Genome-wide association study of lung function phenotypes in a founder population Tsung-Chieh Yao, MD, PhD, Gaixin Du, MS, Lide Han, PhD, Ying Sun, MS,

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Genome-wide association study of lung function phenotypes in a founder population Tsung-Chieh Yao, MD, PhD, Gaixin Du, MS, Lide Han, PhD, Ying Sun, MS, Donglei Hu, PhD, James J. Yang, PhD, Rasika Mathias, ScD, Lindsey A. Roth, MA, Nicholas Rafaels, MS, Emma E. Thompson, PhD, Dagan A. Loisel, PhD, Rebecca Anderson, MS, Celeste Eng, BS, Maitane Arruabarrena Orbegozo, RN, Melody Young, RN, James M. Klocksieben, BA, Elizabeth Anderson, RN, Kathleen Shanovich, MS, RN, Lucille A. Lester, MD, L. Keoki Williams, MD, MPH, Kathleen C. Barnes, PhD, Esteban G. Burchard, MD, MPH, Dan L. Nicolae, PhD, Mark Abney, PhD, Carole Ober, PhD Journal of Allergy and Clinical Immunology Volume 133, Issue 1, Pages 248-255.e10 (January 2014) DOI: 10.1016/j.jaci.2013.06.018 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Manhattan and Q–Q plots of P values from the GWAS of FEV1/FVC (A and B), FEV1 (C and D), and FVC (E and F). SNPs with P < 10−5 are shown in red. The horizontal red line shows the genome-wide significance threshold (P < 2.0 × 10−7). Journal of Allergy and Clinical Immunology 2014 133, 248-255.e10DOI: (10.1016/j.jaci.2013.06.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 The combined effects of genotypes for 80 SNPs on the residual FEV1/FVC in the Hutterites. Hutterites were binned by their total number of alleles associated with reduced FEV1/FVC (x-axis); the mean ± SE residual FEV1/FVC for each bin is plotted on the right y-axis (blue dots and bars), and the number of subjects in each bin is on the left y-axis. The linear regression line through these points is shown in red. Journal of Allergy and Clinical Immunology 2014 133, 248-255.e10DOI: (10.1016/j.jaci.2013.06.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 GRAIL functional connections between the 80 predictive SNPs. Six SNPs with no nearby genes defined by GRAIL are not shown. GRAIL identified 6 pairs of SNPs that implicated the same genes; only 1 SNP from each these 6 pairs is shown in the figure. The regions (SNPs; outer ring) and genes (inner ring) are optimally ordered to display connections with a minimal number of intersections. Only the genes with PGRAIL < .05 have connections displayed. The thickness and redness of the connectors reflects the significance of the connections. Three clusters of β-defensin genes are the most connected sets. Journal of Allergy and Clinical Immunology 2014 133, 248-255.e10DOI: (10.1016/j.jaci.2013.06.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Measures of lung function in the Hutterites. Distributions of standardized values of FEV1 (A), FVC (B), and FEV1/FVC (C) by age and sex (blue, male; orange, female). Correlations between measures of lung function: FEV1 and FVC (D), FEV1 and FEV1/FVC (E), and FVC and FEV1/FVC (F). The linear regression line is shown in red. Journal of Allergy and Clinical Immunology 2014 133, 248-255.e10DOI: (10.1016/j.jaci.2013.06.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Regional association plots for the 3 most significant associations in the GWAS of FEV1/FVC in the Hutterites: THSD4-UACA-TLE3 locus on chromosome 15q23, CCL23-CCL18 locus on chromosome 17q12, and C10orf11 locus on chromosome 10q22.3 in the full sample (A-C, respectively) and in subanalyses that excluded persons with asthma (D-F, respectively). In each plot the most significantly associated SNP is shown as a large blue diamond. The colors of the other SNPs reflect the linkage disequilibrium with that SNP based on r2 values in the Hutterites (red, r2 ≥ 0.8; orange, 0.5 ≤ r2 < 0.8; yellow, 0.2 ≤ r2 < 0.5; white, r2 < 0.2). Journal of Allergy and Clinical Immunology 2014 133, 248-255.e10DOI: (10.1016/j.jaci.2013.06.018) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions