Association of the most statistically significant SNPs with the rate of change in FEV₁ (mL/year) in the meta-analysis of the five cohort studies with ≥3 FEV₁ measurements per participant (n = 10,476).

<p><i>Definition of abbreviations</i>: Chr  =  chromosome; SE  =  standard error; SNP  =  single-nucleotide polymorphism.</p><p>^*Data reported are the meta-analysis results of the SNP-by-time interaction term from the GWAS mixed effects model. A positive β-coefficient indicates an attenuation of FEV₁ decline and a negative β-coefficient an acceleration of FEV₁ decline.</p

Association of the chromosome 15 locus with the rate of change in FEV₁ in the meta-analysis of 14 cohort studies.

<p><b>A</b>) Regional association plot, where the X-axis is Megabase (Mb) position and Y-axes are the negative log of the <i>P</i> value on the left and recombination rate on the right. The sentinel SNP is colored in purple and linkage disequilibrium to the sentinel SNP is depicted by degree of color according to the legend. <b>B</b>) Forest plot for rs4077833, where the size of the square for each study represents its contributing weight to the meta-analysis.</p

Baseline characteristics of cohort studies included in the meta-analysis^*.

<p><i>Definition of abbreviations</i>: ARIC  =  Atherosclerosis Risk in Communities; B58C  =  British 1958 Birth Cohort; BHS  =  Busselton Health Study; CARDIA  =  Coronary Artery Risk Development in Young Adults; CHS  =  Cardiovascular Health Study  =  FHS, Framingham Heart Study; Health ABC  =  Health, Aging, and Body Composition; KORA  =  Cooperative Health Research in the Region of Augsburg; LBC1921  =  Lothian Birth Cohort 1921; LBC1936  =  Lothian Birth Cohort 1936; PIVUS  =  Prospective Investigation of the Vasculature in Uppsala Seniors; RS  =  Rotterdam Study; SAPALDIA  =  Swiss Study on Air Pollution and Lung Diseases in Adults; SD  =  standard deviation; SHIP  =  Study of Health in Pomerania.</p><p>^*Data are presented as mean (SD) unless otherwise indicated; total no. participants  =  27,249, total no. FEV₁ measurements  =  62,130.</p>†<p>Pack-years are calculated among current and former smokers at study baseline.</p

Association of the most statistically significant SNPs with the rate of change in FEV₁ (mL/year) in the meta-analysis of 14 cohort studies (n = 27,249)^*.

<p><i>Definition of abbreviations</i>: Chr  =  chromosome; SE  =  standard error; SNP  =  single-nucleotide polymorphism.</p><p>^*Data reported are the meta-analysis results of the SNP-by-time interaction term from the GWAS mixed effects model. A positive β-coefficient indicates an attenuation of FEV₁ decline and a negative β-coefficient an acceleration of FEV₁ decline.</p

Association of the chromosome 11 locus with the rate of change in FEV₁ in the meta-analysis of the five cohort studies with ≥3 FEV₁ measurements per participant.

<p><b>A</b>) Regional association plot, where the X-axis is Megabase (Mb) position, and the Y-axes are the negative log of the <i>P</i> value on the left and recombination rate on the right. The sentinel SNP is colored in purple and linkage disequilibrium to the sentinel SNP is depicted by degree of color according to the legend. <b>B</b>) Forest plot for rs507211, where the size of the square for each study represents its contributing weight to the meta-analysis.</p

Model estimates for the rate of change in FEV₁ in never smokers and effects of other smoking patterns (compared with never smokers) on the rate of change in FEV₁ (mL/year)^*.

