Can Your Genes Determine How Much You Smoke?

Key Findings:

• Rare variants in CHRNB3 gene linked to reduced cigarette consumption
• Discovery made across three diverse population cohorts
• Carriers of specific variants smoked up to 78% fewer cigarettes
• Research highlights importance of studying diverse genetic backgrounds

The CHRNB3 gene encodes the β3 subunit of the nicotinic acetylcholine receptor, a key component in how nicotine affects the brain.

"We're interested in these protective genetic changes because they show us how some people naturally resist addiction, offering insights into the biological targets that influence smoking patterns," said Giovanni Coppola, PhD, Vice President, RGC. "The approach of developing therapies that mimic naturally occurring protective genetic variants, has already worked in other areas, like with cholesterol-lowering medications that were developed after scientists found people with genetic changes that naturally kept their cholesterol levels low."

How do shared genetic patterns strengthen this discovery?

What makes this finding so compelling is that we observed it independently across three different population cohorts – the Mexico City Prospective Study (MCPS) with Indigenous Mexican participants, the Biobank Japan with East Asian participants, and the UK Biobank with European participants – all showing remarkably similar effect sizes.

"The fact that three completely different variants — one enriched in Indigenous Mexicans, one in East Asians, and an aggregate signal in Europeans — all point to the same gene and produce remarkably similar effect sizes is, in our view, one of the strongest aspects of this study," explained Giovanni. "In genetics, when nature independently arrives at the same answer across a variety of populations, it strongly suggests you have identified something biologically fundamental rather than a statistical artifact."

In the MCPS, carriers of the Indigenous Mexican variant smoked on average about 21% fewer cigarettes per day compared to non-carriers. Even more striking, individuals who carried two copies of the variant — essentially a natural knockout of the gene — smoked approximately 78% fewer cigarettes per day.

"Several key questions remain, such as understanding the gene's mechanism in influencing smoking and its other roles in the brain."

Smoking addiction is a complex behavioral trait influenced by numerous biological, psychological, and social factors, making it challenging to address with a single therapeutic approach. Although existing treatments demonstrate reasonable efficacy, the field has experienced minimal innovation over the past two decades. A fundamental challenge has been identifying new, robust biological targets that may be able to be mimicked or targeted with therapies. Human genetics can offer a potential breakthrough path, by identifying individuals naturally protected from heavy smoking due to their genetic makeup, we can pinpoint precise biological mechanisms that may be worth targeting, exactly as demonstrated in our CHRNB3 study.

Why does genetic diversity matter in research?

Population diversity has always been a cornerstone of RGC's research strategy. This rare variant discovery underscores the critical importance of studying diverse ancestries.

"This study is a testament to the value of studying representative populations in genomic research," added Giovanni. "The key discovery—the p.Glu284Gly variant—exists almost exclusively in people of Indigenous Mexican ancestry. Had we only studied Europeans, as most genomic studies historically have, we would have missed it entirely. Representative research is not just an ethical imperative, it is a scientific one."