Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants Ralf J.P. van der Valk, PhD, Liesbeth Duijts,

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Fraction of exhaled nitric oxide values in childhood are associated with 17q11.2-q12 and 17q12-q21 variants Ralf J.P. van der Valk, PhD, Liesbeth Duijts, MD, PhD, Nicolas J. Timpson, MD, PhD, Muhammad T. Salam, MD, PhD, Marie Standl, MSc, John A. Curtin, PhD, Jon Genuneit, MD, MSc, Marjan Kerhof, MD, PhD, Eskil Kreiner-Møller, MD, Alejandro Cáceres, MD, PhD, Anna Gref, MSc, Liming L. Liang, MD, PhD, H. Rob Taal, MD, PhD, Emmanuelle Bouzigon, MD, PhD, Florence Demenais, MD, Rachel Nadif, PhD, Carole Ober, PhD, Emma E. Thompson, PhD, Karol Estrada, PhD, Albert Hofman, MD, PhD, André G. Uitterlinden, PhD, Cornélia van Duijn, PhD, Fernando Rivadeneira, MD, PhD, Xia Li, MS, Sandrah P. Eckel, PhD, Kiros Berhane, PhD, W. James Gauderman, MD, PhD, Raquel Granell, PhD, David M. Evans, PhD, Beate St Pourcain, PhD, Wendy McArdle, PhD, John P. Kemp, MSc, George Davey Smith, MD, PhD, Carla M.T. Tiesler, MSc, Claudia Flexeder, MSc, Angela Simpson, MD, PhD, Clare S. Murray, MD, PhD, Oliver Fuchs, MD, PhD, Dirkje S. Postma, MD, PhD, Klaus Bønnelykke, MD, PhD, Maties Torrent, MD, PhD, Martin Andersson, MD, PhD, Patrick Sleiman, MD, PhD, Hakon Hakonarson, MD, PhD, William O. Cookson, MD, PhD, Miriam F. Moffatt, PhD, Lavinia Paternoster, PhD, Erik Melén, MD, PhD, Jordi Sunyer, MD, PhD, Hans Bisgaard, MD, DMSci, Gerard H. Koppelman, MD, PhD, Markus Ege, MD, PhD, Adnan Custovic, MD, PhD, Joachim Heinrich, PhD, Frank D. Gilliland, MD, PhD, Alexander J. Henderson, MD, Vincent W.V. Jaddoe, Johan C. de Jongste, MD, PhD Journal of Allergy and Clinical Immunology Volume 134, Issue 1, Pages 46-55 (July 2014) DOI: 10.1016/j.jaci.2013.08.053 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Study design. LCL, Lymphoblastoid cell line. Journal of Allergy and Clinical Immunology 2014 134, 46-55DOI: (10.1016/j.jaci.2013.08.053) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 A, QQ plot of 2,253,077 SNPs of 14 GWA studies (N = 8,858). The black dots represent observed P values, and the red line represents the expected P values under the null distribution. B, Manhattan plot showing the association P values of Feno values of the 14 studies. The −log10 of the P value for each of 2,253,077 SNPs (y-axis) is plotted against the genomic position (x-axis). Journal of Allergy and Clinical Immunology 2014 134, 46-55DOI: (10.1016/j.jaci.2013.08.053) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Association plots of the 17q11.2-q12 (A) and 17q12-q21 (B) regions. For both the 17q11.2-q12 and 17q12-q21 regions, SNPs are plotted with their P values (as −log10 values, left y-axis) as a function of genomic position (x-axis). Estimated recombination rates (right y-axis) taken from HapMap are plotted to reflect the local LD structure around the top associated SNP (purple circle) and correlated proxies (according to a blue to red scale from r2 = 0 to 1). Triangles represent nonsynonymous SNPs. Journal of Allergy and Clinical Immunology 2014 134, 46-55DOI: (10.1016/j.jaci.2013.08.053) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Forest plots of the associations between Feno values and the 3 SNPs associated with Feno values at a P value of less than 5 × 10−8. The SNPs in LYRM9 (A), NOS2 (B), and near ZPBP2-GSDMB (C) are shown. In each plot the triangle indicates the effect size and the CI in the 14 studies. The P values in the plots are without genomic control correction. Journal of Allergy and Clinical Immunology 2014 134, 46-55DOI: (10.1016/j.jaci.2013.08.053) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Forest plots of the associations between Feno values and the 3 SNPs associated with Feno values at a P value of less than 5 × 10−8. The SNPs in LYRM9 (A), NOS2 (B), and near ZPBP2-GSDMB (C) are shown. In each plot the triangle indicates the effect size and the CI in the 14 studies. The P values in the plots are without genomic control correction. Journal of Allergy and Clinical Immunology 2014 134, 46-55DOI: (10.1016/j.jaci.2013.08.053) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions