A Genome-Wide Association Study in Chronic Obstructive Pulmonary Disease (COPD): Identification of Two Major Susceptibility Loci
Sreekumar G. Pillai,Dongliang Ge,Guohua Zhu,Xiangyang Kong,Kevin V. Shianna,Anna C. Need,Sheng Feng,Craig P. Hersh,Per Bakke,Amund Gulsvik,Andreas Ruppert,Karin C. Lødrup Carlsen,Allen D. Roses,Allen D. Roses,Wayne Anderson,Stephen I. Rennard,David A. Lomas,Edwin K. Silverman,David Goldstein +18 more
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TLDR
A genome-wide association study in a homogenous case-control cohort from Bergen, Norway and evaluated the top 100 single nucleotide polymorphisms (SNPs) in the family-based International COPD Genetics Network found two SNPs at the α-nicotinic acetylcholine receptor (CHRNA 3/5) locus showed unambiguous replication and were significantly associated with lung function in both the ICGN and Boston Early-Onset COPD populations.Abstract:
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 alpha(1)-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 alpha-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 x 10(-10), (rs8034191) and 5.74 x 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.read more
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Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.
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Uncovering the roles of rare variants in common disease through whole-genome sequencing
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TL;DR: CPDGene will provide important new information about genetic factors in COPD, and will characterize the disease process using high resolution CT scans, which will potentially permit earlier diagnosis of this disease and may lead to the development of treatments to modify progression.
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An Abundance of Rare Functional Variants in 202 Drug Target Genes Sequenced in 14,002 People
Matthew R. Nelson,Daniel Wegmann,Margaret G. Ehm,Darren Kessner,Pamela L. St. Jean,Claudio J. Verzilli,Judong Shen,Zheng-Zheng Tang,Silviu Alin Bacanu,Dana Fraser,Liling Warren,Jennifer L. Aponte,Matthew Zawistowski,Xiao Liu,Hao Zhang,Yong Zhang,Jun Li,Yun Li,Li Li,Peter Woollard,Simon Topp,Matthew D. Hall,Keith Nangle,Jun Wang,Gonçalo R. Abecasis,Lon R. Cardon,Sebastian Zöllner,John C. Whittaker,Stephanie L. Chissoe,John Novembre,Vincent Mooser +30 more
TL;DR: It is concluded that because of rapid population growth and weak purifying selection, human populations harbor an abundance of rare variants, many of which are deleterious and have relevance to understanding disease risk.
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