<p><i>Definition of abbreviations</i>: ARIC  =  Atherosclerosis Risk in Communities; B58C  =  British 1958 Birth Cohort; BHS  =  Busselton Health Study; CARDIA  =  Coronary Artery Risk Development in Young Adults; CHS  =  Cardiovascular Health Study; FHS  =  Framingham Heart Study; Health ABC  =  Health, Aging, and Body Composition; KORA  =  Cooperative Health Research in the Region of Augsburg; LBC1921  =  Lothian Birth Cohort 1921; LBC1936  =  Lothian Birth Cohort 1936; PIVUS  =  Prospective Investigation of the Vasculature in Uppsala Seniors; RS  =  Rotterdam Study; SAPALDIA  =  Swiss Study on Air Pollution and Lung Diseases in Adults; SE  =  standard error; SHIP  =  Study of Health in Pomerania.</p><p>^*Data shown are the effect estimates (β and SE) of the time and smoking-by-time interaction terms in the preliminary mixed effects model fully adjusted for all specified variables except the SNP terms. Time represents the rate of change in FEV₁ in never smokers and the smoking-by-time interaction term represents the effects of the other three smoking patterns on the rate of change in FEV₁, compared with never smokers. Smoking categories are defined as persistent (smoke throughout follow-up), intermittent (stop and/or start smoking during follow-up) and former (smoke only prior to start of follow-up).</p>†<p>Effect estimates in smoking categories are added to estimates in never smokers to compute the actual rate of change in each group (for example, in ARIC, the point estimate of the rate of change in FEV₁ in persistent smokers was −14.0 − 12.4  =  −26.4 mL/year).</p

Regional association plots of novel loci implicated for pulmonary function.

<p>Three novel loci contained SNPs associated with FEV₁/FVC or FEV₁ at the standard genome-wide significance threshold (<i>P</i>&lt;5×10⁻⁸) in joint meta-analyses of SNP and SNP-by-smoking interaction. SNPs are shown within 500 kb of the most significant SNPs on chromosomes (A) 2q36.3 associated with FEV₁/FVC, (B) 6p21.32 associated with FEV₁/FVC, and (C) 17q24.3 associated with FEV₁. Pairwise r² values were based on the HapMap CEU population, and progressively darker shades of red indicate higher r² values. Estimated recombination rates from HapMap are shown as background lines.</p

Genome-wide significant SNPs from the joint meta-analysis (JMA) of SNP and SNP-by-smoking (ever-smoking or pack-years) interaction in relation to pulmonary function.

<p>After removing SNPs with known associations with FEV₁/FVC or FEV₁, three novel loci with genome-wide significant SNPs (standard threshold of <i>P</i>&lt;5×10⁻⁸) remained from the JMA testing in the current study. The most significant SNP from each locus is shown.</p><p>FEV₁, forced expiratory volume in the first second; FVC, forced vital capacity; JMA, joint meta-analysis; SE, standard error ; SNP, single nucleotide polymorphism.</p>1<p>Weighted average coded allele frequency across the 19 studies. The coded allele refers to the effect allele.</p>2<p>β_SNP, per allele change in the FEV₁/FVC standardized residual due to the SNP main association.</p>3<p>β_INT, per allele change in the FEV₁/FVC standardized residual due to the interaction between SNP and smoking.</p

Genome-wide joint meta-analysis (JMA) of SNP and SNP-by-smoking interaction in relation to pulmonary function.

<p>The Manhattan plots show the chromosomal position of SNPs in comparison to their −log₁₀<i>P</i>_JMA values. JMA results are shown for models with (A) SNP-by-ever-smoking interaction term in relation to FEV₁/FVC, (B) SNP-by-pack-years interaction term in relation to FEV₁/FVC, (C) SNP-by-ever-smoking interaction term in relation to FEV₁, and (D) SNP-by-pack-years interaction term in relation to FEV₁. SNPs located within previously implicated loci are shown, but these loci were not considered when identifying novel loci from the joint modeling of SNP main effects and smoking interactive effects. Novel loci on chromosomes 2, 6, and 17 (shown in blue and circled) were identified as those having SNPs with genome-wide significant <i>P</i> values at the standard threshold (<i>P</i>&lt;5×10⁻⁸ as indicated by the solid red line). Names of the novel gene (or closest genes) are provided.</p