quraishi, B.M. (Bilal M.), Suderman, M.J. (Matthew J.), Magnus, M.C. (Maria C.), Jaddoe, V.W.V. (Vincent), Taylor, J.A. (Jack A.), Anderson, D. (Denise), Zhao, S. (Shanshan), Smit, H.A. (Henriëtte), Josey, M.J. (Michele J.), Bradman, A. (Asa), Baccarelli, A.A. (Andrea), Bustamante, M. (Mariona), Håberg, S.E. (Siri E), Pershagen, G. (Göran), Hertz-Picciotto, I. (Irva), Newschaffer, C. (Craig), Corpeleijn, W.E. (Willemijn), Bouchard, L. (Luigi), Lawlor, D.A. (Debbie A.), Maguire, R.L. (Rachel L.), Barcellos, L.F. (Lisa), Smith, G.D. (George Davey), Eskenazi, B. (B.), Karmaus, W. (Wilfried), Marsit, C.J. (Carmen J.), Hivert, M.-F. (Marie-France), Snieder, H. (Harold), Fallin, M.D. (M. Daniele), Melén, E. (Erik), Munthe-Kaas, M.C. (Monica Cheng), Arshad, H. (Hasan), Wiemels, J. (Joseph), Annesi-Maesano, I. (Isabella), Vrijheid, M. (Martine), Oken, E. (Emily), Holland, N. (Nina), Murphy, S.K. (Susan K.), Sørensen, T.I.A. (Thorkild), Koppelman, G.H. (Gerard), Newnham, J.P. (John), Wilcox, A.J. (Allen), Nystad, W. (Wenche), London, S.J. (Stephanie J.), Felix, J.F. (Janine), and Relton, C.L. (Caroline)

Abstract

Pre-pregnancy maternal obesity is associated with adverse offspring outcomes at birth and later in life. Individual studies have shown that epigenetic modifications such as DNA methylation could contribute. Within the Pregnancy and Childhood Epigenetics (PACE) Consortium, we meta-analysed the association between pre-pregnancy maternal BMI and methylation at over 450,000 sites in newborn blood DNA, across 19 cohorts (9,340 mother-newborn pairs). We attempted to infer causality by comparing the effects of maternal versus paternal BMI and incorporating genetic variation. In four additional cohorts (1,817 mother-child pairs), we meta-analysed the association between maternal BMI at the start of pregnancy and blood methylation in adolescents. In newborns, maternal BMI was associated with small (<0.2% per BMI unit (1 kg/m2), P < 1.06 × 10-7) methylation variation at 9,044 sites throughout the genome. Adjustment for estimated cell proportions greatly attenuated the number of significant CpGs to 104, including 86 sites common to the unadjusted model. At 72/86 sites, the direction of the association was the same in newborns and adolescents, suggesting persistence of signals. However, we found evidence for a6causal intrauterine effect of maternal BMI on newborn methylation at just 8/86 sites. In conclusion, this well-powered analysis identified robust associations between maternal adiposity and variations in newborn blood DNA methylation, but these small effects may be better explained by genetic or lifestyle factors than a causal intrauterine mechanism. This highlights the need for large-scale collaborative approaches and the application of causal inference techniques in epigenetic epidemiology.

Published
2017
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33. 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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34. 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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35. Genome-wide association study identifies 74 loci associated with educational attainment

Author

Okbay, A. (Aysu), Beauchamp, J.P. (Jonathan), Fontana, M.A. (Mark Alan), Lee, J.J. (James J.), Pers, T.H. (Tune), Rietveld, C.A. (Cornelius A.), Turley, P. (Patrick), Chen, G.-B. (Guo-Bo), Emilsson, V. (Valur), Meddens, S.F.W. (S. Fleur W.), Oskarsson, S. (Sven), Pickrell, J.K. (Joseph K.), Thom, K. (Kevin), Timshel, P. (Pascal), Vlaming, R. (Ronald) de, Abdellaoui, A. (Abdel), Ahluwalia, T.S. (Tarunveer Singh), Bacelis, J. (Jonas), Baumbach, C. (Clemens), Bjornsdottir, G. (Gyda), Brandsma, J.H. (Johan), Pina Concas, M. (Maria), Derringer, J., Furlotte, N.A. (Nicholas A.), Galesloot, T.E. (Tessel), Girotto, S., Gupta, R. (Richa), Hall, L.M. (Leanne M.), Harris, S.E. (Sarah), Hofer, E., Horikoshi, M. (Momoko), Huffman, J.E. (Jennifer E.), Kaasik, K. (Kadri), Kalafati, I.-P. (Ioanna-Panagiota), Karlsson, R. (Robert), Kong, A. (Augustine), Lahti, J. (Jari), Lee, S.J. (Sven) van der, Deleeuw, C. (Christiaan), Lind, P.A. (Penelope), Lindgren, K.-O. (Karl-Oskar), Liu, T. (Tian), Mangino, M. (Massimo), Marten, J. (Jonathan), Mihailov, E. (Evelin), Miller, M. (Mike), Most, P.J. (Peter) van der, Oldmeadow, C. (Christopher), Payton, A. (Antony), Pervjakova, N. (Natalia), Peyrot, W.J. (Wouter ), Qian, Y. (Yong), Raitakari, O. (Olli), Rueedi, R. (Rico), Salvi, E. (Erika), Schmidt, B. (Börge), Schraut, K.E. (Katharina E.), Shi, J. (Jianxin), Smith, A.V. (Albert Vernon), Poot, R.A. (Raymond), St Pourcain, B. (Beate), Teumer, A. (Alexander), Thorleifsson, G. (Gudmar), Verweij, N. (Niek), Vuckovic, D. (Dragana), Wellmann, J. (Juergen), Westra, H.J. (Harm-Jan), Yang, J. (Jingyun), Zhao, W. (Wei), Zhu, Z. (Zhihong), Alizadeh, B.Z. (Behrooz), Amin, N. (Najaf), Bakshi, A. (Andrew), Baumeister, S.E. (Sebastian), Biino, G. (Ginevra), Bønnelykke, K. (Klaus), Boyle, P.A. (Patricia), Campbell, H. (Harry), Cappuccio, F.P. (Francesco P.), Davies, G. (Gail), Neve, J.E. (Jan-Emmanuel) de, Deloukas, P. (Panagiotis), Demuth, I. (Ilja), Ding, J. (Jun), Eibich, P. (Peter), Eisele, L. (Lewin), Eklund, N. (Niina), Evans, D.M. (David), Faul, J.D. (Jessica D.), Feitosa, M.F. (Mary Furlan), Forstner, A.J. (Andreas), Gandin, I. (Ilaria), Gunnarsson, B. (Bjarni), Halldorsson, B.V. (Bjarni), Harris, T.B. (Tamara), Holliday, E.G. (Elizabeth), Heath, A.C. (Andrew C.), Hocking, L.J., Homuth, G. (Georg), Horan, M. (Mike), Hottenga, J.J. (Jouke Jan), Jager, P.L. (Philip) de, Joshi, P.K. (Peter), Juqessur, A. (Astanand), Kaakinen, M. (Marika), Kähönen, M. (Mika), Kanoni, S. (Stavroula), Keltigangas-Järvinen, L. (Liisa), Kiemeney, L.A.L.M. (Bart), Kolcic, I. (Ivana), Koskinen, S. (Seppo), Kraja, A. (Aldi), Kroh, M. (Martin), Kutalik, Z. (Zoltán), Latvala, A. (Antti), Launer, L.J. (Lenore), Lebreton, M.P. (Maël P.), Levinson, D.F. (Douglas F.), Lichtenstein, P. (Paul), Lichtner, P. (Peter), Liewald, D.C.M. (David), Loukola, A. (Anu), Madden, P.A. (Pamela), Mägi, R. (Reedik), Mäki-Opas, T. (Tomi), Marioni, R.E. (Riccardo), Marques-Vidal, P. (Pedro), Meddens, G.A. (Gerardus A.), Mcmahon, G. (George), Meisinger, C. (Christa), Meitinger, T. (Thomas), Milaneschi, Y. (Yusplitri), Milani, L. (Lili), Montgomery, G.W. (Grant), Myhre, R. (Ronny), Nelson, C.P. (Christopher P.), Nyholt, D.R. (Dale), Ollier, W.E.R. (William), Palotie, A. (Aarno), Paternoster, L. (Lavinia), Pedersen, N.L. (Nancy), Petrovic, K. (Katja), Porteous, D.J. (David J.), Räikkönen, K. (Katri), Ring, S.M. (Susan M.), Robino, A. (Antonietta), Rostapshova, O. (Olga), Rudan, I. (Igor), Rustichini, A. (Aldo), Salomaa, V. (Veikko), Sanders, A.R. (Alan R.), Sarin, A.-P., Schmidt, R. (Reinhold), Scott, R.J. (Rodney), Smith, B.H. (Blair), Smith, J.A. (Jennifer A), Staessen, J.A. (Jan), Steinhagen-Thiessen, E. (Elisabeth), Strauch, K. (Konstantin), Terracciano, A., Tobin, M.D. (Martin), Ulivi, S. (Shelia), Vaccargiu, S. (Simona), Quaye, L. (Lydia), Rooij, F.J.A. (Frank) van, Venturini, C. (Cristina), Vinkhuyzen, A.A.E. (Anna A.), Völker, U. (Uwe), Völzke, H. (Henry), Vonk, J.M. (Judith), Vozzi, D. (Diego), Waage, J. (Johannes), Ware, E.B. (Erin B.), Willemsen, G.A.H.M. (Gonneke), Attia, J. (John), Bennett, D.A. (David A.), Berger, K. (Klaus), Bertram, L. (Lars), Bisgaard, H. (Hans), Boomsma, D.I. (Dorret), Borecki, I.B. (Ingrid), Bültmann, U. (Ute), Chabris, C.F. (Christopher F.), Cucca, F. (Francesco), Cusi, D. (Daniele), Deary, I.J. (Ian), Dedoussis, G.V. (George), Duijn, C.M. (Cornelia) van, Hagen, K. (Knut), Franke, B. (Barbara), Franke, L. (Lude), Gasparini, P. (Paolo), Gejman, P.V. (Pablo), Gieger, C. (Christian), Grabe, H.J. (Hans Jörgen), Gratten, J. (Jacob), Groenen, P.J.F. (Patrick), Gudnason, V. (Vilmundur), Harst, P. (Pim) van der, Hayward, C. (Caroline), Hinds, D.A. (David A.), Hoffmann, W. (Wolfgang), Hypponen, E. (Elina), Iacono, W.G. (William), Jacobsson, B. (Bo), Jarvelin, M.-R. (Marjo-Riitta), JöCkel, K.-H. (Karl-Heinz), Kaprio, J. (Jaakko), Kardia, S.L.R. (Sharon), Lehtimäki, T. (Terho), Lehrer, S.F. (Steven F.), Magnusson, P.K. (Patrik), Martin, N.G. (Nicholas), McGue, M. (Matt), Metspalu, A. (Andres), Pendleton, N. (Neil), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pirastu, N. (Nicola), Pirastu, M. (Mario), Polasek, O. (Ozren), Posthuma, D. (Danielle), Power, C. (Christopher), Province, M.A. (Mike), Samani, N.J. (Nilesh), Schlessinger, D. (David), Sørensen, T.I.A. (Thorkild), Spector, T.D. (Timothy), Zwart, J-A. (John-Anker), Thorsteinsdottir, U. (Unnur), Thurik, A.R. (Roy), Timpson, N.J. (Nicholas J.), Tiemeier, H.W. (Henning), Tung, J.Y. (Joyce Y.), Uitterlinden, A.G. (André), Vitart, V. (Veronique), Vollenweider, P. (Peter), Weir, D.R. (David), Wilson, J.F. (James F.), Wright, A.F. (Alan), Conley, D.C. (Dalton C.), Krueger, R.F., Smith, A.V. (Davey), Hofman, A. (Albert), Laibson, D. (David), Medland, S.E. (Sarah), Meyer, M.N. (Michelle N.), Yang, J. (Joanna), Johannesson, M. (Magnus), Visscher, P.M. (Peter), Esko, T. (Tõnu), Koellinger, Ph.D. (Philipp), Cesarini, D. (David), Benjamin, D.J. (Daniel J.), Okbay, A. (Aysu), Beauchamp, J.P. (Jonathan), Fontana, M.A. (Mark Alan), Lee, J.J. (James J.), Pers, T.H. (Tune), Rietveld, C.A. (Cornelius A.), Turley, P. (Patrick), Chen, G.-B. (Guo-Bo), Emilsson, V. (Valur), Meddens, S.F.W. (S. Fleur W.), Oskarsson, S. (Sven), Pickrell, J.K. (Joseph K.), Thom, K. (Kevin), Timshel, P. (Pascal), Vlaming, R. (Ronald) de, Abdellaoui, A. (Abdel), Ahluwalia, T.S. (Tarunveer Singh), Bacelis, J. (Jonas), Baumbach, C. (Clemens), Bjornsdottir, G. (Gyda), Brandsma, J.H. (Johan), Pina Concas, M. (Maria), Derringer, J., Furlotte, N.A. (Nicholas A.), Galesloot, T.E. (Tessel), Girotto, S., Gupta, R. (Richa), Hall, L.M. (Leanne M.), Harris, S.E. (Sarah), Hofer, E., Horikoshi, M. (Momoko), Huffman, J.E. (Jennifer E.), Kaasik, K. (Kadri), Kalafati, I.-P. (Ioanna-Panagiota), Karlsson, R. (Robert), Kong, A. (Augustine), Lahti, J. (Jari), Lee, S.J. (Sven) van der, Deleeuw, C. (Christiaan), Lind, P.A. (Penelope), Lindgren, K.-O. (Karl-Oskar), Liu, T. (Tian), Mangino, M. (Massimo), Marten, J. (Jonathan), Mihailov, E. (Evelin), Miller, M. (Mike), Most, P.J. (Peter) van der, Oldmeadow, C. (Christopher), Payton, A. (Antony), Pervjakova, N. (Natalia), Peyrot, W.J. (Wouter ), Qian, Y. (Yong), Raitakari, O. (Olli), Rueedi, R. (Rico), Salvi, E. (Erika), Schmidt, B. (Börge), Schraut, K.E. (Katharina E.), Shi, J. (Jianxin), Smith, A.V. (Albert Vernon), Poot, R.A. (Raymond), St Pourcain, B. (Beate), Teumer, A. (Alexander), Thorleifsson, G. (Gudmar), Verweij, N. (Niek), Vuckovic, D. (Dragana), Wellmann, J. (Juergen), Westra, H.J. (Harm-Jan), Yang, J. (Jingyun), Zhao, W. (Wei), Zhu, Z. (Zhihong), Alizadeh, B.Z. (Behrooz), Amin, N. (Najaf), Bakshi, A. (Andrew), Baumeister, S.E. (Sebastian), Biino, G. (Ginevra), Bønnelykke, K. (Klaus), Boyle, P.A. (Patricia), Campbell, H. (Harry), Cappuccio, F.P. (Francesco P.), Davies, G. (Gail), Neve, J.E. (Jan-Emmanuel) de, Deloukas, P. (Panagiotis), Demuth, I. (Ilja), Ding, J. (Jun), Eibich, P. (Peter), Eisele, L. (Lewin), Eklund, N. (Niina), Evans, D.M. (David), Faul, J.D. (Jessica D.), Feitosa, M.F. (Mary Furlan), Forstner, A.J. (Andreas), Gandin, I. (Ilaria), Gunnarsson, B. (Bjarni), Halldorsson, B.V. (Bjarni), Harris, T.B. (Tamara), Holliday, E.G. (Elizabeth), Heath, A.C. (Andrew C.), Hocking, L.J., Homuth, G. (Georg), Horan, M. (Mike), Hottenga, J.J. (Jouke Jan), Jager, P.L. (Philip) de, Joshi, P.K. (Peter), Juqessur, A. (Astanand), Kaakinen, M. (Marika), Kähönen, M. (Mika), Kanoni, S. (Stavroula), Keltigangas-Järvinen, L. (Liisa), Kiemeney, L.A.L.M. (Bart), Kolcic, I. (Ivana), Koskinen, S. (Seppo), Kraja, A. (Aldi), Kroh, M. (Martin), Kutalik, Z. (Zoltán), Latvala, A. (Antti), Launer, L.J. (Lenore), Lebreton, M.P. (Maël P.), Levinson, D.F. (Douglas F.), Lichtenstein, P. (Paul), Lichtner, P. (Peter), Liewald, D.C.M. (David), Loukola, A. (Anu), Madden, P.A. (Pamela), Mägi, R. (Reedik), Mäki-Opas, T. (Tomi), Marioni, R.E. (Riccardo), Marques-Vidal, P. (Pedro), Meddens, G.A. (Gerardus A.), Mcmahon, G. (George), Meisinger, C. (Christa), Meitinger, T. (Thomas), Milaneschi, Y. (Yusplitri), Milani, L. (Lili), Montgomery, G.W. (Grant), Myhre, R. (Ronny), Nelson, C.P. (Christopher P.), Nyholt, D.R. (Dale), Ollier, W.E.R. (William), Palotie, A. (Aarno), Paternoster, L. (Lavinia), Pedersen, N.L. (Nancy), Petrovic, K. (Katja), Porteous, D.J. (David J.), Räikkönen, K. (Katri), Ring, S.M. (Susan M.), Robino, A. (Antonietta), Rostapshova, O. (Olga), Rudan, I. (Igor), Rustichini, A. (Aldo), Salomaa, V. (Veikko), Sanders, A.R. (Alan R.), Sarin, A.-P., Schmidt, R. (Reinhold), Scott, R.J. (Rodney), Smith, B.H. (Blair), Smith, J.A. (Jennifer A), Staessen, J.A. (Jan), Steinhagen-Thiessen, E. (Elisabeth), Strauch, K. (Konstantin), Terracciano, A., Tobin, M.D. (Martin), Ulivi, S. (Shelia), Vaccargiu, S. (Simona), Quaye, L. (Lydia), Rooij, F.J.A. (Frank) van, Venturini, C. (Cristina), Vinkhuyzen, A.A.E. (Anna A.), Völker, U. (Uwe), Völzke, H. (Henry), Vonk, J.M. (Judith), Vozzi, D. (Diego), Waage, J. (Johannes), Ware, E.B. (Erin B.), Willemsen, G.A.H.M. (Gonneke), Attia, J. (John), Bennett, D.A. (David A.), Berger, K. (Klaus), Bertram, L. (Lars), Bisgaard, H. (Hans), Boomsma, D.I. (Dorret), Borecki, I.B. (Ingrid), Bültmann, U. (Ute), Chabris, C.F. (Christopher F.), Cucca, F. (Francesco), Cusi, D. (Daniele), Deary, I.J. (Ian), Dedoussis, G.V. (George), Duijn, C.M. (Cornelia) van, Hagen, K. (Knut), Franke, B. (Barbara), Franke, L. (Lude), Gasparini, P. (Paolo), Gejman, P.V. (Pablo), Gieger, C. (Christian), Grabe, H.J. (Hans Jörgen), Gratten, J. (Jacob), Groenen, P.J.F. (Patrick), Gudnason, V. (Vilmundur), Harst, P. (Pim) van der, Hayward, C. (Caroline), Hinds, D.A. (David A.), Hoffmann, W. (Wolfgang), Hypponen, E. (Elina), Iacono, W.G. (William), Jacobsson, B. (Bo), Jarvelin, M.-R. (Marjo-Riitta), JöCkel, K.-H. (Karl-Heinz), Kaprio, J. (Jaakko), Kardia, S.L.R. (Sharon), Lehtimäki, T. (Terho), Lehrer, S.F. (Steven F.), Magnusson, P.K. (Patrik), Martin, N.G. (Nicholas), McGue, M. (Matt), Metspalu, A. (Andres), Pendleton, N. (Neil), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Pirastu, N. (Nicola), Pirastu, M. (Mario), Polasek, O. (Ozren), Posthuma, D. (Danielle), Power, C. (Christopher), Province, M.A. (Mike), Samani, N.J. (Nilesh), Schlessinger, D. (David), Sørensen, T.I.A. (Thorkild), Spector, T.D. (Timothy), Zwart, J-A. (John-Anker), Thorsteinsdottir, U. (Unnur), Thurik, A.R. (Roy), Timpson, N.J. (Nicholas J.), Tiemeier, H.W. (Henning), Tung, J.Y. (Joyce Y.), Uitterlinden, A.G. (André), Vitart, V. (Veronique), Vollenweider, P. (Peter), Weir, D.R. (David), Wilson, J.F. (James F.), Wright, A.F. (Alan), Conley, D.C. (Dalton C.), Krueger, R.F., Smith, A.V. (Davey), Hofman, A. (Albert), Laibson, D. (David), Medland, S.E. (Sarah), Meyer, M.N. (Michelle N.), Yang, J. (Joanna), Johannesson, M. (Magnus), Visscher, P.M. (Peter), Esko, T. (Tõnu), Koellinger, Ph.D. (Philipp), Cesarini, D. (David), and Benjamin, D.J. (Daniel J.)

