The Genetics of Being a Drinking Lightweight

When friends ask me to join them at a brewery, they know I won’t finish even half a beer. It’s not that I don’t like the taste, it’s that I get a significant buzz after that amount—more and the room starts to spin. Meanwhile, they down an entire flight and feel great.

It turns out my status as an alcohol lightweight is likely dictated by my genes. Scientists have long known that excessive alcohol consumption has a strong hereditary component. But in recent years they’ve clarified some of the many genes involved across the body and how some of these genetic pathways influence the brain in particular.

The research has important implications for why some people are prone to developing alcohol use disorder—the medical term for alcohol addiction or alcoholism—while others are seemingly immune. Genes comprise roughly half of someone’s risk for the condition, twin studies have shown, “which makes it remarkable how much blame and shame we put on people who have addictions,” says Stephen Holt, an addiction medicine specialist at the Yale School of Medicine.

As the contributions of specific genes are better understood, new drug targets can be developed to combat them.

This clearer understanding of the genetics of drinking comes at a time when studies are showing that alcohol can be harmful even in moderate amounts. By contrast, people genetically predisposed to resist alcohol’s siren call also tend to have better overall health, suggesting that the benefits of carrying some of these genes may extend beyond drinking less.

(Here’s how even occasional binge drinking can have big health consequences.)

Back in the 1980s, scientists found that people with a family history of alcohol abuse whose motor effects are delayed after drinking can consume significant amounts, increasing their own risk of abuse. That makes sense, because someone who has a beer and can barely walk has less enticement to drink than with someone who feels great, says David Rossi, a neuroscientist and alcohol researcher at Washington State University.

Soon after the first sip, alcohol begins infiltrating everyone’s brain through their blood at similar rates. Our differing reactions, then, come down to “whether and how the cells respond to it,” and genes play a significant role in those reactions, says Rossi. More than a hundred genes are thought to be involved with this process, and researchers are still trying to figure out how each impacts the brain—for now, mostly with animal studies.

Last year, researchers studying zebrafish found that one gene called CHRNA3 may be a major regulator of alcohol sensitivity. One of several so-called nicotinic acetylcholine receptor genes, it had been linked in population studies to substance abuse.

The researchers placed fish in a special tank whose water was laced with alcohol, and they soon began experiencing its relaxing effects. After a while, though, fish with normal CHRNA3 genes opted to leave for a plain-water tank. But those with the mutation experienced alcohol’s effects more slowly and imbibed longer.

Those fish “did not seem to get the same warning signals telling them to stop,” says Ajay Mathuru, a neuroscientist at National University of Singapore who conducted the research. Instead, the study notes, they acted “gregarious” as they swam around.

The research involved laboratory animals, but “if something similar happens in humans, certain versions of this gene could mean that a person feels less affected by the same drink and therefore may drink more to reach an effect that others feel more quickly,” Mathuru says.

It turns out the cerebellum, located in the lower back of the head, is a prime location for this type of response. The area has long been linked to motor control, which is why police test sobriety by asking someone to touch their nose or walk a straight line. But through genetic analyses and other work, scientists have come to see it does far more.

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Around a decade ago, rodent studies in Rossi’s lab revealed the genetic influence behind the cerebellum’s response to alcohol. The research involved two types of inbred mice: one with lower alcohol tolerance, the other with higher tolerance.

When the low-tolerant mice consumed alcohol, signals in certain cerebellar neurons were dampened, accelerating coordination problems. But when heavy drinking mice consumed alcohol, the same cells were instead excited, potentially increasing pleasure. Their varying genes influenced which reaction occurred.

The findings highlighted the complexity of the genetic interplay when cerebellar neurons are exposed to alcohol. Rossi’s team is now working to identify the exact genes involved—likely 10 or more—and how the process may be similar in humans. Such identification could pinpoint targets for future substance abuse treatments that turn off the rock star feeling some people experience after drinking, Holt says.

Beyond the brain, another set of genes determines how much someone can drink before experiencing the negative physical reactions that result from alcohol’s breakdown in the liver. The first step in this metabolism process produces the byproduct acetaldehyde, which is toxic to many cells. When enough acetaldehyde circulates in the blood, people feel nauseated or dizzy, their skin flushes, or their mood descends. (Eventually, the chemical further metabolizes into harmless acetate before the body excretes it.)

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It’s long been clear that variants of the genes ALDH2 or ADH1B speed up the initial breakdown, in some people after just a few sips. The variant is more common in people of Japanese, Korean, and Chinese descent, who are therefore less likely to develop an alcohol use disorder. A similar, albeit less intensive reaction, is found in some Ashkenazi Jews.

“You basically end up with a smaller window between what feels good and what feels bad,” says Susan Luczak, a psychologist who has studied these genes at the University of Southern California. “A single genetic mutation here can have a really strong functional difference.”

Alcohol-specific genes, of course, don’t tell the entire story. People who carry other genes predisposing them to post-traumatic stress disorder or to social anxiety may also be prone to increased drinking.

Social factors, such as participating in a fraternity or sorority in college, can also override our genetic predispositions. For example, even when Asian American college students have the problematic version of ALDH2 allele, they may still increase their drinking during their time in school, and some develop alcohol use disorder in adulthood.

“It’s not just the genes, but the additive effects of the environment,” Luczak says.

Other environmental factors instead protect people from alcohol misuse, regardless of their genetic tendencies. Having a strong friend group can do this, researchers have found, perhaps because this mitigates the loneliness that causes some to reach for a bottle.

Clearly, the process is more complex than simply, saying “addiction is in your genes,” Mathuru says. Certain genetic variants “can make some individuals more vulnerable by muting the body’s natural warning signals, while environment and circumstance shape the rest.”

As for me, my genes, whatever variations they might hold, generally keep me from over-imbibing. They also save me a lot of money.