Family-Based Association Study of Pulmonary Function in a Population in Northeast Asia

Abstract

The spirometric measurement of pulmonary function by measuring the forced expiratory volume in one second (FEV1) is a heritable trait that reflects the physiological condition of the lung and airways. Genome-wide linkage and association studies have identified a number of genes and genetic loci associated with pulmonary function. However, limited numbers of studies have been reported for Asian populations. In this study, we aimed to investigate genetic evidence of pulmonary function in a population in northeast Asia. We conducted a family-based association test with 706 GENDISCAN study participants from 72 Mongolian families to determine candidate genetic determinants of pulmonary function. For the replication, we chose seven candidate single nucleotide polymorphisms (SNPs) from the 5 loci, and tested 1062 SNPs for association with FEV1 from 2,729 subjects of the Korea Healthy Twin study. We identified TMEM132C as a potential candidate gene at 12q24.3, which is a previously reported locus of asthma and spirometric indices. We also found two adjacent candidate genes (UNC93A and TTLL2) in the 6q27 region, which has been previously identified as a pulmonary function locus in the Framingham cohort study. Our findings suggest that novel candidate genes (TMEM132C, UNC93A and TTLL2) in two different regions are associated with pulmonary function in a population in northeast Asia.

Fig 1. Manhattan plot of the genome-wide association signal with FEV₁.

The x-axis represents the SNP markers on each chromosome. y-axis shows the −log10(P value). The blue horizontal line represents the genome-wide suggestive threshold P = 1.0 × 10⁻⁵. The greatest P value (P = 2.17 × 10⁻⁶) was observed in rs12582875 on chromosome 12q24.3.

Fig 2. Regional plots for discovery and replication loci associated with FEV₁.

The purple diamonds indicate the most significant SNP of each region, and nearby SNPs are color coded according to the level of LD with the top SNP. The x-axis shows chromosomal position. The left y axis shows the significance of the association, and the right y-axis shows a recombination rate across the region. Estimated recombination rates from the 1000 Genome (JPT+CHB, hg18) database are plotted with the blue line to reflect the local LD structure. Discovery (a) and replication (b) result of the TMEM132C region on 12q24.3. Discovery (c) and replication (d) result of the UNC93A and TTLL2 region on 6q27. The regional plots were created using LocusZoom.