Abstract

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.

Published
2016
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36. A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Author

Ried, J.S. (Janina), Jeff, J. (Janina), Chu, A.Y. (Audrey Y), Bragg-Gresham, J.L. (Jennifer L.), Dongen, J. (Jenny) van, Huffman, J.E. (Jennifer), Ahluwalia, T.S. (Tarunveer Singh), Cadby, G. (Gemma), Eklund, N. (Niina), Eriksson, J. (Joel), Esko, T. (Tõnu), Feitosa, M.F. (Mary Furlan), Goel, A. (Anuj), Gorski, M. (Mathias), Hayward, C. (Caroline), Heard-Costa, N.L. (Nancy), Jackson, A.U. (Anne), Jokinen, E. (Eero), Kanoni, S. (Stavroula), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Lahti, J. (Jari), Luan, J. (Jian'An), Mägi, R. (Reedik), Mahajan, A. (Anubha), Mangino, M. (Massimo), Medina-Gomez, M.C. (Carolina), Monda, K.L. (Keri), Nolte, I.M. (Ilja), Perusse, L. (Louis), Prokopenko, I. (Inga), Qi, L. (Lu), Rose, L.M. (Lynda), Salvi, E. (Erika), Smith, M.T. (Megan T.), Snieder, H. (Harold), Standáková, A. (Alena), Ju Sung, Y. (Yun), Tachmazidou, I. (Ioanna), Teumer, A. (Alexander), Thorleifsson, G. (Gudmar), Harst, P. (Pim) van der, Walker, R.W. (Ryan W.), Wang, S.R. (Sophie), Wild, S.H. (Sarah), Willems, S.M. (Sara), Wong, A. (Andrew), Zhang, W. (Weihua), Albrecht, E. (Eva), Couto-Alves, A. (Alexessander), Bakker, S.J.L. (Stephan), Barlassina, C. (Cristina), Bartz, T.M. (Traci M.), Beilby, J.P. (John), Bellis, C. (Claire), Bergman, R.N. (Richard N.), Bergmann, S.M. (Sven), Blangero, J. (John), Blüher, M. (Matthias), Boerwinkle, E.A. (Eric), Bonnycastle, L.L. (Lori), Bornstein, S.R. (Stefan R.), Bruinenberg, M. (M.), Campbell, H. (Harry), Chen, Y.-D.I. (Yii-Der Ida), Chiang, C.W.K. (Charleston W. K.), Chines, P.S. (Peter), Collins, F.S. (Francis), Cucca, F. (Fracensco), Cupples, L.A. (Adrienne), D'avila, F. (Francesca), Geus, E.J.C. (Eco) de, Dedoussis, G.V. (George), Dimitriou, M. (Maria), Döring, A. (Angela), Hagen, K. (Knut), Farmaki, A.-E. (Aliki-Eleni), Farrall, M. (Martin), Ferreira, T. (Teresa), Fischer, K. (Krista), Forouhi, N.G. (Nita), Friedrich, N. (Nele), Gjesing, A.P. (Anette), Glorioso, N. (Nicola), Graff, M.J. (Maud J.L.), Grallert, H. (Harald), Grarup, N. (Niels), Gräßler, J. (Jürgen), Grewal, J. (Jagvir), Hamsten, A. (Anders), Harder, M.N. (Marie Neergaard), Hartman, C.A. (Catharina A.), Hassinen, M. (Maija), Hastie, N. (Nick), Hattersley, A.T. (Andrew), Havulinna, A.S. (Aki), Heliovaara, M. (Markku), Hillege, H.L. (Hans), Hofman, A. (Albert), Holmen, O.L. (Oddgeir), Homuth, G. (Georg), Hottenga, J.J. (Jouke Jan), Hui, J. (Jennie), Husemoen, L.L.N. (Lise Lotte), Hysi, P.G. (Pirro), Isaacs, A.J. (Aaron), Ittermann, T. (Till), Jalilzadeh, S. (Shapour), James, A. (Alan), Jorgensen, T. (Torben), Jousilahti, P. (Pekka), Jula, A. (Antti), Marie Justesen, J. (Johanne), Justice, A.E. (Anne), Kähönen, M. (Mika), Karaleftheri, M. (Maria), Tee Khaw, K. (Kay), Keinanen-Kiukaanniemi, S. (Sirkka), Kinnunen, L. (Leena), Knekt, P., Koistinen, H. (Heikki), Kolcic, I. (Ivana), Kooner, I.K. (Ishminder K.), Koskinen, S. (Seppo), Kovacs, P. (Peter), Kyriakou, T. (Theodosios), Laitinen, T. (Tomi), Langenberg, C. (Claudia), Lewin, A. (Alex), Lichtner, P. (Peter), Lindgren, C.M. (Cecilia), Lindström, J. (Jaana), Linneberg, A. (Allan), Lorbeer, R. (Roberto), Lorentzon, M. (Mattias), Luben, R.N. (Robert), Lyssenko, V. (Valeriya), Männistö, S. (Satu), Manunta, P. (Paolo), Leach, I.M. (Irene Mateo), McArdle, W.L. (Wendy), Mcknight, B. (Barbara), Mohlke, K.L. (Karen), Mihailov, E. (Evelin), Milani, L. (Lili), Mills, R. (Rebecca), Montasser, M.E. (May E.), Morris, A.P. (Andrew), Müller, G. (Gabriele), Musk, A.W. (Arthur W.), Narisu, N. (Narisu), Ong, K.K. (Ken K.), Oostra, B.A. (Ben), Osmond, C. (Clive), Palotie, A. (Aarno), Pankow, J.S. (James), Paternoster, L. (Lavinia), Penninx, B.W.J.H. (Brenda), Pichler, I. (Irene), Pilia, M.G. (Maria Grazia), Polasek, O. (Ozren), Pramstaller, P.P. (Peter Paul), Raitakari, O.T. (Olli T.), Rankinen, T. (Tuomo), Rao, D.C., Rayner, N.W. (Nigel William), Ribel-Madsen, R. (Rasmus), Rice, T.K. (Treva K.), Richards, M. (Marcus), Ridker, P.M. (Paul), Rivadeneira Ramirez, F. (Fernando), Ryan, K.A. (Kathy A.), Sanna, S. (Serena), Sarzynski, M.A. (Mark A.), Scholtens, S. (Salome), Scott, R.A. (Robert), Sebert, S. (Sylvain), Southam, L. (Lorraine), Sparsø, T. (Thomas), Steinthorsdottir, V. (Valgerdur), Stirrups, K. (Kathy), Stolk, R.P. (Ronald), Strauch, K. (Konstantin), Stringham, H.M. (Heather), Swertz, M. (Morris), Swift, A.J. (Amy), Tönjes, A. (Anke), Tsafantakis, E. (Emmanouil), Most, P.J. (Peter) van der, Vliet-Ostaptchouk, J.V. (Jana) van, Vandenput, L. (Liesbeth), Vartiainen, E. (Erkki), Venturini, C. (Cristina), Verweij, N. (Niek), Viikari, J. (Jorma), Vitart, V. (Veronique), Vohl, M.-C. (Marie-Claude), Vonk, J.M. (Judith), Waeber, G. (Gérard), Widen, E. (Elisabeth), Willemsen, G.A.H.M. (Gonneke), Wilsgaard, T. (Tom), Winkler, T.W. (Thomas W.), Wright, A.F. (Alan), Yerges-Armstrong, L.M. (Laura), Zhao, J.H. (Jing Hua), Zillikens, M.C. (Carola), Boomsma, D.I. (Dorret), Bouchard, C. (Claude), Chambers, J.C. (John), Chasman, D.I. (Daniel), Cusi, D. (Daniele), Gansevoort, R.T. (Ron), Gieger, C. (Christian), Hansen, T. (T.), Hicks, A.A. (Andrew), Hu, F. (Frank), Hveem, K. (Kristian), Jarvelin, M.-R. (Marjo-Riitta), Kajantie, E. (Eero), Kooner, J.S. (Jaspal S.), Kuh, D. (Diana), Kuusisto, J. (Johanna), Laakso, M. (Markku), Lakka, T.A. (Timo), Lehtimäki, T. (Terho), Metspalu, A. (Andres), Njølstad, I. (Inger), Ohlsson, C. (Claes), Oldehinkel, A.J. (Albertine), Palmer, L.J. (Lyle J.), Pedersen, O. (Oluf), Perola, M. (Markus), Peters, A. (Annette), Psaty, B.M. (Bruce), Puolijoki, H. (Hannu), Rauramaa, R. (Rainer), Rudan, I. (Igor), Salomaa, V. (Veikko), Schwarz, P.E.H. (Peter), Shudiner, A.R. (Alan R.), Smit, J.H. (Jan), Sørensen, T.I.A. (Thorkild), Spector, T.D. (Timothy), Zwart, J-A. (John-Anker), Stumvoll, M. (Michael), Tremblay, A. (Angelo), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Uusitupa, M. (Matti), Völker, U. (Uwe), Vollenweider, P. (Peter), Wareham, N.J. (Nick), Watkins, H. (Hugh), Wilson, J.F. (James), Zeggini, E. (Eleftheria), Abecasis, G.R. (Gonçalo), Boehnke, M. (Michael), Borecki, I.B. (Ingrid), Deloukas, P. (Panagiotis), Duijn, C.M. (Cornelia) van, Fox, C.S. (Caroline), Groop, L. (Leif), Heid, I.M. (Iris), Hunter, D.J. (David J.), Kaplan, R.C. (Robert), McCarthy, M.I. (Mark), North, K.E. (Kari), O´Connell, J.R., Schlessinger, D. (David), Thorsteinsdottir, U. (Unnur), Strachan, D.P. (David), Frayling, T.M. (Timothy), Hirschhorn, J.N. (Joel), Müller-Nurasyid, M. (Martina), Loos, R.J.F. (Ruth), Ried, J.S. (Janina), Jeff, J. (Janina), Chu, A.Y. (Audrey Y), Bragg-Gresham, J.L. (Jennifer L.), Dongen, J. (Jenny) van, Huffman, J.E. (Jennifer), Ahluwalia, T.S. (Tarunveer Singh), Cadby, G. (Gemma), Eklund, N. (Niina), Eriksson, J. (Joel), Esko, T. (Tõnu), Feitosa, M.F. (Mary Furlan), Goel, A. (Anuj), Gorski, M. (Mathias), Hayward, C. (Caroline), Heard-Costa, N.L. (Nancy), Jackson, A.U. (Anne), Jokinen, E. (Eero), Kanoni, S. (Stavroula), Kristiansson, K. (Kati), Kutalik, Z. (Zoltán), Lahti, J. (Jari), Luan, J. (Jian'An), Mägi, R. (Reedik), Mahajan, A. (Anubha), Mangino, M. (Massimo), Medina-Gomez, M.C. (Carolina), Monda, K.L. (Keri), Nolte, I.M. (Ilja), Perusse, L. (Louis), Prokopenko, I. (Inga), Qi, L. (Lu), Rose, L.M. (Lynda), Salvi, E. (Erika), Smith, M.T. (Megan T.), Snieder, H. (Harold), Standáková, A. (Alena), Ju Sung, Y. (Yun), Tachmazidou, I. (Ioanna), Teumer, A. (Alexander), Thorleifsson, G. (Gudmar), Harst, P. (Pim) van der, Walker, R.W. (Ryan W.), Wang, S.R. (Sophie), Wild, S.H. (Sarah), Willems, S.M. (Sara), Wong, A. (Andrew), Zhang, W. (Weihua), Albrecht, E. (Eva), Couto-Alves, A. (Alexessander), Bakker, S.J.L. (Stephan), Barlassina, C. (Cristina), Bartz, T.M. (Traci M.), Beilby, J.P. (John), Bellis, C. (Claire), Bergman, R.N. (Richard N.), Bergmann, S.M. (Sven), Blangero, J. (John), Blüher, M. (Matthias), Boerwinkle, E.A. (Eric), Bonnycastle, L.L. (Lori), Bornstein, S.R. (Stefan R.), Bruinenberg, M. (M.), Campbell, H. (Harry), Chen, Y.-D.I. (Yii-Der Ida), Chiang, C.W.K. (Charleston W. K.), Chines, P.S. (Peter), Collins, F.S. (Francis), Cucca, F. (Fracensco), Cupples, L.A. (Adrienne), D'avila, F. (Francesca), Geus, E.J.C. (Eco) de, Dedoussis, G.V. (George), Dimitriou, M. (Maria), Döring, A. (Angela), Hagen, K. (Knut), Farmaki, A.-E. (Aliki-Eleni), Farrall, M. (Martin), Ferreira, T. (Teresa), Fischer, K. (Krista), Forouhi, N.G. (Nita), Friedrich, N. (Nele), Gjesing, A.P. (Anette), Glorioso, N. (Nicola), Graff, M.J. (Maud J.L.), Grallert, H. (Harald), Grarup, N. (Niels), Gräßler, J. (Jürgen), Grewal, J. (Jagvir), Hamsten, A. (Anders), Harder, M.N. (Marie Neergaard), Hartman, C.A. (Catharina A.), Hassinen, M. (Maija), Hastie, N. (Nick), Hattersley, A.T. (Andrew), Havulinna, A.S. (Aki), Heliovaara, M. (Markku), Hillege, H.L. (Hans), Hofman, A. (Albert), Holmen, O.L. (Oddgeir), Homuth, G. (Georg), Hottenga, J.J. (Jouke Jan), Hui, J. (Jennie), Husemoen, L.L.N. (Lise Lotte), Hysi, P.G. (Pirro), Isaacs, A.J. (Aaron), Ittermann, T. (Till), Jalilzadeh, S. (Shapour), James, A. (Alan), Jorgensen, T. (Torben), Jousilahti, P. (Pekka), Jula, A. (Antti), Marie Justesen, J. (Johanne), Justice, A.E. (Anne), Kähönen, M. (Mika), Karaleftheri, M. (Maria), Tee Khaw, K. (Kay), Keinanen-Kiukaanniemi, S. (Sirkka), Kinnunen, L. (Leena), Knekt, P., Koistinen, H. (Heikki), Kolcic, I. (Ivana), Kooner, I.K. (Ishminder K.), Koskinen, S. (Seppo), Kovacs, P. (Peter), Kyriakou, T. (Theodosios), Laitinen, T. (Tomi), Langenberg, C. (Claudia), Lewin, A. (Alex), Lichtner, P. (Peter), Lindgren, C.M. (Cecilia), Lindström, J. (Jaana), Linneberg, A. (Allan), Lorbeer, R. (Roberto), Lorentzon, M. (Mattias), Luben, R.N. (Robert), Lyssenko, V. (Valeriya), Männistö, S. (Satu), Manunta, P. (Paolo), Leach, I.M. (Irene Mateo), McArdle, W.L. (Wendy), Mcknight, B. (Barbara), Mohlke, K.L. (Karen), Mihailov, E. (Evelin), Milani, L. (Lili), Mills, R. (Rebecca), Montasser, M.E. (May E.), Morris, A.P. (Andrew), Müller, G. (Gabriele), Musk, A.W. (Arthur W.), Narisu, N. (Narisu), Ong, K.K. (Ken K.), Oostra, B.A. (Ben), Osmond, C. (Clive), Palotie, A. (Aarno), Pankow, J.S. (James), Paternoster, L. (Lavinia), Penninx, B.W.J.H. (Brenda), Pichler, I. (Irene), Pilia, M.G. (Maria Grazia), Polasek, O. (Ozren), Pramstaller, P.P. (Peter Paul), Raitakari, O.T. (Olli T.), Rankinen, T. (Tuomo), Rao, D.C., Rayner, N.W. (Nigel William), Ribel-Madsen, R. (Rasmus), Rice, T.K. (Treva K.), Richards, M. (Marcus), Ridker, P.M. (Paul), Rivadeneira Ramirez, F. (Fernando), Ryan, K.A. (Kathy A.), Sanna, S. (Serena), Sarzynski, M.A. (Mark A.), Scholtens, S. (Salome), Scott, R.A. (Robert), Sebert, S. (Sylvain), Southam, L. (Lorraine), Sparsø, T. (Thomas), Steinthorsdottir, V. (Valgerdur), Stirrups, K. (Kathy), Stolk, R.P. (Ronald), Strauch, K. (Konstantin), Stringham, H.M. (Heather), Swertz, M. (Morris), Swift, A.J. (Amy), Tönjes, A. (Anke), Tsafantakis, E. 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(David), Frayling, T.M. (Timothy), Hirschhorn, J.N. (Joel), Müller-Nurasyid, M. (Martina), and Loos, R.J.F. (Ruth)

