Rare coding variants in CHRNB2 reduce the likelihood of smoking

Area of Science:

• Genetics
• Neuroscience
• Pharmacology

Background:

• Human genetic studies on smoking behavior have primarily focused on common variants.
• Investigating rare coding variants offers potential for identifying novel drug targets for smoking cessation.

Purpose of the Study:

• To conduct an exome-wide association study (EWAS) to identify genetic factors influencing smoking behavior.
• To explore the role of rare variants in CHRNB2, encoding the beta-2 subunit of the alpha4beta2 nicotinic acetylcholine receptor, in smoking phenotypes.

Main Methods:

• Performed an exome-wide association study (EWAS) on smoking phenotypes in a large cohort of up to 749,459 individuals.
• Analyzed rare predicted loss-of-function and likely deleterious missense variants in CHRNB2.
• Investigated an independent common variant association (rs2072659) in the same gene.

Main Results:

• Discovered a significant protective association between rare CHRNB2 variants and heavy smoking (OR=0.65, P=1.9×10⁻⁸).
• Aggregate rare variants in CHRNB2 were associated with a 35% decreased odds of heavy smoking.
• Identified an independent common variant association in CHRNB2 in the protective direction (rs2072659, OR=0.96, P=5.3×10⁻⁶), suggesting an allelic series.

Conclusions:

• Genetic findings in humans corroborate decades-old experimental observations in mice regarding the role of the beta-2 subunit in nicotine response.
• The genetic discovery highlights CHRNB2 as a promising target for developing new pharmacological treatments for nicotine addiction.
• Future drug design efforts should consider targeting CHRNB2 in the brain for smoking cessation therapies.