Multiple distinct CHRNB3-CHRNA6 variants are genetic risk factors for nicotine dependence in African Americans and European Americans

Abstract

Aims: Studies have shown association between common variants in the α6-β3 nicotinic receptor subunit gene cluster and nicotine dependence in European ancestry populations. We investigate whether this generalizes to African Americans, whether the association is specific to nicotine dependence and whether this region contains additional genetic contributors to nicotine dependence.

Design: We examined consistency of association across studies and race between the α6β3 nicotinic receptor subunit locus and nicotine, alcohol, marijuana and cocaine dependence in three independent studies.

Setting: United States of America.

Participants: European Americans and African Americans from three case-control studies of substance dependence.

Measurements: Subjects were evaluated using the Semi-Structured Assessment for the Genetics of Alcoholism. Nicotine dependence was determined using the Fagerström Test for Nicotine Dependence.

Findings: The single nucleotide polymorphism rs13273442 was associated significantly with nicotine dependence across all three studies in both ancestry groups [odds ratio (OR) = 0.75, P = 5.8 × 10(-4) European Americans; OR = 0.80, P = 0.05 African Americans]. No other substance dependence was associated consistently with this variant in either group. Another SNP in the region, rs4952, remains modestly associated with nicotine dependence in the combined data after conditioning on rs13273442.

Conclusions: The common variant rs13273442 in the CHRNB3-CHNRA6 region is associated significantly with nicotine dependence in European Americans and African Americans across studies recruited for nicotine, alcohol and cocaine dependence. Although these data are modestly powered for other substances, our results provide no evidence that correlates of rs13273442 represent a general substance dependence liability. Additional variants probably account for some of the association of this region to nicotine dependence.

Keywords: African Americans; European Americans; chromosome 8; genetic risk; rs13273442; rs1451240; rs4952; rs6474412; substance dependence.

Figure 1. Comorbidity in the combined COGEND, COGA, and FSCD data

Areas of the circles are proportional to the fraction of the sample dependent on each substance. Alcohol Dependence (38.8% of the subjects), Cocaine Dependence (22.6%), and Marijuana Dependence (17.4%) were defined by DSM-IV criteria. Nicotine Dependence (49.2%) was defined as FTND score > 4. Overlap represents comorbidity. For instance, in these data, most of the subjects who were dependent on cocaine were also dependent on alcohol. In this sample, 34.4% of the individuals were not dependent on any of the 4 substances.