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author:("gulik, amend")
1.  On the Follow-Up of Genome-Wide Association Studies: An Overall Test for the Most Promising S.N.P.’s 
Genetic epidemiology  2011;35(5):303-309.
Even in large-scale genome-wide association studies, only a fraction of the true associations are detected at the genome-wide significance level. When few or no associations reach the significance threshold, one strategy is to follow-up on the most promising candidates, i.e. the single nucleotide polymorphisms with the smallest association-test p-values, by genotyping them in additional studies. In this communication, we propose an overall test for genome-wide association studies that analyzes the SNP’s with the most promising p-values simultaneously and thereby allows an early assessment of whether the follow- up of the selected SNP’s is likely promising. We theoretically derive the properties of the proposed overall test under the null hypothesis and assess its power based on simulation studies. An application to a GWAS for chronic obstructive pulmonary disease suggests that there are true association signals among the top SNPs and that an additional follow-up study is promising.
PMCID: PMC4096304  PMID: 21374717
genome wide association studies; snps association tests; chronic obstructive pulmonary disease; statistical genetics; multiple testing
2.  Dissecting direct and indirect genetic effects on chronic obstructive pulmonary disease (COPD) susceptibility 
Human genetics  2013;132(4):431-441.
Cigarette smoking is the major environmental risk factor for chronic obstructive pulmonary disease (COPD). Genome-wide association studies have provided compelling associations for three loci with COPD. In this study, we aimed to estimate direct, i.e., independent from smoking, and indirect effects of those loci on COPD development using mediation analysis. We included a total of 3,424 COPD cases and 1,872 unaffected controls with data on two smoking-related phenotypes: lifetime average smoking intensity and cumulative exposure to tobacco smoke (pack years). Our analysis revealed that effects of two linked variants (rs1051730 and rs8034191) in the AGPHD1/CHRNA3 cluster on COPD development are significantly, yet not entirely, mediated by the smoking-related phenotypes. Approximately 30 % of the total effect of variants in the AGPHD1/CHRNA3 cluster on COPD development was mediated by pack years. Simultaneous analysis of modestly (r2 = 0.21) linked markers in CHRNA3 and IREB2 revealed that an even larger (~42 %) proportion of the total effect of the CHRNA3 locus on COPD was mediated by pack years after adjustment for an IREB2 single nucleotide polymorphism. This study confirms the existence of direct effects of the AGPHD1/CHRNA3, IREB2, FAM13A and HHIP loci on COPD development. While the association of the AGPHD1/CHRNA3 locus with COPD is significantly mediated by smoking-related phenotypes, IREB2 appears to affect COPD independently of smoking.
PMCID: PMC3600068  PMID: 23299987
3.  The Association of Genome-Wide Significant Spirometric Loci with Chronic Obstructive Pulmonary Disease Susceptibility 
Two recent metaanalyses of genome-wide association studies conducted by the CHARGE and SpiroMeta consortia identified novel loci yielding evidence of association at or near genome-wide significance (GWS) with FEV1 and FEV1/FVC. We hypothesized that a subset of these markers would also be associated with chronic obstructive pulmonary disease (COPD) susceptibility. Thirty-two single-nucleotide polymorphisms (SNPs) in or near 17 genes in 11 previously identified GWS spirometric genomic regions were tested for association with COPD status in four COPD case-control study samples (NETT/NAS, the Norway case-control study, ECLIPSE, and the first 1,000 subjects in COPDGene; total sample size, 3,456 cases and 1,906 controls). In addition to testing the 32 spirometric GWS SNPs, we tested a dense panel of imputed HapMap2 SNP markers from the 17 genes located near the 32 GWS SNPs and in a set of 21 well studied COPD candidate genes. Of the previously identified GWS spirometric genomic regions, three loci harbored SNPs associated with COPD susceptibility at a 5% false discovery rate: the 4q24 locus including FLJ20184/INTS12/GSTCD/NPNT, the 6p21 locus including AGER and PPT2, and the 5q33 locus including ADAM19. In conclusion, markers previously associated at or near GWS with spirometric measures were tested for association with COPD status in data from four COPD case-control studies, and three loci showed evidence of association with COPD susceptibility at a 5% false discovery rate.
PMCID: PMC3262664  PMID: 21659657
4.  Genome-wide association study of smoking behaviors in COPD patients 
Thorax  2011;66(10):894-902.
Cigarette smoking is a major risk factor for COPD and COPD severity. Previous genome-wide association studies (GWAS) have identified numerous single nucleotide polymorphisms (SNPs) associated with the number of cigarettes smoked per day (CPD) and a Dopamine Beta-Hydroxylase (DBH) locus associated with smoking cessation in multiple populations.
To identify SNPs associated with lifetime average and current CPD, age at smoking initiation, and smoking cessation in COPD subjects.
GWAS were conducted in 4 independent cohorts encompassing 3,441 ever-smoking COPD subjects (GOLD stage II or higher). Untyped SNPs were imputed using HapMap (phase II) panel. Results from all cohorts were meta-analyzed.
Several SNPs near the HLA region on chromosome 6p21 and in an intergenic region on chromosome 2q21 showed associations with age at smoking initiation, both with the lowest p=2×10−7. No SNPs were associated with lifetime average CPD, current CPD or smoking cessation with p<10−6. Nominally significant associations with candidate SNPs within alpha-nicotinic acetylcholine receptors 3/5 (CHRNA3/CHRNA5; e.g. p=0.00011 for SNP rs1051730) and Cytochrome P450 2A6 (CYP2A6; e.g. p=2.78×10−5 for a nonsynonymous SNP rs1801272) regions were observed for lifetime average CPD, however only CYP2A6 showed evidence of significant association with current CPD. A candidate SNP (rs3025343) in the DBH was significantly (p=0.015) associated with smoking cessation.
We identified two candidate regions associated with age at smoking initiation in COPD subjects. Associations of CHRNA3/CHRNA5 and CYP2A6 loci with CPD and DBH with smoking cessation are also likely of importance in the smoking behaviors of COPD patients.
PMCID: PMC3302576  PMID: 21685187
Chronic Obstructive Pulmonary Disease (COPD); Genome Wide Association study (GWAS); smoking behaviors; Single Nucleotide Polymorphism (SNP)
5.  Genome-wide Association Study Identifies BICD1 as a Susceptibility Gene for Emphysema 
Rationale: Chronic obstructive pulmonary disease (COPD), characterized by airflow limitation, is a disorder with high phenotypic and genetic heterogeneity. Pulmonary emphysema is a major but variable component of COPD; familial data suggest that different components of COPD, such as emphysema, may be influenced by specific genetic factors.
Objectives: To identify genetic determinants of emphysema assessed through high-resolution chest computed tomography in individuals with COPD.
Methods: We performed a genome-wide association study (GWAS) of emphysema determined from chest computed tomography scans with a total of 2,380 individuals with COPD in three independent cohorts of white individuals from (1) a cohort from Bergen, Norway, (2) the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Study, and (3) the National Emphysema Treatment Trial (NETT). We tested single-nucleotide polymorphism associations with the presence or absence of emphysema determined by radiologist assessment in two of the three cohorts and a quantitative emphysema trait (percentage of lung voxels less than –950 Hounsfield units) in all three cohorts.
Measurements and Main Results: We identified association of a single-nucleotide polymorphism in BICD1 with the presence or absence of emphysema (P = 5.2 × 10−7 with at least mild emphysema vs. control subjects; P = 4.8 × 10−8 with moderate and more severe emphysema vs. control subjects).
Conclusions: Our study suggests that genetic variants in BICD1 are associated with qualitative emphysema in COPD. Variants in BICD1 are associated with length of telomeres, which suggests that a mechanism linked to accelerated aging may be involved in the pathogenesis of emphysema.
Clinical trial registered with (NCT00292552).
PMCID: PMC3040393  PMID: 20709820
emphysema; chronic obstructive pulmonary disease; BICD1; single-nucleotide polymorphism
6.  A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci 
PLoS Genetics  2009;5(3):e1000421.
There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD). The only known genetic risk factor is severe deficiency of α1-antitrypsin, which is present in 1–2% of individuals with COPD. We conducted a genome-wide association study (GWAS) in a homogenous case-control cohort from Bergen, Norway (823 COPD cases and 810 smoking controls) and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network (ICGN; 1891 Caucasian individuals from 606 pedigrees) study. The polymorphisms that showed replication were further evaluated in 389 subjects from the US National Emphysema Treatment Trial (NETT) and 472 controls from the Normative Aging Study (NAS) and then in a fourth cohort of 949 individuals from 127 extended pedigrees from the Boston Early-Onset COPD population. Logistic regression models with adjustments of covariates were used to analyze the case-control populations. Family-based association analyses were conducted for a diagnosis of COPD and lung function in the family populations. Two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) locus were identified in the genome-wide association study. They showed unambiguous replication in the ICGN family-based analysis and in the NETT case-control analysis with combined p-values of 1.48×10−10, (rs8034191) and 5.74×10−10 (rs1051730). Furthermore, these SNPs were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations. The C allele of the rs8034191 SNP was estimated to have a population attributable risk for COPD of 12.2%. The association of hedgehog interacting protein (HHIP) locus on chromosome 4 was also consistently replicated, but did not reach genome-wide significance levels. Genome-wide significant association of the HHIP locus with lung function was identified in the Framingham Heart study (Wilk et al., companion article in this issue of PLoS Genetics; doi:10.1371/journal.pgen.1000429). The CHRNA 3/5 and the HHIP loci make a significant contribution to the risk of COPD. CHRNA3/5 is the same locus that has been implicated in the risk of lung cancer.
Author Summary
There is considerable variability in the susceptibility of smokers to develop chronic obstructive pulmonary disease (COPD), which is a heritable multi-factorial trait. Identifying the genetic determinants of COPD risk will have tremendous public health importance. This study describes the first genome-wide association study (GWAS) in COPD. We conducted a GWAS in a homogenous case-control cohort from Norway and evaluated the top 100 single nucleotide polymorphisms in the family-based International COPD Genetics Network. The polymorphisms that showed replication were further evaluated in subjects from the US National Emphysema Treatment Trial and controls from the Normative Aging Study and then in a fourth cohort of extended pedigrees from the Boston Early-Onset COPD population. Two polymorphisms in the α-nicotinic acetylcholine receptor 3/5 locus on chromosome 15 showed unambiguous evidence of association with COPD. This locus has previously been implicated in both smoking behavior and risk of lung cancer, suggesting the possibility of multiple functional polymorphisms in the region or a single polymorphism with wide phenotypic consequences. The hedgehog interacting protein (HHIP) locus on chromosome 4, which is associated with COPD, is also a significant risk locus for COPD.
PMCID: PMC2650282  PMID: 19300482

Results 1-6 (6)