Rare coding variants in CHRNB3 associate with reduced daily cigarette smoking across ancestries

Area of Science:

• Genetics
• Neuroscience
• Pharmacology

Background:

• Rare genetic variants can identify drug targets for beneficial health effects.
• CHRNB3 encodes the β3 subunit of nicotinic acetylcholine receptors, which are involved in nicotine's action in the brain.

Purpose of the Study:

• To investigate the association between rare coding variants in CHRNB3 and daily cigarette consumption.
• To explore CHRNB3 as a potential therapeutic target for nicotine addiction.

Main Methods:

• Exome-wide association study of daily cigarette consumption in 37,897 smokers from the Mexico City Prospective Study.
• Analysis of CHRNB3 variants in independent cohorts from Japan Biobank and UK Biobank.

Main Results:

• A deleterious missense variant (p.Glu284Gly) in CHRNB3 associated with reduced cigarette consumption in Indigenous Mexican ancestry individuals.
• A predicted loss-of-function variant in CHRNB3 associated with reduced smoking in East Asian ancestry individuals (Japan Biobank).
• Rare deleterious and loss-of-function variants in CHRNB3 collectively associated with reduced smoking in European ancestry individuals (UK Biobank).

Conclusions:

• Loss of function in CHRNB3 is significantly associated with reduced daily cigarette smoking.
• Inhibition of the β3 nicotinic acetylcholine receptor subunit presents a potential therapeutic strategy for nicotine addiction.