Abstract

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain >99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways.

Published
2016
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37. Correction: The influence of age and sex on genetic associations with adult body size and shape : a large-scale genome-wide interaction study.

Author

Winkler, T.W., Justice, A.E., Graff, M., Barata, L., Feitosa, M.F., Chu, S., Czajkowski, J., Esko, T., Fall, T., Kilpeläinen, T.O., Lu, Y., Mägi, R., Mihailov, E., Pers, T.H., Rüeger, S., Teumer, A., Ehret, G.B., Ferreira, T., Heard-Costa, N.L., Karjalainen, J., Lagou, V., Mahajan, A., Neinast, M.D., Prokopenko, I., Simino, J., Teslovich, T.M., Jansen, R., Westra, H.J., White, C.C., Absher, D., Ahluwalia, T.S., Ahmad, S., Albrecht, E., Alves, A.C., Bragg-Gresham, J.L., de Craen, A.J., Bis, J.C., Bonnefond, A., Boucher, G., Cadby, G., Cheng, Y.C., Chiang, C.W., Delgado, G., Demirkan, A., Dueker, N., Eklund, N., Eiriksdottir, G., Eriksson, J., Feenstra, B., Fischer, K., Frau, F., Galesloot, T.E., Geller, F., Goel, A., Gorski, M., Grammer, T.B., Gustafsson, S., Haitjema, S., Hottenga, J.J., Huffman, J.E., Jackson, A.U., Jacobs, K.B., Johansson, Å., Kaakinen, M., Kleber, M.E., Lahti, J., Mateo Leach, I., Lehne, B., Liu, Y., Lo, K.S., Lorentzon, M., Luan, J., Madden, P.A., Mangino, M., McKnight, B., Medina-Gomez, C., Monda, K.L., Montasser, M.E., Müller, G., Müller-Nurasyid, M., Nolte, I.M., Panoutsopoulou, K., Pascoe, L., Paternoster, L., Rayner, N.W., Renström, F., Rizzi, F., Rose, L.M., Ryan, K.A., Salo, P., Sanna, S., Scharnagl, H., Shi, J., Smith, A.V., Southam, L., Stančáková, A., Steinthorsdottir, V., Strawbridge, R.J., Sung, Y.J., Tachmazidou, I., Tanaka, T., Thorleifsson, G., Trompet, S., Pervjakova, N., Tyrer, J.P., Vandenput, L., van der Laan, S.W., van der Velde, N., van Setten, J., van Vliet-Ostaptchouk, J.V., Verweij, N., Vlachopoulou, E., Waite, L.L., Wang, S.R., Wang, Z., Wild, S.H., Willenborg, C., Wilson, J.F., Wong, A., Yang, J., Yengo, L., Yerges-Armstrong, L.M., Yu, L., Zhang, W., Zhao, J.H., Andersson, E.A., Bakker, S.J., Baldassarre, D., Banasik, K., Barcella, M., Barlassina, C., Bellis, C., Benaglio, P., Blangero, J., Blüher, M., Bonnet, F., Bonnycastle, L.L., Boyd, H.A., Bruinenberg, M., Buchman, A.S., Campbell, H., Chen, Y.I., Chines, P.S., 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S.J., Koenig, W., Kolcic, I., Kovacs, P., Krarup, N.T., Kratzer, W., Krüger, J., Kuh, D., Kumari, M., Kyriakou, T., Langenberg, C., Lannfelt, L., Lanzani, C., Lotay, V., Launer, L.J., Leander, K., Lindström, J., Linneberg, A., Liu, Y.P., Lobbens, S., Luben, R., Lyssenko, V., Männistö, S., Magnusson, P.K., McArdle, W.L., Menni, C., Merger, S., Milani, L., Montgomery, G.W., Morris, A.P., Narisu, N., Nelis, M., Ong, K.K., Palotie, A., Pérusse, L., Pichler, I., Pilia, M.G., Pouta, A., Rheinberger, M., Ribel-Madsen, R., Richards, M., Rice, K.M., Rice, T.K., Rivolta, C., Salomaa, V., Sanders, A.R., Sarzynski, M.A., Scholtens, S., Scott, R.A., Scott, W.R., Sebert, S., Sengupta, S., Sennblad, B., Seufferlein, T., Silveira, A., Slagboom, P.E., Smit, J.H., Sparsø, T.H., Stirrups, K., Stolk, R.P., Stringham, H.M., Swertz, M.A., Swift, A.J., Syvänen, A.C., Tan, S.T., Thorand, B., Tönjes, A., Tremblay, A., Tsafantakis, E., van der Most, P.J., Völker, U., Vohl, M.C., Vonk, J.M., Waldenberger, M., Walker, R.W., Wennauer, R., Widén, E., Willemsen, G., Wilsgaard, T., Wright, A.F., Zillikens, M.C., van Dijk, S.C., van Schoor, N.M., Asselbergs, F.W., de Bakker, P.I., Beckmann, J.S., Beilby, J., Bennett, D.A., Bergman, R.N., Bergmann, S., Böger, C.A., Boehm, B.O., Boerwinkle, E., Boomsma, D.I., Bornstein, S.R., Bottinger, E.P., Bouchard, C., Chambers, J.C., Chanock, S.J., Chasman, D.I., Cucca, F., Cusi, D., Dedoussis, G., Erdmann, J., Eriksson, J.G., Evans, D.A., de Faire, U., Farrall, M., Ferrucci, L., Ford, I., Franke, L., Franks, P.W., Froguel, P., Gansevoort, R.T., Gieger, C., Grönberg, H., Gudnason, V., Gyllensten, U., Hall, P., Hamsten, A., van der Harst, P., Hayward, C., Heliövaara, M., Hengstenberg, C., Hicks, A.A., Hingorani, A., Hofman, A., Hu, F., Huikuri, H.V., Hveem, K., James, A.L., Jordan, J.M., Jula, A., Kähönen, M., Kajantie, E., Kathiresan, S., Kiemeney, L.A., Kivimaki, M., Knekt, P.B., Koistinen, H.A., Kooner, J.S., Koskinen, S., Kuusisto, J., Maerz, W., Martin, N.G., Laakso, M., Lakka, T.A., Lehtimäki, T., Lettre, G., Levinson, D.F., Lind, L., Lokki, M.L., Mäntyselkä, P., Melbye, M., Metspalu, A., Mitchell, B.D., Moll, F.L., Murray, J.C., Musk, A.W., Nieminen, M.S., Njølstad, I., Ohlsson, C., Oldehinkel, A.J., Oostra, B.A., Palmer, L.J., Pankow, J.S., Pasterkamp, G., Pedersen, N.L., Pedersen, O., Penninx, B.W., Perola, M., Peters, A., Polaek, O., Pramstaller, P.P., Psaty, B.M., Qi, L., Quertermous, T., Raitakari, O.T., Rankinen, T., Rauramaa, R., Ridker, P.M., Rioux, J.D., Rivadeneira, F., Rotter, J.I., Rudan, I., den Ruijter, H.M., Saltevo, J., Sattar, N., Schunkert, H., Schwarz, P.E., Shuldiner, A.R., Sinisalo, J., Snieder, H., Sørensen, T.I., Spector, T.D., Staessen, J.A., Stefania, B., Thorsteinsdottir, U., Stumvoll, M., Tardif, J.C., Tremoli, E., Tuomilehto, J., Uitterlinden, A.G., Uusitupa, M., Verbeek, A.L., Vermeulen, S.H., Viikari, J.S., Vitart, V., Völzke, H., Vollenweider, P., Waeber, G., Walker, M., Wallaschofski, H., Wareham, N.J., Watkins, H., Zeggini, E., arcOGEN, Consortium, CHARGE, Consortium, DIAGRAM, Consortium, GLGC, Consortium, Global-BPGen, Consortium, ICBP, Consortium, MAGIC, Consortium, Chakravarti, A., Clegg, D.J., Cupples, L.A., Gordon-Larsen, P., Jaquish, C.E., Rao, D.C., Abecasis, G.R., Assimes, T.L., Barroso, I., Berndt, S.I., Boehnke, M., Deloukas, P., Fox, C.S., Groop, L.C., Hunter, D.J., Ingelsson, E., Kaplan, R.C., McCarthy, M.I., Mohlke, K.L., O'Connell, J.R., Schlessinger, D., Strachan, D.P., Stefansson, K., van Duijn, C.M., Hirschhorn, J.N., Lindgren, C.M., Heid, I.M., North, K.E., Borecki, I.B., Kutalik, Z., and Loos, R.J.

Abstract

This corrects the article DOI: 10.1371/journal.pgen.1005378.

Published
2016

38. Novel Genes for Airway Wall Thickness Identified with Combined Genome Wide Association and Expression Analyses

Author

Dijkstra, A.E., Postma, D.S., Ginneken, B. van, Wielpuetz, M.O., Schmidt, M., Becker, N., Owsijewitsch, M., Kauczor, H.-U., Koning, H.J. de, Lammers, J.W., Oudkerk, M., Brandsma, C.-A., Bosse, Y., Nickle, D.C., Sin, D.D., Hiemstra, P.S., Wijmenga, C., Smolonska, J., Zanen, P., Vonk, J.M., Berge, M. ten, Boezen, H.M., Groen, H.J.M., Dijkstra, A.E., Postma, D.S., Ginneken, B. van, Wielpuetz, M.O., Schmidt, M., Becker, N., Owsijewitsch, M., Kauczor, H.-U., Koning, H.J. de, Lammers, J.W., Oudkerk, M., Brandsma, C.-A., Bosse, Y., Nickle, D.C., Sin, D.D., Hiemstra, P.S., Wijmenga, C., Smolonska, J., Zanen, P., Vonk, J.M., Berge, M. ten, Boezen, H.M., and Groen, H.J.M.

