Genome-wide association analysis identifies six new loci associated with forced vital capacity

Abstract

Forced vital capacity (FVC), a spirometric measure of pulmonary function, reflects lung volume and is used to diagnose and monitor lung diseases. We performed genome-wide association study meta-analysis of FVC in 52,253 individuals from 26 studies and followed up the top associations in 32,917 additional individuals of European ancestry. We found six new regions associated at genome-wide significance (P < 5 × 10−8) with FVC in or near EFEMP1, BMP6, MIR-129-2/HSD17B12, PRDM11, WWOX, and KCNJ2. Two (GSTCD and PTCH1) loci previously associated with spirometric measures were related to FVC. Newly implicated regions were followed-up in samples of African American, Korean, Chinese, and Hispanic individuals. We detected transcripts for all six newly implicated genes in human lung tissue. The new loci may inform mechanisms involved in lung development and pathogenesis of restrictive lung disease.

Loss of PRDM11 promotes MYC-driven lymphomagenesis

“…Both the gene structures and the amino acid sequences, except for the C-terminus, are highly conserved between humans and mice ( Figure 1B and supplemental Figure 1A-B). In accordance with published data from human tissues, 3,29 murine Prdm11 expression is generally low, with the highest expression in spleen, lung, mesenteric lymph node, and kidney ( Figure 1C).…”

Genetic variants affecting cross-sectional lung function in adults show little or no effect on longitudinal lung function decline

“…4 Genome-wide association studies (GWAS) to date have identified numerous regions associated with lung function measured at a single point in time (ie, cross-sectional lung function). [5][6][7][8][9] The lung function attained at a given time point in adulthood will be influenced by factors that affect either the development of lung function in earlier life or the rate of subsequent decline in lung function or both. Both cross-sectional lung function and longitudinal change in lung function are heritable.…”

Dysregulated fibulin-5 expression and elastogenesis in COPD lungs: pyromaniac or fire fighter?

“…Recently, another member of the fibulin family of ECM glycoproteins—fibulin-3—has been implicated in diverse respiratory disorders. A large genome-wide association (GWA) study has associated single nucleotide poylmorphisms in the EFEMP1 gene, encoding fibulin-3, with forced vital capacity (FVC) 7. Moreover, fibulin-3 protein levels—measured in plasma or pleural fluid with an ELISA—appears to be an accurate diagnostic biomarker for patients with mesothelioma 8…”

“…Collaborative research within large consortia has become standard state-of-the art methodology in genetic studies such as GWA studies, but has, until now, only rarely been applied to expression studies in the respiratory field. The assets of large-scale collaborations in GWA studies, encompassing replication of significant associations in independent cohorts and meta-analysis of results obtained in separate smaller cohorts are obvious, and have vastly improved the external validity of the results of genetic studies 7 9. We welcome a similar collaborative approach by the Lung eQTL Consortium for lung gene expression studies 3…”