Flowchart describing each of the 3 main analytical pathways used to explore the genetic architecture of smoking resistance.

<p>Analyses are described in full in the methods. MAF: minor allele frequency.</p

QQ plots for SKAT and AMELIA analyses using primary controls.

<p>QQ plots for SKAT and AMELIA analyses using primary controls.</p

QQ plots of single-variant association test statistics for all exonic variants (A) and for exonic variants with MAF>5% (B).

<p>QQ plots of single-variant association test statistics for all exonic variants (A) and for exonic variants with MAF>5% (B).</p

Immunohistochemistry staining for Coiled-Coil Domain-Containing Protein 38 (CCDC38) in a normal human bronchial epithelium at ×40 magnification.

<p>When compared to the unstained isotype control (Rabbit IgG) (A), staining identifies moderate cytoplasmic expression of CCDC38 particularly in the columnar epithelial cells and the bronchial smooth muscle layer (B). Image representative of three independent staining procedures.</p

Gene Ontology (GO) terms reaching Bonferroni corrected significance for enrichment amongst the 1533 genes harbouring novel putatively functional variants in the resistant smokers, using DAVID.

<p>Gene Ontology (GO) terms reaching Bonferroni corrected significance for enrichment amongst the 1533 genes harbouring novel putatively functional variants in the resistant smokers, using DAVID.</p

SKAT and AMELIA analysis results using primary controls, ranked by SKAT P value.

#<p>Only genes with >4 SNPs with MAF<5% were tested by AMELIA.</p

Single variant association results for 20 top exonic SNPs.

<p>MAF = minor allele frequency.</p><p>*Fisher's Exact test of case and primary control allele counts.</p>1<p>Borderline evidence for association with airflow obstruction (P = 0.052 in ever-smokers) <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004314#pgen.1004314-Wilk2" target="_blank">[9]</a>.</p>2<p>Weak evidence of association with airflow obstruction (P = 0.04) <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1004314#pgen.1004314-Wilk2" target="_blank">[9]</a>.</p

Common and low-frequent <i>SERPINA1</i> SNPs and their association with AAT serum level, univariate and conditional on significantly associated SNPs (N = 5569^a), in SAPALDIA.

<p>Abbreviations: AAT, alpha1-antitrypsin; MAF, minor allele frequency; SNP, single nucleotide polymorphism.</p><p>Chromosomal position is based on reference panel, NCBI build 36.3.</p>a<p>Includes subjects for whom all the 16 SNPs have been successfully genotyped.</p>b<p>SNP selection was based on extreme trait sequence data (A), tagging SNPs according to HapMap (B), TAMAL software (C) and publication about functionality (D); see <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1003585#s4" target="_blank">Materials and Methods</a> for a more detailed description.</p>c<p>Univariate analyses were adjusted for non-genetic factors only (sex, age, recruiting area and current smoking status). Allele effects are shown in absolute numbers and P<0.005 was considered statistically significant.</p>d<p>In a forward selection approach of stepwise regression, the four SNPs in bold contributed statistically significantly to the variability in AAT serum levels and were included in the final statistical model. Allele effects and p-values refer to this final model.</p

Minor allele effects on FEV1 of low-frequent and common SNPs in the <i>SERPINA</i> gene cluster in ever-smokers undergoing lung resection.

<p>Abbreviations: FEV1, forced expiratory volume in one second; MAF, minor allele frequency; SNP, single nucleotide polymorphism.</p><p>Imp-r² is an indicator for imputation quality. The analyses were adjusted for age, sex and height.</p>a<p>Rs4905179 was genotyped in UBC.</p

Regional plot for the <i>SERPINA</i> gene cluster (93.8–94.2 Mb on chromosome 14q32.13, reference panel: NCBI build 36.3).

<p>Presented are -log(10) p-values and LD (r²) with top-ranking SNP rs2736887 (purple diamond) for all SNPs in this region. The blue line shows recombination rate.</p