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.2009 Mar;5(3):e1000429.
doi: 10.1371/journal.pgen.1000429. Epub 2009 Mar 20.

A genome-wide association study of pulmonary function measures in the Framingham Heart Study

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A genome-wide association study of pulmonary function measures in the Framingham Heart Study

Jemma B Wilk et al. PLoS Genet.2009 Mar.

Abstract

The ratio of forced expiratory volume in one second to forced vital capacity (FEV(1)/FVC) is a measure used to diagnose airflow obstruction and is highly heritable. We performed a genome-wide association study in 7,691 Framingham Heart Study participants to identify single-nucleotide polymorphisms (SNPs) associated with the FEV(1)/FVC ratio, analyzed as a percent of the predicted value. Identified SNPs were examined in an independent set of 835 Family Heart Study participants enriched for airflow obstruction. Four SNPs in tight linkage disequilibrium on chromosome 4q31 were associated with the percent predicted FEV(1)/FVC ratio with p-values of genome-wide significance in the Framingham sample (best p-value = 3.6e-09). One of the four chromosome 4q31 SNPs (rs13147758; p-value 2.3e-08 in Framingham) was genotyped in the Family Heart Study and produced evidence of association with the same phenotype, percent predicted FEV(1)/FVC (p-value = 2.0e-04). The effect estimates for association in the Framingham and Family Heart studies were in the same direction, with the minor allele (G) associated with higher FEV(1)/FVC ratio levels. Results from the Family Heart Study demonstrated that the association extended to FEV(1) and dichotomous airflow obstruction phenotypes, particularly among smokers. The SNP rs13147758 was associated with the percent predicted FEV(1)/FVC ratio in independent samples from the Framingham and Family Heart Studies producing a combined p-value of 8.3e-11, and this region of chromosome 4 around 145.68 megabases was associated with COPD in three additional populations reported in the accompanying manuscript. The associated SNPs do not lie within a gene transcript but are near the hedgehog-interacting protein (HHIP) gene and several expressed sequence tags cloned from fetal lung. Though it is unclear what gene or regulatory effect explains the association, the region warrants further investigation.

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Conflict of interest statement

EKS received an honorarium for a talk on COPD genetics in 2006, grant support for two studies of COPD genetics (2004–2008), and consulting fees (2006–2008) from GlaxoSmithKline. EKS received an honorarium from Wyeth for a talk on COPD genetics in 2004. EKS received an honorarium from Bayer for a symposium at the ERS Meeting in 2005. EKS received honoraria for talks in 2007 and 2008 and consulting fees in 2008 from AstraZeneca.

Figures

Figure 1
Figure 1. Quantile-Quantile Plot of GWA results for percent predicted FEV1/FVC.
Figure 2
Figure 2. Plot of chromosome 4 association with percent predicted FEV1/FVC in imputed Framingham Heart Study data.
X-axis is the physical position in kb with arrows denoting genes and expressed sequence tags in the region, the left y-axis plots the −log(p-value), and the right y-axis plots the CEPH recombination rate. The blue diamond identifies the labeled SNP of interest, and LD with the SNP is depicted by color of additional diamonds: red-strong LD (r2≥0.8), orange-moderate LD (0.5≤r2<0.8), yellow-low LD (0.2≤r2<0.5), white-no LD (r2<0.2).
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