Rare, low frequency and common coding variants in CHRNA5 and their contribution to nicotine dependence in European and African Americans

Abstract

The common nonsynonymous variant rs16969968 in the α5 nicotinic receptor subunit gene (CHRNA5) is the strongest genetic risk factor for nicotine dependence in European Americans and contributes to risk in African Americans. To comprehensively examine whether other CHRNA5 coding variation influences nicotine dependence risk, we performed targeted sequencing on 1582 nicotine dependent cases (Fagerström Test for Nicotine Dependence score≥4) and 1238 non-dependent controls, with independent replication of common and low frequency variants using 12 studies with exome chip data. Nicotine dependence was examined using logistic regression with individual common variants (MAF≥0.05), aggregate low frequency variants (0.05>MAF≥0.005), and aggregate rare variants (MAF<0.005). Meta-analysis of primary results was performed with replication studies containing 12 174 heavy and 11 290 light smokers. Next-generation sequencing with 180X coverage identified 24 nonsynonymous variants and 2 frameshift deletions in CHRNA5, including 9 novel variants in the 2820 subjects. Meta-analysis confirmed the risk effect of the only common variant (rs16969968, European ancestry: OR=1.3, p=3.5×10−11; African ancestry: OR=1.3, p=0.01) and demonstrated that 3 low frequency variants contributed an independent risk (aggregate term, European ancestry: OR=1.3, p=0.005; African ancestry: OR=1.4, p=0.0006). The remaining 22 rare coding variants were associated with increased risk of nicotine dependence in the European American primary sample (OR=12.9, p=0.01) and in the same risk direction in African Americans (OR=1.5, p=0.37). Our results indicate that common, low frequency and rare CHRNA5 coding variants are independently associated with nicotine dependence risk. These newly identified variants likely influence risk for smoking-related diseases such as lung cancer.

Genome-wide association study confirms lung cancer susceptibility loci on chromosomes 5p15 and 15q25 in an African-American population

“…In 2012, a large meta-analysis in African American smokers showed a significant association between rs2036527 and self-reported CPD, but not between rs16969968 CPD [56]. However, a more recent meta-analysis showed rs16969968 is associated with increased risk for nicotine dependence in European and African Americans and provided evidence that the A allele increases risk for heavy smoking [64]. In another study, rs16969968 was not found to be consistently associated with smoking abstinence in African Americans; whereas rs2036527 was associated with active pharmacotherapy [65].…”

Neurobiology of addiction: a neurocircuitry analysis

“…153 In humans, only a few specific genes have been identified with polymorphisms (alleles) that either predispose an individual to or protect an individual from drug addiction, 156 but the number is growing. For example, genome-wide association studies have implicated two acetylcholine receptors, the α4 nicotinic receptor subunit 157 and α5 nicotinic receptor subunit, 158 in the vulnerability to nicotine dependence and a single-nucleotide polymorphism associated with regulating the trafficking and gating properties of AMPA-selective glutamate receptors ( CNIH3 ) in opioid dependence. 159 …”

Genome-wide single nucleotide polymorphism heritability of nicotine dependence as a multidimensional phenotype

“…Future studies with larger samples are needed to replicate these findings and to confirm the observed effects on individual symptoms of the DSM-IV and FTND scales. It should also be noted that the current findings are limited to common genetic variants; however, recent findings implicate a possible role for rare variants (Olfson et al , 2015, Vrieze et al , 2014), suggesting the need for future whole-genome studies incorporating common and rare polymorphisms. Readers should also consider that SAGE is a selected sample of individuals (i.e., drug addicted cases and controls).…”