A rare missense mutation in CHRNA4 associates with smoking behavior and its consequences

Abstract

Using Icelandic whole-genome sequence data and an imputation approach we searched for rare sequence variants in CHRNA4 and tested them for association with nicotine dependence. We show that carriers of a rare missense variant (allele frequency=0.24%) within CHRNA4, encoding an R336C substitution, have greater risk of nicotine addiction than non-carriers as assessed by the Fagerstrom Test for Nicotine Dependence (P=1.2 × 10−4). The variant also confers risk of several serious smoking-related diseases previously shown to be associated with the D398N substitution in CHRNA5. We observed odds ratios (ORs) of 1.7–2.3 for lung cancer (LC; P=4.0 × 10−4), chronic obstructive pulmonary disease (COPD; P=9.3 × 10−4), peripheral artery disease (PAD; P=0.090) and abdominal aortic aneurysms (AAAs; P=0.12), and the variant associates strongly with the early-onset forms of LC (OR=4.49, P=2.2 × 10−4), COPD (OR=3.22, P=2.9 × 10−4), PAD (OR=3.47, P=9.2 × 10−3) and AAA (OR=6.44, P=6.3 × 10−3). Joint analysis of the four smoking-related diseases reveals significant association (P=6.8 × 10−5), particularly for early-onset cases (P=2.1 × 10−7). Our results are in agreement with functional studies showing that the human α4β2 isoform of the channel containing R336C has less sensitivity for its agonists than the wild-type form following nicotine incubation.

Genome-wide association study across European and African American ancestries identifies a SNP in DNMT3B contributing to nicotine dependence

“… 23 Rare CHRNA4 variants have also been found to associate with nicotine dependence. 67 , 68 Our study supported common CHRNA4 SNP associations among EUR samples, but no association was detected for these SNPs among AA studies ( Table 1 ).…”

Sequence variants in ARHGAP15, COLQ and FAM155A associate with diverticular disease and diverticulitis

“…We found that heavy smokers ( N =26,113, >10 pack-years)3839 have higher risk of developing diverticular disease than never smokers ( N =22,815) (Supplementary Methods), with relative risk=1.35; 95% CI: 1.21–1.51, P =1.11 × 10 −7 (adjusted for sex and age). However, smoking showed no interaction with the effect of any of the three diverticular disease variants.…”

Neuropeptide systems and new treatments for nicotine addiction

“…Some of the first GWA studies showed that variations in the sequence of α3, α5, and β4 nAChR subunit genes affects the risk for developing and maintaining a nicotine addiction (Berrettini et al 2008; Chen et al 2009; Liu et al 2010; Wen et al 2016). More recent genetic studies revealed that variability in the α4 nAChR subunit gene affects the risk for developing nicotine addiction in humans (Hancock et al 2015; Thorgeirsson et al 2016). …”