Large-scale genome-wide association study of Asian population reveals genetic factors in FRMD4A and other loci influencing smoking initiation and nicotine dependence

Abstract

Diseases related to smoking are the second leading cause of death in the world. Cigarette smoking is a risk factor for several diseases such as cancer and cardiovascular and respiratory disorders. Despite increasing evidence of genetic determination, the susceptibility genes and loci underlying various aspects of smoking behavior are largely unknown. Moreover, almost all reported genome-wide association studies (GWASs) have been performed on samples of European origin, limiting the applicability of the results to other ethnic populations. In this first GWAS on smoking behavior in an Asian population, after analyzing 8,842 DNA samples from the Korea Association Resource project with 352,228 single nucleotide polymorphisms (SNPs) genotyped for each sample, we identified 8 SNPs significantly associated with smoking initiation (SI) and 4 with nicotine dependence (ND). Because of the current unavailability of an independent Asian smoking sample, we replicated the discoveries in independent samples of European-American and African-American origin. Of the 12 SNPs examined in the replicated samples, we identified two SNPs, in the regulator of G-protein signaling 17 gene (rs7747583, p valuemeta = 6.40 × 10−6; rs2349433, p valuemeta = 5.57 × 10−6), associated with SI. Also, we found two SNPs significantly associated with ND; one in the FERM domain containing 4A (rs4424567, p valuemeta = 2.30 × 10−6) and the other at 7q31.1 (rs848353, p valuemeta = 9.16 × 10−8). These SNPs represent novel targets for examination of smoking behavior and warrant further investigation using independent samples.

DNA methylation profiling in human lung tissue identifies genes associated with COPD

“…FRMD4A is a gene involved in regulation of epithelial cell polarization 30 and a genetic variant in FRMD4A was found to be associated with nicotine dependence. 31 CpG sites in this gene were found to have methylation levels associated with prenatal smoke exposure 32 and were differentially methylated by smoking status in buccal mucosa. 33 Variants in the THSD4 locus have been found to be associated with lung function 34 and, in particular, lung function in severe COPD.…”

Smoking-Associated Site-Specific Differential Methylation in Buccal Mucosa in the COPDGene Study

“…The gene product of FRMD4A is an epidermal stem cell marker (32); genetic polymorphisms at this locus have been associated with nicotine dependence in East Asian populations (33), and a smoking cessation genotype success score (34) in European populations. The product of the PARVA gene is a focal adhesion protein (35); relative hypermethylation at this locus has been reported in the small airway epithelium of smokers (21).…”

The genetics of addiction

“…This special issue also includes the results from a GWAS of nicotine addiction in individuals of Asian descent (Yoon et al 2012). This GWAS identified association with a gene ( FRMD4A ) involved in protein scaffolding that is essential for synaptic plasticity.…”