Abstract

Contains fulltext : 153524.pdf (Publisher’s version ) (Open Access), Rationale Airway wall thickness (AWT) is affected by both environmental and genetic factors and is strongly associated with airflow limitation in smaller airways. Objectives The aim of our study was to investigate its genetic component. Methods AWT was measured on low-dose CT-scans in male heavy smokers participating in a lung cancer screening study (n = 2,640). Genome wide association studies on AWT were performed under an additive model using linear regression (adjusted for pack-years, lung volume), followed by meta-analysis. An independent cohort was used for validation of the most strongly associated single nucleotide polymorphisms (SNPs). The functional relevance of significant SNPs was evaluated. Measurements and main results Three significant loci on chromosomes 2q (rs734556, p = 6.2x10-7) and 10q (rs10794108, p = 8.6x10-8; rs7078439, p = 2.3x10-7) were associated with AWT and confirmed in the meta-analysis in cohorts with comparable lung function: p-values 4.6x10-8, 7.4x10-8 and 7.5x10-8, respectively. SNP rs734556 was associated with decreased lung tissue expression of SERPINE2, a susceptibility gene for emphysema. Two nominally significant SNPs showed effects with similar direction: rs10251504 in MAGI2 (p = 5.8x10-7) and rs4796712 in NT5C3B (p = 3.1x10-6). Higher MAGI2 expression in bronchial biopsies of COPD patients was significantly associated with lower inflammatory cell numbers, lower NT5C3B expression with worse lung function. The NT5C3B risk allele was associated with higher lung tissue expression (p = 1.09x10-41). Conclusions Genetic variants contribute to AWT. Amongst others, the identified genes are involved in emphysema, airway obstruction and bronchial inflammation.

Published
2015

39. The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape: A Large-Scale Genome-Wide Interaction Study

Author

Winkler, T.W. (Thomas W.), Justice, A.E. (Anne), Graff, M.J. (Maud J.L.), Barata, L. (Llilda), Feitosa, M.F. (Mary Furlan), Chu, S. (Su), Czajkowski, J. (Jacek), Esko, T. (Tõnu), Fall, M. (Magnus), Kilpeläinen, T.O. (Tuomas), Lu, Y. (Yingchang), Mägi, R. (Reedik), Mihailov, E. (Evelin), Pers, T.H. (Tune), Rüeger, S. (Sina), Teumer, A. (Alexander), Ehret, G.B. (Georg), Ferreira, T. (Teresa), Heard-Costa, N.L. (Nancy), Karjalainen, J. (Juha), Lagou, V. (Vasiliki), Mahajan, A. (Anubha), Neinast, M.D. (Michael D.), Prokopenko, I. (Inga), Simino, J. (Jeannette), Teslovich, T.M. (Tanya M.), Jansen, R., Westra, H.J. (Harm-Jan), White, C.C. (Charles), Absher, D. (Devin), Ahluwalia, T.S. (Tarunveer Singh), Ahmad, S. (Shafqat), Albrecht, E. (Eva), Alves, A.C. (Alexessander Couto), Bragg-Gresham, J.L. (Jennifer L.), Craen, A.J. (Anton) de, Bis, J.C. (Joshua), Bonnefond, A. (Amélie), Boucher, G. (Gabrielle), Cadby, G. (Gemma), Cheng, Y.-C. (Yu-Ching), Chiang, C.W. (Charleston W K), Delgado, G., Demirkan, A. (Ayşe), Dueker, N. (Nicole), Eklund, N. (Niina), Eiriksdottir, G. (Gudny), Eriksson, J. (Joel), Feenstra, B. (Bjarke), Fischer, K. (Krista), Frau, F. (Francesca), Galesloot, T.E. (Tessel), Geller, F. (Frank), Goel, A. (Anuj), Gorski, M. (Mathias), Grammer, T.B. (Tanja), Gustafsson, S. (Stefan), Haitjema, S. (Saskia), Hottenga, J.J. (Jouke Jan), Huffman, J.E. (Jennifer), Jackson, A.U. (Anne), Jacobs, K.B. (Kevin), Johansson, A. (Åsa), Kaakinen, M. (Marika), Kleber, M.E. (Marcus), Lahti, J. (Jari), Leach, I.M. (Irene Mateo), Lehne, B. (Benjamin), Liu, Y. (Youfang), Lo, K.S., Lorentzon, M. (Mattias), Luan, J. (Jian'An), Madden, P.A. (Pamela), Mangino, M. (Massimo), McKnight, B. (Barbara), Medina-Gomez, C. (Carolina), Monda, K.L. (Keri), Montasser, M.E. (May E.), Müller, G. (Gabriele), Müller-Nurasyid, M. (Martina), Nolte, I.M. (Ilja), Panoutsopoulou, K. (Kalliope), Pascoe, L. (Laura), Paternoster, L. (Lavinia), Rayner, N.W. (Nigel William), Renström, F. (Frida), Rizzi, F. (Federica), Rose, L.M. (Lynda), Ryan, K.A. (Kathy A.), Salo, P. (Perttu), Sanna, S. (Serena), Scharnagl, H. (Hubert), Shi, J. (Jianxin), Smith, A.V. (Albert Vernon), Southam, L. (Lorraine), Stancáková, A. (Alena), Steinthorsdottir, V. (Valgerdur), Strawbridge, R.J. (Rona), Sung, Y.J. (Yun Ju), Tachmazidou, I. (Ioanna), Tanaka, T. (Toshiko), Thorleifsson, G. (Gudmar), Trompet, S. (Stella), Pervjakova, N. (Natalia), Tyrer, J.P. (Jonathan), Vandenput, L. (Liesbeth), Van Der Laan, S.W. (Sander W.), Velde, N. (Nathalie) van der, Setten, J. (Jessica) van, Vliet-Ostaptchouk, J.V. (Jana) van, Verweij, N. (Niek), Vlachopoulou, E. (Efthymia), Waite, L. (Lindsay), Wang, S.R. (Sophie), Wang, Z. (Zhaoming), Wild, S.H. (Sarah), Willenborg, C. (Christina), Wilson, J.F. (James), Wong, A. (Andrew), Yang, J. (Jian), Yengo, L. (Loic), Yerges-Armstrong, L.M. (Laura), Yu, L. (Lei), Zhang, W. (Weihua), Zhao, J.H. (Jing Hua), Andersson, E.A. (Ehm Astrid), Bakker, S.J.L. (Stephan), Baldassarre, D. (Damiano), Banasik, K. (Karina), Barcella, M. (Matteo), Barlassina, C. (Cristina), Bellis, C. (Claire), Benaglio, P. (Paola), Blangero, J. (John), Blüher, M. (Matthias), Bonnet, F. (Fabrice), Bonnycastle, L.L. (Lori), Boyd, H.A. (Heather), Bruinenberg, M. (M.), Buchman, A.S. (Aron S.), Campbell, H. (Harry), Chen, Y.D. (Y.), Chines, P.S. (Peter), Claudi-Boehm, S. (Simone), Cole, J.W. (John W.), Collins, F.S. (Francis), Geus, E.J.C. (Eco) de, Groot, L.C.P.G.M. (Lisette) de, Dimitriou, M. (Maria), Duan, J. (Jubao), Enroth, S. (Stefan), Eury, E. (Elodie), Farmaki, A.-E. (Aliki-Eleni), Forouhi, N.G. (Nita), Friedrich, N. (Nele), Gejman, P.V. (Pablo), Gigante, B. (Bruna), Glorioso, N. (Nicola), Go, A.T.J.I. (Attie), Gottesman, R.F. (Rebecca), Gräßler, J. (Jürgen), Grallert, H. (Harald), Grarup, N. (Niels), Gu, Y.-M. (Yu-Mei), Broer, L. (Linda), Ham, A.C. (Annelies), Hansen, T. (T.), Harris, T.B. (Tamara), Hartman, C.A. (Catharina A.), Hassinen, M. (Maija), Hastie, N. (Nick), Hattersley, A.T. (Andrew), Heath, A.C. (Andrew), Henders, A.K. (Anjali), Hernandez, D.G. (Dena), Hillege, H.L. (Hans), Holmen, O.L. (Oddgeir), Hovingh, G.K. (Kees), Hui, J. (Jennie), Husemoen, L.L. (Lise L.), Hutri-Kähönen, N. (Nina), Hysi, P.G. (Pirro), Illig, T. (Thomas), Jager, P.L. (Philip) de, Jalilzadeh, S. (Shapour), Jorgensen, T. (Torben), Jukema, J.W. (Jan Wouter), Juonala, M. (Markus), Kanoni, S. (Stavroula), Karaleftheri, M. (Maria), Khaw, K.T., Kinnunen, L. (Leena), Kittner, T. (Thomas), Koenig, W. (Wolfgang), Kolcic, I. (Ivana), Kovacs, P. (Peter), Krarup, N.T. (Nikolaj T.), Kratzer, W. (Wolfgang), Krüger, J. (Janine), Kuh, D. (Diana), Kumari, M. (Meena), Kyriakou, T. (Theodosios), Langenberg, C. (Claudia), Lannfelt, L. (Lars), Lanzani, C. (Chiara), Lotay, V. (Vaneet), Launer, L.J. (Lenore), Leander, K. (Karin), Lindström, J. (Jaana), Linneberg, A. (Allan), Liu, Y.-P. (Yan-Ping), Lobbens, S. (Stéphane), Luben, R.N. (Robert), Lyssenko, V. (Valeriya), Männistö, S. (Satu), Magnusson, P.K. (Patrik), McArdle, W.L. (Wendy), Menni, C. (Cristina), Merger, S. (Sigrun), Milani, L. (Lili), Montgomery, G.W. (Grant W.), Morris, A.P. (Andrew), Narisu, N. (Narisu), Nelis, M. (Mari), Ong, K.K. (Ken), Palotie, A. (Aarno), Perusse, L. (Louis), Pichler, I. (Irene), Pilia, M.G. (Maria Grazia), Pouta, A. (Anneli), Rheinberger, M. (Myriam), Ribel-Madsen, R. (Rasmus), Richards, M. (Marcus), Rice, K.M. (Kenneth), Rice, T.K. (Treva K.), Rivolta, C. (Carlo), Salomaa, V. (Veikko), Sanders, A.R. (Alan), Sarzynski, M.A. (Mark A.), Scholtens, S. (Salome), Scott, R.A. (Robert), Scott, W.R. (William R.), Sebert, S. (Sylvain), Sengupta, S. (Sebanti), Sennblad, B. (Bengt), Seufferlein, T. (Thomas), Silveira, A. (Angela), Slagboom, P.E. (Eline), Smit, J.H. (Jan), Sparsø, T. (Thomas), Stirrups, K. (Kathy), Stolk, R.P. (Ronald), Stringham, H.M. (Heather), Swertz, M.A. (Morris A.), Swift, A.J. (Amy), Syvänen, A.C., Tan, S.-T. (Sian-Tsung), Thorand, B. (Barbara), Tönjes, A. (Anke), Tremblay, A. (Angelo), Tsafantakis, E. (Emmanouil), Most, P.J. (Peter) van der, Völker, U. (Uwe), Vohl, M.-C. (Marie-Claude), Vonk, J.M. (Judith), Waldenberger, M. (Melanie), Walker, R.W. (Ryan W.), Wennauer, R. (Roman), Widen, E., Willemsen, G.A.H.M. (Gonneke), Wilsgaard, T. (Tom), Wright, A.F. (Alan), Zillikens, M.C. (Carola), Van Dijk, S. (Suzanne), Schoor, N.M. (Natasja) van, Asselbergs, F.W. (Folkert), Bakker, P.I.W. (Paul) de, Beckmann, J.S. (Jacques), Beilby, J.P. (John), Bennett, D.A. (David A.), Bergman, R.N. (Richard), Bergmann, S.M. (Sven), Böger, C.A. (Carsten), Boehm, B.O. (Bernhard), Boerwinkle, E.A. (Eric), Boomsma, D.I. (Dorret), Bornstein, S.R. (Stefan), Bottinger, E.P. (Erwin), Bouchard, C. (Claude), Chambers, J.C. (John), Chanock, S.J. (Stephen), Chasman, D.I. (Daniel), Cucca, F. (Francesco), Cusi, D. (Daniele), Dedoussis, G.V. (George), Erdmann, J. (Jeanette), Hagen, K. (Knut), Evans, D., Faire, U. (Ulf) de, Farrall, M. (Martin), Ferrucci, L. (Luigi), Ford, I. (Ian), Franke, L. (Lude), Franks, P.W. (Paul), Froguel, P. (Philippe), Gansevoort, R.T. (Ron), Gieger, C. (Christian), Grönberg, H. (Henrik), Gudnason, V. (Vilmundur), Gyllensten, U. (Ulf), Hall, P. (Per), Hamsten, A. (Anders), Harst, P. (Pim) van der, Hayward, C. (Caroline), Heliovaara, M. (Markku), Hengstenberg, C. (Christian), Hicks, A.A. (Andrew), Hingorani, A. (Aroon), Hofman, A. (Albert), Hu, F. (Frank), Huikuri, H.V. (Heikki), Hveem, K. (Kristian), James, A. (Alan), Jordan, J.M. (Joanne M.), Jula, A. (Antti), Kähönen, M. (Mika), Kajantie, E. (Eero), Kathiresan, S. (Sekar), Kiemeney, L.A.L.M. (Bart), Kivimaki, M. (Mika), Knekt, P., Koistinen, H. (Heikki), Kooner, J.S. (Jaspal S.), Koskinen, S. (Seppo), Kuusisto, J. (Johanna), Maerz, W. (Winfried), Martin, N.G. (Nicholas), Laakso, M. (Markku), Lakka, T.A. (Timo), Lehtimäki, T. (Terho), Lettre, G. (Guillaume), Levinson, D.F. (Douglas), Kao, W.H.L. (Wen), Lokki, M.L., Mäntyselkä, P. (Pekka), Melbye, M. (Mads), Metspalu, A. (Andres), Mitchell, B.D. (Braxton), Moll, F.L. (Frans), Murray, J.C. (Jeffrey), Musk, A.W. (Arthur), Nieminen, M.S. (Markku), Njølstad, I. (Inger), Ohlsson, C. (Claes), Oldehinkel, A.J. (Albertine), Oostra, B.A. (Ben), Palmer, C. (Cameron), Pankow, J.S. (James), Pasterkamp, G. (Gerard), Pedersen, N.L. (Nancy), Pedersen, O. (Oluf), Penninx, B.W.J.H. (Brenda), Perola, M. (Markus), Peters, A. (Annette), Polasek, O. (Ozren), Pramstaller, P.P. (Peter Paul), Psaty, B.M. (Bruce M.), Qi, L. (Lu), Quertermous, T. (Thomas), Raitakari, O.T. (Olli T.), Rankinen, T. (Tuomo), Rauramaa, R. (Rainer), Ridker, P.M. (Paul), Rioux, J.D. (John), Rivadeneira Ramirez, F. (Fernando), Rotter, J.I. (Jerome I.), Rudan, I. (Igor), Ruijter, H.M. (Hester ) den, Saltevo, J. (Juha), Sattar, N. (Naveed), Schunkert, H. (Heribert), Schwarz, P.E.H. (Peter), Shuldiner, A.R. (Alan), Sinisalo, J. (Juha), Snieder, H. (Harold), Sørensen, T.I.A. (Thorkild), Spector, T.D. (Timothy), Staessen, J.A. (Jan A.), Stefania, B. (Bandinelli), Thorsteinsdottir, U. (Unnur), Stumvoll, M. (Michael), Tardif, J.-C. (Jean-Claude), Tremoli, E. (Elena), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Uusitupa, M. (Matti), Verbeek, A.L.M., Vermeulen, S.H.H.M. (Sita), Viikari, J. (Jorma), Vitart, V. (Veronique), Völzke, H. (Henry), Vollenweider, P. (Peter), Waeber, G. (Gérard), Walker, M. (Mark), Wallaschofski, H. (Henri), Wareham, N.J. (Nick), Watkins, H. (Hugh), Zeggini, E. (Eleftheria), Chakravarti, A. (Aravinda), Clegg, D.J. (Deborah J.), Cupples, L.A. (Adrienne), Gordon-Larsen, P. (Penny), Jaquish, C.E. (Cashell), Rao, D.C. (Dabeeru C.), Abecasis, G.R. (Goncalo R.), Assimes, T.L. (Themistocles), Barroso, I.E. (Inês), Berndt, S.I. (Sonja), Boehnke, M. (Michael), Deloukas, P. (Panagiotis), Fox, C.S. (Caroline), Groop, L. (Leif), Hunter, D. (David), Ingelsson, E. (Erik), Kaplan, R.C. (Robert), McCarthy, M.I. (Mark I.), Mohlke, K.L. (Karen), O´Connell, J.R., Schlessinger, D. (David), Strachan, D.P. (David), Zwart, J-A. (John-Anker), Duijn, C.M. (Cornelia) van, Hirschhorn, J.N. (Joel), Lindgren, C.M. (Cecilia M.), Heid, I.M. (Iris), North, K.E. (Kari), Borecki, I.B. (Ingrid), Kutalik, Z. (Zoltán), Loos, R.J.F. (Ruth), Winkler, T.W. (Thomas W.), Justice, A.E. (Anne), Graff, M.J. (Maud J.L.), Barata, L. (Llilda), Feitosa, M.F. (Mary Furlan), Chu, S. (Su), Czajkowski, J. (Jacek), Esko, T. (Tõnu), Fall, M. (Magnus), Kilpeläinen, T.O. (Tuomas), Lu, Y. (Yingchang), Mägi, R. (Reedik), Mihailov, E. (Evelin), Pers, T.H. (Tune), Rüeger, S. (Sina), Teumer, A. (Alexander), Ehret, G.B. (Georg), Ferreira, T. (Teresa), Heard-Costa, N.L. (Nancy), Karjalainen, J. (Juha), Lagou, V. (Vasiliki), Mahajan, A. (Anubha), Neinast, M.D. (Michael D.), Prokopenko, I. (Inga), Simino, J. (Jeannette), Teslovich, T.M. (Tanya M.), Jansen, R., Westra, H.J. (Harm-Jan), White, C.C. (Charles), Absher, D. (Devin), Ahluwalia, T.S. (Tarunveer Singh), Ahmad, S. (Shafqat), Albrecht, E. (Eva), Alves, A.C. (Alexessander Couto), Bragg-Gresham, J.L. (Jennifer L.), Craen, A.J. (Anton) de, Bis, J.C. (Joshua), Bonnefond, A. (Amélie), Boucher, G. (Gabrielle), Cadby, G. (Gemma), Cheng, Y.-C. (Yu-Ching), Chiang, C.W. (Charleston W K), Delgado, G., Demirkan, A. (Ayşe), Dueker, N. (Nicole), Eklund, N. (Niina), Eiriksdottir, G. (Gudny), Eriksson, J. (Joel), Feenstra, B. (Bjarke), Fischer, K. (Krista), Frau, F. (Francesca), Galesloot, T.E. (Tessel), Geller, F. (Frank), Goel, A. (Anuj), Gorski, M. (Mathias), Grammer, T.B. (Tanja), Gustafsson, S. (Stefan), Haitjema, S. (Saskia), Hottenga, J.J. (Jouke Jan), Huffman, J.E. (Jennifer), Jackson, A.U. (Anne), Jacobs, K.B. (Kevin), Johansson, A. (Åsa), Kaakinen, M. (Marika), Kleber, M.E. (Marcus), Lahti, J. (Jari), Leach, I.M. (Irene Mateo), Lehne, B. (Benjamin), Liu, Y. (Youfang), Lo, K.S., Lorentzon, M. (Mattias), Luan, J. (Jian'An), Madden, P.A. (Pamela), Mangino, M. 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Abstract

