Haseman-Elston regression lines at D17S2180 for (a) all eligible sib pairs and (b) node 10 subgroup

<p><b>Copyright information:</b></p><p>Taken from "Use of tree-based models to identify subgroups and increase power to detect linkage to cardiovascular disease traits"</p><p>http://www.biomedcentral.com/1471-2156/4/s1/S66</p><p>BMC Genetics 2003;4(Suppl 1):S66-S66.</p><p>Published online 31 Dec 2003</p><p>PMCID:PMC1866504.</p><p></p

Genome-wide joint meta-analysis of SNP and SNP-by-smoking interaction identifies novel loci for pulmonary function.

Genome-wide association studies have identified numerous genetic loci for spirometic measures of pulmonary function, forced expiratory volume in one second (FEV(1)), and its ratio to forced vital capacity (FEV(1)/FVC). Given that cigarette smoking adversely affects pulmonary function, we conducted genome-wide joint meta-analyses (JMA) of single nucleotide polymorphism (SNP) and SNP-by-smoking (ever-smoking or pack-years) associations on FEV(1) and FEV(1)/FVC across 19 studies (total N = 50,047). We identified three novel loci not previously associated with pulmonary function. SNPs in or near DNER (smallest P(JMA = )5.00×10(-11)), HLA-DQB1 and HLA-DQA2 (smallest P(JMA = )4.35×10(-9)), and KCNJ2 and SOX9 (smallest P(JMA = )1.28×10(-8)) were associated with FEV(1)/FVC or FEV(1) in meta-analysis models including SNP main effects, smoking main effects, and SNP-by-smoking (ever-smoking or pack-years) interaction. The HLA region has been widely implicated for autoimmune and lung phenotypes, unlike the other novel loci, which have not been widely implicated. We evaluated DNER, KCNJ2, and SOX9 and found them to be expressed in human lung tissue. DNER and SOX9 further showed evidence of differential expression in human airway epithelium in smokers compared to non-smokers. Our findings demonstrated that joint testing of SNP and SNP-by-environment interaction identified novel loci associated with complex traits that are missed when considering only the genetic main effects

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

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

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

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