Identification of a new locus at 16q12 associated with time to asthma onset Chloé Sarnowski, PhD, Pierre-Emmanuel Sugier, MSc, Raquel Granell, PhD, Debbie.

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Identification of a new locus at 16q12 associated with time to asthma onset Chloé Sarnowski, PhD, Pierre-Emmanuel Sugier, MSc, Raquel Granell, PhD, Debbie Jarvis, MD, Marie-Hélène Dizier, PhD, Markus Ege, MD, Medea Imboden, PhD, Catherine Laprise, PhD, Elza K. Khusnutdinova, PhD, Maxim B. Freidin, PhD, William O.C. Cookson, MD, DPhil, Miriam Moffatt, DPhil, Mark Lathrop, PhD, Valérie Siroux, PhD, Ludmila M. Ogorodova, MD, PhD, Alexandra S. Karunas, MD, PhD, Alan James, MD, Nicole M. Probst-Hensch, PhD, Erika von Mutius, MD, Isabelle Pin, MD, PhD, Manolis Kogevinas, MD, PhD, A. John Henderson, MD, Florence Demenais, MD, Emmanuelle Bouzigon, MD, PhD Journal of Allergy and Clinical Immunology Volume 138, Issue 4, Pages 1071-1080 (October 2016) DOI: 10.1016/j.jaci.2016.03.018 Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Manhattan plot showing association P values of the genome-wide association results for TAO from the meta-analysis. The −log10 of the P value for each of 2,387,926 SNPs (y-axis) is plotted against the genomic position (x-axis). The solid red line indicates the genome-wide significance threshold of a P value of 5 × 10−8. Journal of Allergy and Clinical Immunology 2016 138, 1071-1080DOI: (10.1016/j.jaci.2016.03.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Regional association plot of the 16q12 region using Locuzoom software.26 SNPs are plotted with their P values (−log10 values, left y-axis) as a function of genomic position (x-axis). Estimated recombination rates (right y-axis) taken from the 1000 Genomes Project (EUR) are plotted to reflect the local linkage disequilibrium structure around the top associated SNP (purple circle) and correlated proxies (according to a blue to red scale from and r2 value of 0-1). Journal of Allergy and Clinical Immunology 2016 138, 1071-1080DOI: (10.1016/j.jaci.2016.03.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Relationship between TAO-associated SNPs and age of asthma onset. A, Association between age of asthma onset and genotypes at individual loci. B, Median of age of asthma onset as a function of the total number of risk alleles of SNPs found associated with the age-of-asthma onset and carried by asthmatic subjects. C, Median of age of asthma onset by quintile of genetic risk score. Journal of Allergy and Clinical Immunology 2016 138, 1071-1080DOI: (10.1016/j.jaci.2016.03.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Map of the 16q12 region (build 37.3 position: 50,723,355 to 50,860,722) and haplotype reconstruction for SNPs found to be associated with inflammatory bowel disease (among which was Crohn disease, blue), leprosy (green), or asthma (red) or with expression of CYLD or NOD2 (black). The linkage disequilibrium plot was obtained by using the Hapmap2 CEU reference sample from Haploview37 (values and colors reflect r2 and D′ values, respectively). The 16q12 top SNP (rs1861760) associated with TAO is indicated in boldface. Journal of Allergy and Clinical Immunology 2016 138, 1071-1080DOI: (10.1016/j.jaci.2016.03.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2016 138, 1071-1080DOI: (10.1016/j.jaci.2016.03.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2016 138, 1071-1080DOI: (10.1016/j.jaci.2016.03.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2016 138, 1071-1080DOI: (10.1016/j.jaci.2016.03.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2016 138, 1071-1080DOI: (10.1016/j.jaci.2016.03.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Journal of Allergy and Clinical Immunology 2016 138, 1071-1080DOI: (10.1016/j.jaci.2016.03.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Journal of Allergy and Clinical Immunology 2016 138, 1071-1080DOI: (10.1016/j.jaci.2016.03.018) Copyright © 2016 American Academy of Allergy, Asthma & Immunology Terms and Conditions