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age- and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to ~2.8M SNPs with BMI and WHRadjBMI in four strata (men ≤50y, men >50y, women ≤50y, women >50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR<5%) age-specific effects, of which 11 had larger effects in younger (<50y) than in older adults (≥50y). No sex-dependent effects were identified for B

Published
2015
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40. New genetic loci link adipose and insulin biology to body fat distribution.

Author

ADIPOGen Consortium, CARDIOGRAMplusC4D Consortium, CKDGen Consortium, GEFOS Consortium, GENIE Consortium, International Endogene Consortium, LifeLines Cohort Study, MAGIC Investigators, MuTHER Consortium, PAGE Consortium, ReproGen Consortium, GLGC, ICBP, Dastani, Z., Hivert, MF., Timpson, N., Perry, JR., Yuan, X., Scott, RA., Henneman, P., Heid, IM., Kizer, JR., Lyytikainen, LP., Fuchsberger, C., Tanaka, T., Morris, AP., Small, K., Isaacs, A., Beekman, M., Coassin, S., Lohman, K., Qi, L., Kanoni, S., Pankow, JS., Uh, HW., Wu, Y., Bidulescu, A., Rasmussen-Torvik, LJ., Greenwood, CM., Ladouceur, M., Grimsby, J., Manning, AK., Liu, CT., Kooner, J., Mooser, VE., Vollenweider, P., Kapur, KA., Chambers, J., Wareham, NJ., Langenberg, C., Frants, R., Willemsvan-vanDijk, K., Oostra, BA., Willems, SM., Lamina, C., Winkler, T., Psaty, BM., Tracy, RP., Brody, J., Chen, I., Viikari, J., Kähönen, M., Pramstaller, PP., Evans, DM., St Pourcain, B., Sattar, N., Wood, A., Bandinelli, S., Carlson, OD., Egan, JM., Böhringer, S., van Heemst, D., Kedenko, L., Kristiansson, K., Nuotio, ML., Loo, BM., Harris, T., Garcia, M., Kanaya, A., Haun, M., Klopp, N., Wichmann, HE., Deloukas, P., Katsareli, E., Couper, DJ., Duncan, BB., Kloppenburg, M., Adair, LS., Borja, JB., Wilson, JG., Musani, S., Guo, X., Johnson, T., Semple, R., Teslovich, TM., Allison, MA., Redline, S., Buxbaum, SG., Mohlke, KL., Meulenbelt, I., Ballantyne, CM., Dedoussis, GV., Hu, FB., Liu, Y., Paulweber, B., Spector, TD., Slagboom, P., Ferrucci, L., Jula, A., Perola, M., Raitakari, O., Florez, JC., Salomaa, V., Eriksson, JG., Frayling, TM., Hicks, AA., Lehtimäki, T., Smith, GD., Siscovick, DS., Kronenberg, F., van Duijn, C., Loos, RJ., Waterworth, DM., Meigs, JB., Dupuis, J., Richards, JB., Willenborg, C., Farrall, M., Assimes, TL., Thompson, JR., Ingelsson, E., Saleheen, D., Erdmann, J., Goldstein, BA., Stirrups, K., König, IR., Cazier, JB., Johansson£££Åsa£££ Å., Hall, AS., Lee, JY., Willer, CJ., Chambers, JC., 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Abstract

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Published
2015

41. New genetic loci link adipose and insulin biology to body fat distribution

Author

Shungin, D. (Dmitry), Winkler, T.W. (Thomas W.), Croteau-Chonka, D.C. (Damien), Ferreira, T. (Teresa), Locke, A. (Adam), Mägi, R. (Reedik), Strawbridge, R.J. (Rona), Pers, T.H. (Tune), Fischer, K. (Krista), Justice, A.E. (Anne), Workalemahu, T. (Tsegaselassie), Wu, J.M.W. (Joseph M. W.), Buchkovich, M.L. (Martin), Heard-Costa, N.L. (Nancy), Roman, T.S. (Tamara S.), Drong, A. (Alexander), Song, C. (Ci), Gustafsson, S. (Stefan), Day, F.R. (Felix), Esko, T. (Tõnu), Fall, M. (Magnus), Kutalik, Z. (Zolta'n), Luan, J., Randall, J.C. (Joshua), Scherag, A. (Andre), Vedantam, S. (Sailaja), Wood, A.R. (Andrew), Chen, J. (Jin), Fehrmann, R.S.N. (Rudolf), Karjalainen, J. (Juha), Kahali, B. (Bratati), Liu, C.-T. (Ching-Ti), Schmidt, E.M. (Ellen), Absher, D. (Devin), Amin, N. (Najaf), Beekman, M. (Marian), Bragg-Gresham, J.L. (Jennifer L.), Buyske, S. (Steven), Demirkan, A. (Ayşe), Ehret, G.B. (Georg), Feitosa, M.F. (Mary Furlan), Goel, A. (Anuj), Jackson, A.U. (Anne), Johnson, T. (Toby), Kleber, M.E. (Marcus), Kristiansson, K. (Kati), Mangino, M. (Massimo), Leach, I.M. (Irene Mateo), Medina-Gomez, M.C. (Carolina), Palmer, C. (Cameron), Pasko, D. (Dorota), Pechlivanis, S. (Sonali), Peters, M.J. (Marjolein), Prokopenko, I. (Inga), Stanca'kova', A. (Alena), Sung, Y.J. (Yun Ju), Tanaka, T. (Toshiko), Teumer, A. (Alexander), Vliet-Ostaptchouk, J.V. (Jana) van, Yengo, L. (Loic), Zhang, W. (Weihua), Albrecht, E. (Eva), Ärnlöv, J. (Johan), Arscott, G.M. (Gillian M.), Bandinelli, S. (Stefania), Barrett, A. (Angela), Bellis, C. (Claire), Bennett, A.J. (Amanda), Berne, C. (Christian), Blüher, M. (Matthias), Böhringer, S. (Stefan), Bonnet, F. (Fabrice), Böttcher, Y. (Yvonne), Bruinenberg, M. (M.), Carba, D.B. (Delia B.), Caspersen, I.H. (Ida H.), Clarke, R. (Robert), Daw, E.W. (E. Warwick), Deelen, J. (Joris), Deelman, E. (Ewa), Delgado, G., Doney, A.S.F. (Alex), Eklund, N. (Niina), Erdos, M.R. (Michael), Estrada Gil, K. (Karol), Eury, E. (Elodie), Friedrich, N. (Nele), Garcia, M. (Melissa), Giedraitis, V. (Vilmantas), Gigante, B. (Bruna), Go, A.T.J.I. (Attie), Golay, A. (Alain), Grallert, H. (Harald), Grammer, T.B. (Tanja), Gräsler, J. (Jürgen), Grewal, J. (Jagvir), Groves, C.J. (Christopher), Haller, T. (Toomas), Hallmans, G. (Göran), Hartman, C.A. (Catharina), Hassinen, M. (Maija), Hayward, C. (Caroline), Heikkilä, K. (Kauko), Herzig, K.H., Helmer, Q. (Quinta), Hillege, H.L. (Hans), Holmen, O.L. (Oddgeir), Hunt, S.C. (Steven), Isaacs, A. (Aaron), Ittermann, T. (Till), James, A.L. (Alan), Johansson, I. (Inger), Juliusdottir, T. (Thorhildur), Kalafati, I.-P. (Ioanna-Panagiota), Kinnunen, L. (Leena), Koenig, W. (Wolfgang), Kooner, I.K. (Ishminder K.), Kratzer, W. (Wolfgang), Lamina, C. (Claudia), Leander, K. (Karin), Lee, N.R. (Nanette R.), Lichtner, P. (Peter), Lind, L. (Lars), Lindström, J. (Jaana), Lobbens, S. (Stéphane), Lorentzon, M. (Mattias), MacH, F. (François), Magnusson, P.K. (Patrik), Mahajan, A. (Anubha), McArdle, W.L. (Wendy), Menni, C. (Cristina), Merger, S. (Sigrun), Mihailov, E. (Evelin), Milani, L. (Lili), Mills, R. (Rebecca), Moayyeri, A. (Alireza), Monda, K.L. (Keri), Mooijaart, S.P. (Simon), Mühleisen, T.W. (Thomas), Mulas, A. (Antonella), Müller, G. (Gabriele), Müller-Nurasyid, M. (Martina), Nagaraja, R. (Ramaiah), Nalls, M.A. (Michael), Narisu, N. (Narisu), Glorioso, N. (Nicola), Nolte, I.M. (Ilja M.), Olden, M. (Matthias), Rayner, N.W. (Nigel William), Renström, F. (Frida), Ried, J.S. (Janina), Robertson, N.R. (Neil R.), Rose, L.M. (Lynda), Sanna, S. (Serena), Scharnagl, H. (Hubert), Scholtens, S. (Salome), Sennblad, B. (Bengt), Seufferlein, T. (Thomas), Sitlani, C.M. (Colleen), Smith, A.V. (Davey), Stirrups, K. (Kathy), Stringham, H.M. (Heather), Sundstrom, J. (Johan), Swertz, M. (Morris), Swift, A.J. (Amy), Syvanen, A.C., Tayo, B. (Bamidele), Thorand, B. (Barbara), Thorleifsson, G. (Gudmar), Tomaschitz, A. (Andreas), Troffa, C. (Chiara), Oort, F.V.A. (Floor) van, Verweij, N. (Niek), Vonk, J.M. (Judith), Waite, L. (Lindsay), Wennauer, R. (Roman), Wilsgaard, T. (Tom), Wojczynski, M.K. (Mary ), Wong, A. (Andrew), Zhang, Q. (Qunyuan), Zhao, J.H. (Jing Hua), Brennan, E.P. (Eoin P.), Choi, M. (Murim), Eriksson, P. (Per), Folkersen, L. (Lasse), Franco-Cereceda, A. (Anders), Gharavi, A.G. (Ali G.), Hedman, A.K. (Asa), Hivert, M.-F. (Marie-France), Huang, J. (Jinyan), Kanoni, S. (Stavroula), Karpe, F. (Fredrik), Keildson, S. (Sarah), Kiryluk, K. (Krzysztof), Liang, L. (Liming), Lifton, R.P. (Richard), Ma, B. (Baoshan), McKnight, A.J. (Amy J.), McPherson, R. (Ruth), Metspalu, A. (Andres), Min, J.L. (Josine L.), Moffatt, M.F. (Miriam), Montgomery, G.W. (Grant), Murabito, J. (Joanne), Nicholson, G. (Ggeorge), Dimas, A.S. (Antigone), Olsson, C. (Christian), Perry, J.R.B. (John), Reinmaa, E. (Eva), Salem, R.M. (Rany), Sandholm, N. (Niina), Schadt, E.E. (Eric), Scott, R.A. (Robert), Stolk, L. (Lisette), Vallejo, E.E. (Edgar E.), Westra, H.J. (Harm-Jan), Zondervan, K.T. 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(Berit), Jousilahti, P. (Pekka), Jula, A. (Antti), Kaprio, J. (Jaakko), Kee, F. (F.), Keinanen-Kiukaanniemi, S. (Sirkka), Kooner, J.S. (Jaspal S.), Kooperberg, C. (Charles), Kovacs, P. (Peter), Kraja, A. (Aldi), Kumari, M. (Meena), Kuulasmaa, K. (Kari), Kuusisto, J. (Johanna), Lakka, T.A. (Timo), Langenberg, C. (Claudia), Le Marchand, L. (Loic), Lehtimäki, T. (Terho), Lyssenko, V. (Valeriya), Männistö, S. (Satu), Marette, A. (Andre'), Matise, T.C. (Tara C.), McKenzie, C.A. (Colin A.), McKnight, B. (Barbara), Musk, A.W. (Arthur), Möhlenkamp, S. (Stefan), Morris, A.D. (Andrew), Nelis, M. (Mari), Ohlsson, C. (Claes), Oldehinkel, A.J. (Albertine), Ong, K.K. (Ken K.), Penninx, B.W.J.H. (Brenda), Peters, A. (Annette), Pramstaller, P.P. (Peter Paul), Raitakari, O. (Olli), Rankinen, T. (Tuomo), Rao, D.C. (Dabeeru C.), Rice, T.K. (Treva K.), Ridker, P.M. (Paul), Ritchie, M.D. (Marylyn D.), Rudan, I. (Igor), Salomaa, V. (Veikko), Samani, N.J. (Nilesh), Saramies, J. (Jouko), Sarzynski, M.A. (Mark A.), Schwarz, P.E.H. (Peter E. H.), Shuldiner, A.R. (Alan), Staessen, J.A. (Jan), Steinthorsdottir, V. (Valgerdur), Stolk, R.P. (Ronald), Strauch, K. (Konstantin), Tönjes, A. (Anke), Tremblay, A. (Angelo), Tremoli, E. (Elena), Vohl, M.-C. (Marie-Claude), Völker, U. (Uwe), Vollenweider, P. (Peter), Wilson, J.F. (James F), Witteman, J.C.M. (Jacqueline), Adair, L.S. (Linda), Bochud, M. (Murielle), Boehm, B.O. (Bernhard), Bornstein, S.R. (Stefan R.), Bouchard, C. (Claude), Cauchi, S. (Ste'phane), Caulfield, M. (Mark), Chambers, J.C. (John C.), Chasman, D.I. (Daniel), Cooper, R.S. (Richard S.), Dedoussis, G.V. (George), Ferrucci, L. (Luigi), Froguel, P. (Philippe), Grabe, H.J. (Hans Jörgen), Hamsten, A. (Anders), Hui, J. (Jennie), Hveem, K. (Kristian), Jöckel, K.-H. (Karl-Heinz), Kivimaki, M. (Mika), Kuh, D. (Diana), Laakso, M. (Markku), Liu, Y. (YongMei), März, W. (Winfried), Munroe, P. (Patricia), Njølstad, I. (Inger), Oostra, B.A. (Ben), Palmer, C.N.A. (Colin), Pedersen, N.L. (Nancy L.), Perola, M. (Markus), Perusse, L. (Louis), Peters, U. (Ulrike), Power, C. (Christopher), Quertermous, T. (Thomas), Rauramaa, R. (Rainer), Rivadeneira Ramirez, F. (Fernando), Saaristo, T. (Timo), Saleheen, D., Sinisalo, J. (Juha), Slagboom, P.E. (Eline), Snieder, H. (Harold), Spector, T.D. (Timothy), Thorsteinsdottir, U. (Unnur), Stumvoll, M. (Michael), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Uusitupa, M. (Matti), Harst, P. (Pim) van der, Veronesi, G. (Giovanni), Walker, M. (Mark), Wareham, N.J. (Nick), Watkins, H. (Hugh), Wichmann, H.E. (Heinz Erich), Abecasis, G.R. (Gonçalo), Assimes, T.L. (Themistocles), Berndt, S.I. (Sonja), Boehnke, M. (Michael), Borecki, I.B. (Ingrid), Deloukas, P. (Panagiotis), Franke, L. (Lude), Frayling, T.M. (Timothy), Groop, L. (Leif), Hunter, D. (David), Kaplan, R.C. (Robert), O´Connell, J.R., Qi, L. (Lu), Schlessinger, D. (David), Strachan, D.P. (David), Zwart, J-A. (John-Anker), Duijn, C.M. (Cornelia) van, Willer, C.J. (Cristen), Visscher, P.M. (Peter), Yang, J. (Joanna), Hirschhorn, J.N. (Joel N.), Zillikens, M.C. (Carola), McCarthy, M.I. (Mark), Speliotes, E.K. (Elizabeth), North, K.E. (Kari), Fox, C.S. (Caroline S.), Barroso, I.E. (Inês), Franks, P.W. (Paul), Anderson, D. (Denise), Ingelsson, E. (Erik), Heid, I.M. (Iris), Loos, R.J.F. (Ruth), Cupples, L.A. (Adrienne), Morris, A.P. (Andrew), Lindgren, C.M. (Cecilia), Mohlke, K.L. (Karen), Shungin, D. (Dmitry), Winkler, T.W. (Thomas W.), Croteau-Chonka, D.C. (Damien), Ferreira, T. (Teresa), Locke, A. (Adam), Mägi, R. (Reedik), Strawbridge, R.J. (Rona), Pers, T.H. (Tune), Fischer, K. (Krista), Justice, A.E. (Anne), Workalemahu, T. (Tsegaselassie), Wu, J.M.W. (Joseph M. W.), Buchkovich, M.L. (Martin), Heard-Costa, N.L. (Nancy), Roman, T.S. (Tamara S.), Drong, A. (Alexander), Song, C. (Ci), Gustafsson, S. (Stefan), Day, F.R. (Felix), Esko, T. (Tõnu), Fall, M. (Magnus), Kutalik, Z. (Zolta'n), Luan, J., Randall, J.C. (Joshua), Scherag, A. (Andre), Vedantam, S. (Sailaja), Wood, A.R. (Andrew), Chen, J. (Jin), Fehrmann, R.S.N. (Rudolf), Karjalainen, J. (Juha), Kahali, B. (Bratati), Liu, C.-T. (Ching-Ti), Schmidt, E.M. (Ellen), Absher, D. (Devin), Amin, N. (Najaf), Beekman, M. (Marian), Bragg-Gresham, J.L. (Jennifer L.), Buyske, S. (Steven), Demirkan, A. (Ayşe), Ehret, G.B. (Georg), Feitosa, M.F. (Mary Furlan), Goel, A. (Anuj), Jackson, A.U. (Anne), Johnson, T. (Toby), Kleber, M.E. (Marcus), Kristiansson, K. (Kati), Mangino, M. (Massimo), Leach, I.M. (Irene Mateo), Medina-Gomez, M.C. (Carolina), Palmer, C. (Cameron), Pasko, D. (Dorota), Pechlivanis, S. (Sonali), Peters, M.J. (Marjolein), Prokopenko, I. (Inga), Stanca'kova', A. (Alena), Sung, Y.J. (Yun Ju), Tanaka, T. (Toshiko), Teumer, A. (Alexander), Vliet-Ostaptchouk, J.V. (Jana) van, Yengo, L. (Loic), Zhang, W. (Weihua), Albrecht, E. (Eva), Ärnlöv, J. (Johan), Arscott, G.M. (Gillian M.), Bandinelli, S. (Stefania), Barrett, A. (Angela), Bellis, C. (Claire), Bennett, A.J. (Amanda), Berne, C. (Christian), Blüher, M. (Matthias), Böhringer, S. (Stefan), Bonnet, F. (Fabrice), Böttcher, Y. (Yvonne), Bruinenberg, M. (M.), Carba, D.B. (Delia B.), Caspersen, I.H. (Ida H.), Clarke, R. (Robert), Daw, E.W. (E. Warwick), Deelen, J. (Joris), Deelman, E. (Ewa), Delgado, G., Doney, A.S.F. (Alex), Eklund, N. (Niina), Erdos, M.R. (Michael), Estrada Gil, K. (Karol), Eury, E. (Elodie), Friedrich, N. (Nele), Garcia, M. (Melissa), Giedraitis, V. (Vilmantas), Gigante, B. (Bruna), Go, A.T.J.I. (Attie), Golay, A. (Alain), Grallert, H. (Harald), Grammer, T.B. (Tanja), Gräsler, J. (Jürgen), Grewal, J. (Jagvir), Groves, C.J. (Christopher), Haller, T. (Toomas), Hallmans, G. (Göran), Hartman, C.A. (Catharina), Hassinen, M. (Maija), Hayward, C. (Caroline), Heikkilä, K. (Kauko), Herzig, K.H., Helmer, Q. (Quinta), Hillege, H.L. (Hans), Holmen, O.L. (Oddgeir), Hunt, S.C. (Steven), Isaacs, A. (Aaron), Ittermann, T. (Till), James, A.L. (Alan), Johansson, I. (Inger), Juliusdottir, T. (Thorhildur), Kalafati, I.-P. (Ioanna-Panagiota), Kinnunen, L. (Leena), Koenig, W. (Wolfgang), Kooner, I.K. (Ishminder K.), Kratzer, W. (Wolfgang), Lamina, C. (Claudia), Leander, K. (Karin), Lee, N.R. (Nanette R.), Lichtner, P. (Peter), Lind, L. (Lars), Lindström, J. (Jaana), Lobbens, S. (Stéphane), Lorentzon, M. (Mattias), MacH, F. (François), Magnusson, P.K. (Patrik), Mahajan, A. (Anubha), McArdle, W.L. (Wendy), Menni, C. (Cristina), Merger, S. (Sigrun), Mihailov, E. (Evelin), Milani, L. (Lili), Mills, R. (Rebecca), Moayyeri, A. (Alireza), Monda, K.L. (Keri), Mooijaart, S.P. (Simon), Mühleisen, T.W. (Thomas), Mulas, A. (Antonella), Müller, G. (Gabriele), Müller-Nurasyid, M. (Martina), Nagaraja, R. (Ramaiah), Nalls, M.A. (Michael), Narisu, N. (Narisu), Glorioso, N. (Nicola), Nolte, I.M. (Ilja M.), Olden, M. (Matthias), Rayner, N.W. (Nigel William), Renström, F. (Frida), Ried, J.S. (Janina), Robertson, N.R. (Neil R.), Rose, L.M. (Lynda), Sanna, S. (Serena), Scharnagl, H. (Hubert), Scholtens, S. (Salome), Sennblad, B. (Bengt), Seufferlein, T. (Thomas), Sitlani, C.M. (Colleen), Smith, A.V. (Davey), Stirrups, K. (Kathy), Stringham, H.M. (Heather), Sundstrom, J. (Johan), Swertz, M. (Morris), Swift, A.J. (Amy), Syvanen, A.C., Tayo, B. (Bamidele), Thorand, B. (Barbara), Thorleifsson, G. (Gudmar), Tomaschitz, A. (Andreas), Troffa, C. (Chiara), Oort, F.V.A. (Floor) van, Verweij, N. (Niek), Vonk, J.M. (Judith), Waite, L. (Lindsay), Wennauer, R. (Roman), Wilsgaard, T. (Tom), Wojczynski, M.K. (Mary ), Wong, A. (Andrew), Zhang, Q. (Qunyuan), Zhao, J.H. (Jing Hua), Brennan, E.P. (Eoin P.), Choi, M. (Murim), Eriksson, P. (Per), Folkersen, L. (Lasse), Franco-Cereceda, A. (Anders), Gharavi, A.G. (Ali G.), Hedman, A.K. (Asa), Hivert, M.-F. (Marie-France), Huang, J. (Jinyan), Kanoni, S. (Stavroula), Karpe, F. (Fredrik), Keildson, S. (Sarah), Kiryluk, K. (Krzysztof), Liang, L. (Liming), Lifton, R.P. (Richard), Ma, B. (Baoshan), McKnight, A.J. (Amy J.), McPherson, R. (Ruth), Metspalu, A. (Andres), Min, J.L. (Josine L.), Moffatt, M.F. (Miriam), Montgomery, G.W. (Grant), Murabito, J. (Joanne), Nicholson, G. (Ggeorge), Dimas, A.S. (Antigone), Olsson, C. (Christian), Perry, J.R.B. (John), Reinmaa, E. (Eva), Salem, R.M. (Rany), Sandholm, N. (Niina), Schadt, E.E. (Eric), Scott, R.A. (Robert), Stolk, L. (Lisette), Vallejo, E.E. (Edgar E.), Westra, H.J. (Harm-Jan), Zondervan, K.T. (Krina), Amouyel, P. (Philippe), Arveiler, D. (Dominique), Bakker, S.J.L. (Stephan), Beilby, J.P. (John), Bergman, R.N. (Richard), Blangero, J. (John), Brown, M.J. (Morris), Burnier, M. (Michel), Campbell, H. (Harry), Chakravarti, A. (Aravinda), Chines, P.S. (Peter), Claudi-Boehm, S. (Simone), Collins, F.S. (Francis), Crawford, D.C. (Dana), Danesh, J. (John), Faire, U. (Ulf) de, Geus, E.J.C. (Eco) de, Dörr, M. (Marcus), Erbel, R. (Raimund), Hagen, K. (Knut), Farrall, M. (Martin), Ferrannini, E. (Ele), Ferrieres, J. (Jean), Forouhi, N.G. (Nita), Forrester, T. (Terrence), Franco, O.H. (Oscar), Gansevoort, R.T. (Ron), Gieger, C. (Christian), Gudnason, V. (Vilmundur), Haiman, C.A. (Christopher), Harris, T.B. (Tamara), Hattersley, A.T. (Andrew), Heliovaara, M. (Markku), Hicks, A.A. (Andrew), Hingorani, A. (Aroon), Hoffmann, W. (Wolfgang), Hofman, A. (Albert), Homuth, G. (Georg), Humphries, S.E. (Steve), Hypponen, E. (Elina), Illig, T. (Thomas), Jarvelin, M.-R. (Marjo-Riitta), Johansen, B. (Berit), Jousilahti, P. (Pekka), Jula, A. (Antti), Kaprio, J. (Jaakko), Kee, F. (F.), Keinanen-Kiukaanniemi, S. (Sirkka), Kooner, J.S. (Jaspal S.), Kooperberg, C. (Charles), Kovacs, P. (Peter), Kraja, A. (Aldi), Kumari, M. (Meena), Kuulasmaa, K. (Kari), Kuusisto, J. (Johanna), Lakka, T.A. (Timo), Langenberg, C. (Claudia), Le Marchand, L. (Loic), Lehtimäki, T. (Terho), Lyssenko, V. (Valeriya), Männistö, S. (Satu), Marette, A. (Andre'), Matise, T.C. (Tara C.), McKenzie, C.A. (Colin A.), McKnight, B. (Barbara), Musk, A.W. (Arthur), Möhlenkamp, S. (Stefan), Morris, A.D. (Andrew), Nelis, M. (Mari), Ohlsson, C. (Claes), Oldehinkel, A.J. (Albertine), Ong, K.K. (Ken K.), Penninx, B.W.J.H. (Brenda), Peters, A. (Annette), Pramstaller, P.P. (Peter Paul), Raitakari, O. (Olli), Rankinen, T. (Tuomo), Rao, D.C. (Dabeeru C.), Rice, T.K. (Treva K.), Ridker, P.M. (Paul), Ritchie, M.D. (Marylyn D.), Rudan, I. (Igor), Salomaa, V. (Veikko), Samani, N.J. (Nilesh), Saramies, J. (Jouko), Sarzynski, M.A. (Mark A.), Schwarz, P.E.H. (Peter E. H.), Shuldiner, A.R. (Alan), Staessen, J.A. (Jan), Steinthorsdottir, V. (Valgerdur), Stolk, R.P. (Ronald), Strauch, K. (Konstantin), Tönjes, A. (Anke), Tremblay, A. (Angelo), Tremoli, E. (Elena), Vohl, M.-C. (Marie-Claude), Völker, U. (Uwe), Vollenweider, P. (Peter), Wilson, J.F. (James F), Witteman, J.C.M. (Jacqueline), Adair, L.S. (Linda), Bochud, M. (Murielle), Boehm, B.O. (Bernhard), Bornstein, S.R. (Stefan R.), Bouchard, C. (Claude), Cauchi, S. (Ste'phane), Caulfield, M. (Mark), Chambers, J.C. (John C.), Chasman, D.I. (Daniel), Cooper, R.S. (Richard S.), Dedoussis, G.V. (George), Ferrucci, L. (Luigi), Froguel, P. (Philippe), Grabe, H.J. (Hans Jörgen), Hamsten, A. (Anders), Hui, J. (Jennie), Hveem, K. (Kristian), Jöckel, K.-H. (Karl-Heinz), Kivimaki, M. (Mika), Kuh, D. (Diana), Laakso, M. (Markku), Liu, Y. (YongMei), März, W. (Winfried), Munroe, P. (Patricia), Njølstad, I. (Inger), Oostra, B.A. (Ben), Palmer, C.N.A. (Colin), Pedersen, N.L. (Nancy L.), Perola, M. (Markus), Perusse, L. (Louis), Peters, U. (Ulrike), Power, C. (Christopher), Quertermous, T. (Thomas), Rauramaa, R. (Rainer), Rivadeneira Ramirez, F. (Fernando), Saaristo, T. (Timo), Saleheen, D., Sinisalo, J. (Juha), Slagboom, P.E. (Eline), Snieder, H. (Harold), Spector, T.D. (Timothy), Thorsteinsdottir, U. (Unnur), Stumvoll, M. (Michael), Tuomilehto, J. (Jaakko), Uitterlinden, A.G. (André), Uusitupa, M. (Matti), Harst, P. (Pim) van der, Veronesi, G. (Giovanni), Walker, M. (Mark), Wareham, N.J. (Nick), Watkins, H. (Hugh), Wichmann, H.E. (Heinz Erich), Abecasis, G.R. (Gonçalo), Assimes, T.L. (Themistocles), Berndt, S.I. (Sonja), Boehnke, M. (Michael), Borecki, I.B. (Ingrid), Deloukas, P. (Panagiotis), Franke, L. (Lude), Frayling, T.M. (Timothy), Groop, L. (Leif), Hunter, D. (David), Kaplan, R.C. (Robert), O´Connell, J.R., Qi, L. (Lu), Schlessinger, D. (David), Strachan, D.P. (David), Zwart, J-A. (John-Anker), Duijn, C.M. (Cornelia) van, Willer, C.J. (Cristen), Visscher, P.M. (Peter), Yang, J. (Joanna), Hirschhorn, J.N. (Joel N.), Zillikens, M.C. (Carola), McCarthy, M.I. (Mark), Speliotes, E.K. (Elizabeth), North, K.E. (Kari), Fox, C.S. (Caroline S.), Barroso, I.E. (Inês), Franks, P.W. (Paul), Anderson, D. (Denise), Ingelsson, E. (Erik), Heid, I.M. (Iris), Loos, R.J.F. (Ruth), Cupples, L.A. (Adrienne), Morris, A.P. (Andrew), Lindgren, C.M. (Cecilia), and Mohlke, K.L. (Karen)

Abstract

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10-8). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.

Published
2015
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42. Novel Genes for Airway Wall Thickness Identified with Combined Genome Wide Association and Expression Analyses

Author

Dijkstra, A.E., Postma, D.S., Ginneken, B. van, Wielpuetz, M.O., Schmidt, M., Becker, N., Owsijewitsch, M., Kauczor, H.-U., Koning, H.J. de, Lammers, J.W., Oudkerk, M., Brandsma, C.-A., Bosse, Y., Nickle, D.C., Sin, D.D., Hiemstra, P.S., Wijmenga, C., Smolonska, J., Zanen, P., Vonk, J.M., Berge, M. ten, Boezen, H.M., Groen, H.J.M., Dijkstra, A.E., Postma, D.S., Ginneken, B. van, Wielpuetz, M.O., Schmidt, M., Becker, N., Owsijewitsch, M., Kauczor, H.-U., Koning, H.J. de, Lammers, J.W., Oudkerk, M., Brandsma, C.-A., Bosse, Y., Nickle, D.C., Sin, D.D., Hiemstra, P.S., Wijmenga, C., Smolonska, J., Zanen, P., Vonk, J.M., Berge, M. ten, Boezen, H.M., and Groen, H.J.M.

Abstract

Contains fulltext : 153524.pdf (Publisher’s version ) (Open Access), Rationale Airway wall thickness (AWT) is affected by both environmental and genetic factors and is strongly associated with airflow limitation in smaller airways. Objectives The aim of our study was to investigate its genetic component. Methods AWT was measured on low-dose CT-scans in male heavy smokers participating in a lung cancer screening study (n = 2,640). Genome wide association studies on AWT were performed under an additive model using linear regression (adjusted for pack-years, lung volume), followed by meta-analysis. An independent cohort was used for validation of the most strongly associated single nucleotide polymorphisms (SNPs). The functional relevance of significant SNPs was evaluated. Measurements and main results Three significant loci on chromosomes 2q (rs734556, p = 6.2x10-7) and 10q (rs10794108, p = 8.6x10-8; rs7078439, p = 2.3x10-7) were associated with AWT and confirmed in the meta-analysis in cohorts with comparable lung function: p-values 4.6x10-8, 7.4x10-8 and 7.5x10-8, respectively. SNP rs734556 was associated with decreased lung tissue expression of SERPINE2, a susceptibility gene for emphysema. Two nominally significant SNPs showed effects with similar direction: rs10251504 in MAGI2 (p = 5.8x10-7) and rs4796712 in NT5C3B (p = 3.1x10-6). Higher MAGI2 expression in bronchial biopsies of COPD patients was significantly associated with lower inflammatory cell numbers, lower NT5C3B expression with worse lung function. The NT5C3B risk allele was associated with higher lung tissue expression (p = 1.09x10-41). Conclusions Genetic variants contribute to AWT. Amongst others, the identified genes are involved in emphysema, airway obstruction and bronchial inflammation.

Published
2015

43. Novel Genes for Airway Wall Thickness Identified with Combined Genome Wide Association and Expression Analyses

Author

Dijkstra, A.E., Postma, D.S., Ginneken, B. van, Wielpuetz, M.O., Schmidt, M., Becker, N., Owsijewitsch, M., Kauczor, H.-U., Koning, H.J. de, Lammers, J.W., Oudkerk, M., Brandsma, C.-A., Bosse, Y., Nickle, D.C., Sin, D.D., Hiemstra, P.S., Wijmenga, C., Smolonska, J., Zanen, P., Vonk, J.M., Berge, M. ten, Boezen, H.M., Groen, H.J.M., Dijkstra, A.E., Postma, D.S., Ginneken, B. van, Wielpuetz, M.O., Schmidt, M., Becker, N., Owsijewitsch, M., Kauczor, H.-U., Koning, H.J. de, Lammers, J.W., Oudkerk, M., Brandsma, C.-A., Bosse, Y., Nickle, D.C., Sin, D.D., Hiemstra, P.S., Wijmenga, C., Smolonska, J., Zanen, P., Vonk, J.M., Berge, M. ten, Boezen, H.M., and Groen, H.J.M.

Abstract

Contains fulltext : 153524.pdf (Publisher’s version ) (Open Access), Rationale Airway wall thickness (AWT) is affected by both environmental and genetic factors and is strongly associated with airflow limitation in smaller airways. Objectives The aim of our study was to investigate its genetic component. Methods AWT was measured on low-dose CT-scans in male heavy smokers participating in a lung cancer screening study (n = 2,640). Genome wide association studies on AWT were performed under an additive model using linear regression (adjusted for pack-years, lung volume), followed by meta-analysis. An independent cohort was used for validation of the most strongly associated single nucleotide polymorphisms (SNPs). The functional relevance of significant SNPs was evaluated. Measurements and main results Three significant loci on chromosomes 2q (rs734556, p = 6.2x10-7) and 10q (rs10794108, p = 8.6x10-8; rs7078439, p = 2.3x10-7) were associated with AWT and confirmed in the meta-analysis in cohorts with comparable lung function: p-values 4.6x10-8, 7.4x10-8 and 7.5x10-8, respectively. SNP rs734556 was associated with decreased lung tissue expression of SERPINE2, a susceptibility gene for emphysema. Two nominally significant SNPs showed effects with similar direction: rs10251504 in MAGI2 (p = 5.8x10-7) and rs4796712 in NT5C3B (p = 3.1x10-6). Higher MAGI2 expression in bronchial biopsies of COPD patients was significantly associated with lower inflammatory cell numbers, lower NT5C3B expression with worse lung function. The NT5C3B risk allele was associated with higher lung tissue expression (p = 1.09x10-41). Conclusions Genetic variants contribute to AWT. Amongst others, the identified genes are involved in emphysema, airway obstruction and bronchial inflammation.

Published
2015

44. 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
Full Text
View/download PDF

45. 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
Full Text
View/download PDF

46. Defining the role of common variation in the genomic and biological architecture of adult human height.

Author

Genomics (eMEMERGEGE) Consortium, MIGen Consortium, PAGEGE Consortium, LifeLines Cohort Study, Electronic Medical, Records, McCarty, CA., Starren, J., Peissig, P., Berg, R., Rasmussen, L., Linneman, J., Miller, A., Choudary, V., Chen, L., Waudby, C., Kitchner, T., Reeser, J., Fost, N., Ritchie, M., Wilke, RA., Chisholm, RL., Avila, PC., Greenland, P., Hayes, M., Kho, A., Kibbe, WA., Lemke, AA., Lowe, WL., Smith, ME., Wolf, WA., Pacheco, JA., Thompson, WK., Humowiecki, J., Law, M., Chute, C., Kullo, I., Koenig, B., de Andrade, M., Bielinski, S., Pathak, J., Savova, G., Wu, J., Henriksen, J., Ding, K., Hart, L., Palbicki, J., Larson, EB., Newton, K., Ludman, E., Spangler, L., Hart, G., Carrell, D., Jarvik, G., Crane, P., Burke, W., Fullerton, SM., Trinidad, SB., Carlson, C., Hutchinson, F., McDavid, A., Roden, DM., Clayton, E., Haines, JL., Masys, DR., Churchill, LR., Cornfield, D., Crawford, D., Darbar, D., Denny, JC., Malin, BA., Ritchie, MD., Schildcrout, JS., Xu, H., Ramirez, AH., Basford, M., Pulley, J., Alizadeh, B., de Boer RA., Boezen, HM., Bruinenberg, M., Franke, L., van der Harst, P., Hillege, HL., van der Klauw MM., Navis, G., Ormel, J., Postma, DS., Rosmalen, JG., Slaets, JP., Snieder, H., Stolk, RP., Wolffenbuttel, BH., Wijmenga, C., Kathiresan, S., Voight, BF., Purcell, S., Musunuru, K., Ardissino, D., Mannucci, PM., Anand, S., Engert, JC., Samani, NJ., Schunkert, H., Erdmann, J., Reilly, MP., Rader, DJ., Morgan, T., Spertus, JA., Stoll, M., Girelli, D., McKeown, PP., Patterson, CC., Siscovick, DS., O'Donnell, CJ., Elosua, R., Peltonen, L., Salomaa, V., Schwartz, SM., Melander, O., Altshuler, D., Merlini, PA., Berzuini, C., Bernardinelli, L., Peyvandi, F., Tubaro, M., Celli, P., Ferrario, M., Fetiveau, R., Marziliano, N., Casari, G., Galli, M., Ribichini, F., Rossi, M., Bernardi, F., Zonzin, P., Piazza, A., Yee, J., Friedlander, Y., Marrugat, J., Lucas, G., Subirana, I., Sala, J., Ramos, R., Meigs, JB., Williams, G., Nathan, DM., MacRae, CA., 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Lyssenko, V., Magnusson, P.K., Mahajan, A., Maillard, M., McArdle, W.L., McKenzie, C.A., McLachlan, S., McLaren, P.J., Menni, C., Merger, S., Milani, L., Moayyeri, A., Monda, K.L., Morken, M.A., Müller, G., Müller-Nurasyid, M., Musk, A.W., Narisu, N., Nauck, M., Nolte, I.M., Nöthen, M.M., Oozageer, L., Pilz, S., Rayner, N.W., Renstrom, F., Robertson, N.R., Rose, L.M., Roussel, R., Sanna, S., Scharnagl, H., Scholtens, S., Schumacher, F.R., Scott, R.A., Sehmi, J., Seufferlein, T., Shi, J., Silventoinen, K., Smit, J.H., Smith, A.V., Smolonska, J., Stanton, A.V., Stirrups, K., Stott, D.J., Stringham, H.M., Sundström, J., Swertz, M.A., Syvänen, A.C., Tayo, B.O., Tyrer, J.P., van Dijk, S., van Schoor, N.M., van der Velde, N., van Heemst, D., van Oort, F.V., Vermeulen, S.H., Verweij, N., Vonk, J.M., Waite, L.L., Waldenberger, M., Wennauer, R., Wilkens, L.R., Willenborg, C., Wilsgaard, T., Wojczynski, M.K., Wong, A., Wright, A.F., Zhang, Q., Arveiler, D., Bakker, S.J., Beilby, J., Bergman, R.N., Bergmann, S., Biffar, R., Blangero, J., Boomsma, D.I., Bornstein, S.R., Bovet, P., Brambilla, P., Brown, M.J., Campbell, H., Caulfield, M.J., Chakravarti, A., Collins, R., Collins, F.S., Crawford, D.C., Cupples, L.A., Danesh, J., de Faire, U., den Ruijter, H.M., Erbel, R., Eriksson, J.G., Farrall, M., Ferrannini, E., Ferrières, J., Ford, I., Forouhi, N.G., Forrester, T., Gansevoort, R.T., Gejman, P.V., Gieger, C., Golay, A., Gottesman, O., Gudnason, V., Gyllensten, U., Haas, D.W., Hall, A.S., Harris, T.B., Hattersley, A.T., Heath, A.C., Hicks, A.A., Hindorff, L.A., Hingorani, A.D., Hofman, A., Hovingh, G.K., Humphries, S.E., Hunt, S.C., Hypponen, E., Jacobs, K.B., Jarvelin, M.R., Jousilahti, P., Jula, A.M., Kaprio, J., Kastelein, J.J., Kayser, M., Kee, F., Keinanen-Kiukaanniemi, S.M., Kiemeney, L.A., Kooner, J.S., Koskinen, S., Kovacs, P., Kraja, A.T., Kumari, M., Kuusisto, J., Lakka, T.A., Langenberg, C., Le Marchand, L., Lehtimäki, T., Lupoli, S., Madden, P.A., Männistö, S., Manunta, P., Marette, A., Matise, T.C., McKnight, B., Meitinger, T., Moll, F.L., Montgomery, G.W., Morris, A.D., Morris, A.P., Murray, J.C., Nelis, M., Ohlsson, C., Oldehinkel, A.J., Ong, K.K., Ouwehand, W.H., Pasterkamp, G., Peters, A., Pramstaller, P.P., Price, J.F., Qi, L., Raitakari, O.T., Rankinen, T., Rao, D.C., Rice, T.K., Rudan, I., Samani, N.J., Saramies, J., Sarzynski, M.A., Schwarz, P.E., Sebert, S., Sever, P., Shuldiner, A.R., Sinisalo, J., Steinthorsdottir, V., Stolk, R.P., Tardif, J.C., Tönjes, A., Tremblay, A., Tremoli, E., Virtamo, J., Vohl, M.C., Amouyel, P., Asselbergs, F.W., Assimes, T.L., Bochud, M., Boehm, B.O., Bottinger, E.P., Bouchard, C., Cauchi, S., Chambers, J.C., Chanock, S.J., Cooper, R.S., de Bakker, P.I., Dedoussis, G., Ferrucci, L., Franks, P.W., Froguel, P., Groop, L.C., Haiman, C.A., Hamsten, A., Hayes, M.G., Hui, J., Hunter, D.J., Hveem, K., Jukema, J.W., Kaplan, R.C., Kivimaki, M., Kuh, D., Laakso, M., Liu, Y., Martin, N.G., März, W., Melbye, M., Moebus, S., Munroe, P.B., Njølstad, I., Oostra, B.A., Palmer, C.N., Pedersen, N.L., Perola, M., Pérusse, L., Powell, J.E., Power, C., Quertermous, T., Rauramaa, R., Reinmaa, E., Ridker, P.M., Rivadeneira, F., Rotter, J.I., Saaristo, T.E., Saleheen, D., Schlessinger, D., Slagboom, P.E., Spector, T.D., Strauch, K., Stumvoll, M., Tuomilehto, J., Uusitupa, M., Völzke, H., Walker, M., Wareham, N.J., Watkins, H., Wichmann, H.E., Wilson, J.F., Zanen, P., Heid, I.M., Lindgren, C.M., Mohlke, K.L., Speliotes, E.K., Barroso, I., Fox, C.S., North, K.E., Strachan, D.P., Beckmann, J.S., Berndt, S.I., Boehnke, M., Borecki, I.B., McCarthy, M.I., Metspalu, A., Uitterlinden, A.G., van Duijn, C.M., Willer, C.J., Price, A.L., Lettre, G., Loos, R.J., Weedon, M.N., Ingelsson, E., O'Connell, J.R., Abecasis, G.R., Chasman, D.I., Goddard, M.E., Visscher, P.M., Hirschhorn, J.N., and Frayling, T.M.

Abstract

Using genome-wide data from 253,288 individuals, we identified 697 variants at genome-wide significance that together explained one-fifth of the heritability for adult height. By testing different numbers of variants in independent studies, we show that the most strongly associated ∼2,000, ∼3,700 and ∼9,500 SNPs explained ∼21%, ∼24% and ∼29% of phenotypic variance. Furthermore, all common variants together captured 60% of heritability. The 697 variants clustered in 423 loci were enriched for genes, pathways and tissue types known to be involved in growth and together implicated genes and pathways not highlighted in earlier efforts, such as signaling by fibroblast growth factors, WNT/β-catenin and chondroitin sulfate-related genes. We identified several genes and pathways not previously connected with human skeletal growth, including mTOR, osteoglycin and binding of hyaluronic acid. Our results indicate a genetic architecture for human height that is characterized by a very large but finite number (thousands) of causal variants.

Published
2014

47. Gene-centric meta-analysis in 87,736 individuals of European ancestry identifies multiple blood-pressure-related loci

Author

Tragante, V. (Vinicius), Barnes, M.J. (Michael), Ganesh, S.K. (Santhi), Lanktree, M.B. (Matthew), Guo, W. (Weixiang), Franceschini, N. (Nora), Smith, A.V. (Davey), Johnson, T. (Toby), Holmes, M.V. (Michael), Padmanabhan, S. (Sandosh), Karczewski, K.J. (Konrad), Almoguera, B. (Berta), Barnard, J. (John), Baumert, J. (Jens), Chang, Y.-P.C. (Yen-Pei), Elbers, C.C. (Clara), Farrall, M. (Martin), Fischer, M.E. (Mary), Gaunt, T.R. (Tom), Gho, J.M.I.H. (Johannes), Gieger, C. (Christian), Goel, A. (Anuj), Gong, Y. (Yeming), Isaacs, A.J. (Aaron), Kleber, M.E. (Marcus), Leach, I.M. (Irene Mateo), McDonough, C.W. (Caitrin), Meijs, M.F.L. (Matthijs), Melander, O. (Olle), Nelson, C.P. (Christopher P.), Nolte, I.M. (Ilja), Pankratz, V.S. (Shane), Price, T.S. (Thomas), Shaffer, J. (Jonathan), Shah, S. (Sonia), Tomaszewski, M. (Maciej), Most, P.J. (Peter) van der, Iperen, E.P.A. (Erik) van, Vonk, J.M. (Judith), Witkowska, H.E. (Ewa), Wong, C.O.L. (Caroline), Zhang, L. (Lingling), Beitelshees, A.L. (Amber), Berenson, G. (Gerald), Bhatt, D.L. (Deepak), Brown, M.J. (Morris), Burt, A.D. (Alastair), Cooper-Dehoff, R.M. (Rhonda), Connell, J. (John), Cruickshanks, K.J. (Karen), Curtis, S.P. (Sean), Davey-Smith, G. (George), Delles, C. (Christian), Gansevoort, R.T. (Ron), Guo, X. (Xiuqing), Haiqing, S. (Shen), Hastie, C.E. (Claire), Hofker, M.A. (Marten), Hovingh, G.K. (Kees), Kim, D.S. (Daniel), Kirkland, S.A. (Susan), Klein, B.E.K. (Barbara), Li, Y.R. (Yun), Maiwald, R. (Robert), Newton-Cheh, C. (Christopher), O'Brien, E. (Eoin), Onland-Moret, N.C. (Charlotte), Palmas, W. (Walter), Parsa, A. (Afshin), Penninx, B.W.J.H. (Brenda), Pettinger, M. (Mary), Vasan, R.S. (Ramachandran Srini), Ranchalis, J.E. (Jane), Ridker, P.M. (Paul), Rose, L.M. (Lynda), Sever, P. (Peter), Shimbo, D. (Daichi), Steele, L. (Linda), Stolk, R.P. (Ronald), Thorand, B. (Barbara), Trip, M.D. (Mieke), Duijn, C.M. (Cornelia) van, Verschuren, W.M.M. (W. M. Monique), Wijmenga, C. (Cisca), Wyatt, S. (Sally), Young, J.C. (J. C.), Zwinderman, A.H. (Ailko), Bezzina, C.R. (Connie), Boerwinkle, E.A. (Eric), Casas, J.P. (Juan), Caulfield, M. (Mark), Chakravarti, A. (Aravinda), Chasman, D.I. (Daniel), Davidson, K.W. (Karina), Doevendans, P.A. (Pieter), Dominiczak, A. (Anna), Fitzgerald, G.A. (Garret), Gums, J.G. (John), Fornage, M. (Myriam), Hakonarson, H. (Hakon), Halder, H. (Han) van, Hillege, H.L. (Hans), Illig, T. (Thomas), Jarvik, G.P. (Gail), Johnson, J.A. (Jennifer ), Kastelein, J.J.P. (John), Koenig, W. (Wolfgang), Kumari, M. (Meena), März, W. (Winfried), Murray, S.S. (Sarah), O'Connell, J.R. (Jeffery), Oldehinkel, A.J. (Albertine), Pankow, J.S. (James), Rader, D.J. (Daniel), Redline, S. (Susan), Reilly, M.P. (Muredach), Schadt, E.E. (Eric), Kottke-Marchant, K. (Kandice), Snieder, H. (Harold), Snyder, M. (Michael), Stanton, A. (Alice), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Harst, P. (Pim) van der, Schouw, Y.T. (Yvonne) van der, Samani, N.J. (Nilesh), Watkins, H. (Hugh), Johnson, A.D. (Andrew), Reiner, A.P. (Alex), Zhu, X. (Xiaofeng), Bakker, P.I.W. (Paul) de, Levy, D. (Daniel), Asselbergs, F.W. (Folkert), Munroe, P. (Patricia), Keating, J. (John), Tragante, V. (Vinicius), Barnes, M.J. (Michael), Ganesh, S.K. (Santhi), Lanktree, M.B. (Matthew), Guo, W. (Weixiang), Franceschini, N. (Nora), Smith, A.V. (Davey), Johnson, T. (Toby), Holmes, M.V. (Michael), Padmanabhan, S. (Sandosh), Karczewski, K.J. (Konrad), Almoguera, B. (Berta), Barnard, J. (John), Baumert, J. (Jens), Chang, Y.-P.C. (Yen-Pei), Elbers, C.C. (Clara), Farrall, M. (Martin), Fischer, M.E. (Mary), Gaunt, T.R. (Tom), Gho, J.M.I.H. (Johannes), Gieger, C. (Christian), Goel, A. (Anuj), Gong, Y. (Yeming), Isaacs, A.J. (Aaron), Kleber, M.E. (Marcus), Leach, I.M. (Irene Mateo), McDonough, C.W. (Caitrin), Meijs, M.F.L. (Matthijs), Melander, O. (Olle), Nelson, C.P. (Christopher P.), Nolte, I.M. (Ilja), Pankratz, V.S. (Shane), Price, T.S. (Thomas), Shaffer, J. (Jonathan), Shah, S. (Sonia), Tomaszewski, M. (Maciej), Most, P.J. (Peter) van der, Iperen, E.P.A. (Erik) van, Vonk, J.M. (Judith), Witkowska, H.E. (Ewa), Wong, C.O.L. (Caroline), Zhang, L. (Lingling), Beitelshees, A.L. (Amber), Berenson, G. (Gerald), Bhatt, D.L. (Deepak), Brown, M.J. (Morris), Burt, A.D. (Alastair), Cooper-Dehoff, R.M. (Rhonda), Connell, J. (John), Cruickshanks, K.J. (Karen), Curtis, S.P. (Sean), Davey-Smith, G. (George), Delles, C. (Christian), Gansevoort, R.T. (Ron), Guo, X. (Xiuqing), Haiqing, S. (Shen), Hastie, C.E. (Claire), Hofker, M.A. (Marten), Hovingh, G.K. (Kees), Kim, D.S. (Daniel), Kirkland, S.A. (Susan), Klein, B.E.K. (Barbara), Li, Y.R. (Yun), Maiwald, R. (Robert), Newton-Cheh, C. (Christopher), O'Brien, E. (Eoin), Onland-Moret, N.C. (Charlotte), Palmas, W. (Walter), Parsa, A. (Afshin), Penninx, B.W.J.H. (Brenda), Pettinger, M. (Mary), Vasan, R.S. (Ramachandran Srini), Ranchalis, J.E. (Jane), Ridker, P.M. (Paul), Rose, L.M. (Lynda), Sever, P. (Peter), Shimbo, D. (Daichi), Steele, L. (Linda), Stolk, R.P. (Ronald), Thorand, B. (Barbara), Trip, M.D. (Mieke), Duijn, C.M. (Cornelia) van, Verschuren, W.M.M. (W. M. Monique), Wijmenga, C. (Cisca), Wyatt, S. (Sally), Young, J.C. (J. C.), Zwinderman, A.H. (Ailko), Bezzina, C.R. (Connie), Boerwinkle, E.A. (Eric), Casas, J.P. (Juan), Caulfield, M. (Mark), Chakravarti, A. (Aravinda), Chasman, D.I. (Daniel), Davidson, K.W. (Karina), Doevendans, P.A. (Pieter), Dominiczak, A. (Anna), Fitzgerald, G.A. (Garret), Gums, J.G. (John), Fornage, M. (Myriam), Hakonarson, H. (Hakon), Halder, H. (Han) van, Hillege, H.L. (Hans), Illig, T. (Thomas), Jarvik, G.P. (Gail), Johnson, J.A. (Jennifer ), Kastelein, J.J.P. (John), Koenig, W. (Wolfgang), Kumari, M. (Meena), März, W. (Winfried), Murray, S.S. (Sarah), O'Connell, J.R. (Jeffery), Oldehinkel, A.J. (Albertine), Pankow, J.S. (James), Rader, D.J. (Daniel), Redline, S. (Susan), Reilly, M.P. (Muredach), Schadt, E.E. (Eric), Kottke-Marchant, K. (Kandice), Snieder, H. (Harold), Snyder, M. (Michael), Stanton, A. (Alice), Tobin, M.D. (Martin), Uitterlinden, A.G. (André), Harst, P. (Pim) van der, Schouw, Y.T. (Yvonne) van der, Samani, N.J. (Nilesh), Watkins, H. (Hugh), Johnson, A.D. (Andrew), Reiner, A.P. (Alex), Zhu, X. (Xiaofeng), Bakker, P.I.W. (Paul) de, Levy, D. (Daniel), Asselbergs, F.W. (Folkert), Munroe, P. (Patricia), and Keating, J. (John)

Abstract

Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10-7) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.

Published
2014
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48. 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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49. Comined effects of smoking and alcohol on metabolic syndrome: the lifelines cohort study

Author

Slagter, S.N., Vliet-Ostaptchouk, J.V., Vonk, J.M., Boezen, H.M., Dullaart, R.P.F., Muller Kobold, A.C., Feskens, E.J.M., van Beek, A.P., van der Klauw, M.M., Wolffenbuttel, B.H.R., Slagter, S.N., Vliet-Ostaptchouk, J.V., Vonk, J.M., Boezen, H.M., Dullaart, R.P.F., Muller Kobold, A.C., Feskens, E.J.M., van Beek, A.P., van der Klauw, M.M., and Wolffenbuttel, B.H.R.

Abstract

Introduction - The development of metabolic syndrome (MetS) is influenced by environmental factors such as smoking and alcohol consumption. We determined the combined effects of smoking and alcohol on MetS and its individual components. Methods - 64,046 participants aged 18–80 years from the LifeLines Cohort study were categorized into three body mass index (BMI) classes (BMI1 drink/day) and tobacco showed higher triglycerides levels. Up to 2 drinks/day was associated with a smaller waist circumference in overweight and obese individuals. Consumption of >2 drinks/day increased blood pressure, with the strongest associations found for heavy smokers. The overall metabolic profile of wine drinkers was better than that of non-drinkers or drinkers of beer or spirits/mixed drinks. Conclusion - Light alcohol consumption may moderate the negative associations of smoking with MetS. Our results suggest that the lifestyle advice that emphasizes smoking cessation and the restriction of alcohol consumption to a maximum of 1 drink/day, is a good approach to reduce the prevalence of MetS. Figures

Published
2014

50. Low-dose CT measurements of airway dimensions and emphysema associated with airflow limitation in heavy smokers: a cross sectional study

Author

Dijkstra, A.E., Postma, D.S., Hacken, N. Ten, Vonk, J.M., Oudkerk, M., Ooijen, PM van, Zanen, P., Mohamed Hoesein, F.A., Ginneken, B. van, Schmidt, M., Groen, H.J., Dijkstra, A.E., Postma, D.S., Hacken, N. Ten, Vonk, J.M., Oudkerk, M., Ooijen, PM van, Zanen, P., Mohamed Hoesein, F.A., Ginneken, B. van, Schmidt, M., and Groen, H.J.

Abstract

Contains fulltext : 118757.pdf (publisher's version ) (Open Access), BACKGROUND: Increased airway wall thickness (AWT) and parenchymal lung destruction both contribute to airflow limitation. Advances in computed tomography (CT) post-processing imaging allow to quantify these features. The aim of this Dutch population study is to assess the relationships between AWT, lung function, emphysema and respiratory symptoms. METHODS: AWT and emphysema were assessed by low-dose CT in 500 male heavy smokers, randomly selected from a lung cancer screening population. AWT was measured in each lung lobe in cross-sectionally reformatted images with an automated imaging program at locations with an internal diameter of 3.5 mm, and validated in smaller cohorts of patients. The 15th percentile method (Perc15) was used to assess the severity of emphysema. Information about respiratory symptoms and smoking behavior was collected by questionnaires and lung function by spirometry. RESULTS: Median AWT in airways with an internal diameter of 3.5 mm (AWT3.5) was 0.57 (0.44 - 0.74) mm. Median AWT in subjects without symptoms was 0.52 (0.41-0.66) and in those with dyspnea and/or wheezing 0.65 (0.52-0.81) mm (p<0.001). In the multivariate analysis only AWT3.5 and emphysema independently explained 31.1\%and 9.5\%of the variance in FEV1\%predicted, respectively, after adjustment for smoking behavior. CONCLUSIONS: Post processing standardization of airway wall measurements provides a reliable and useful method to assess airway wall thickness. Increased airway wall thickness contributes more to airflow limitation than emphysema in a smoking male population even after adjustment for smoking behavior.

Published
2013

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