Art Courtesy of Patricia Joseph.
It is no secret that the genes we inherit from our parents determine simple physical traits such as hair color and height. That comes down to a mixture of certain genes, which include a randomness component related to the allele—or gene variant—we inherit. But when it comes to more complex human features, the connection to our genes is less clear. The impact of genes on behavior like alcohol use or even sexual orientation has long been the subject of scientific debate.
In an article published in the Yale Scientific Magazine in 1929 (Vol. 3 No. 2), Yale Professor R. P. Angier weighed in on this ‘nature vs. nurture’ debate. He questioned if our traits are impacted not only by complex genetic combinations, but also by the environment in which we live. He discussed two major schools of thought: the instinctivists and the environmentalists. The former hold the belief that our instinct, which we inherit and thus have no control over, drives our actions. The environmentalists differ. They believe that only the most basic of actions—like knowing how to swallow or turn one’s head—are inherited, while all other actions are learned through a process of trial and error. Angier himself took a binary approach to this debate, concluding that traits fall into one category or the other. “Alcoholism used to be labeled as a hereditary trait,” he wrote, “No competent medical man thinks so nowadays.”
Since then, the current understanding of genetics and environmental factors has combined these two schools of thought, with alcohol misuse serving as an interesting test case. Both genetics and our environment play a role. “One is not against the other, but rather they both contribute to the predisposition to psychiatric and behavioral traits,” said Renato Polimanti, an associate professor of psychiatry at the Yale School of Medicine. So, how did we come to prove Angier wrong?
The Unique Case of Alcohol Use Disorder
Alcohol use disorder (AUD) is a leading cause of death and disability worldwide and is characterized by frequent and problematic drinking behaviors, such as binge drinking, loss of control, and continued drinking despite harmful consequences. In the 170 years since the term “alcoholism” was first classified as a behavior, problematic drinking has been a widely studied condition to settle the nature versus nurture argument.
Early on, it was believed that alcoholism was inherited. This simple view, however, quickly started to change. By 1929, as Angier wrote, the general view had completely reversed: alcoholism was primarily seen as the result of environmental factors. When AUD was classified as a brain disorder in 1956, as we generally understand it today, this issue took a far more complicated turn.
As it turns out, there is no “alcoholic” gene in the human genome, nor is there an absolute “AUD-causing” environment or situation. Alcoholism has a substantial impact on both mental and physical health and can present different features among affected individuals. Due to this, the mechanisms and possible causes of alcoholism cannot be as easily identified as diseases such as hemophilia, which presents clear physical symptoms. But in the decades since Angier’s article, scientists have made strides in figuring out the mystery of what really underlies this unique disease.
Searching for AUD in Our Genes
In 1990, an initially promising study of the genetic basis of alcoholism was conducted by Kenneth Blum, a professor at the University of Texas Health Science Center. The study found that there was a very strong connection between the D2 dopamine receptor gene and the development of alcoholism or problematic drinking behaviors. In their patient sample, the researchers found that in those with AUD, all had a higher frequency of one specific allele in the dopamine D2 receptor gene, suggesting that it was strongly associated with AUD.
However, one year later, Joel Gelernter, a professor of genetics and neuroscience at the Yale School of Medicine, along with his team could not find the association between the D2 dopamine receptor gene and AUD, showing a lack of replicability in the earlier study.
While the D2 dopamine receptor gene did not have the effect expected on alcoholism, the study contributed to moving forward genetic research. “We know now that it was only a first step of a very long road of complex genetics,” said Renato Polimanti, a colleague of Gelernter at the Yale School of Medicine. In contrast to Angier’s conclusion that AUD is decided by the environment, scientists have since found multiple genetic players.
The effort to uncover the genetic mysteries of AUD was—and is—long from over. Between the D2 dopamine receptor findings in the 1990s and 2020, researchers have identified more than a dozen variants for AUD. In 2020, a research team including Gelernter, Polimanti, and Hang Zhou, an assistant professor of psychiatry at Yale, was able to greatly expand upon previous findings regarding alcoholism through a genome-wide association study published in Nature Neuroscience.
The team was able to identify twenty-nine genes linked to increased risk of problematic alcohol use—nineteen of them novel—in the human genome, extending the known genetic architecture of the disorder and giving other scientists a wider breadth of targets for follow-up studies. Researchers found that six to eleven percent of the phenotypic variation—referring to differences in what physical and behavioral traits are expressed—could be explained by genetic information.
The goal of genetic studies, however, is not only to find associations but also to understand how these variants might promote the development of AUD. In their study, the Yale team discovered that the risk genes were correlated to changes in certain brain regions. This finding suggested to researchers that the risk variants promoted certain brain pathways that contribute to the development of behavior patterns and disorders.
Such pathways are not exclusive to AUD. The researchers discovered a strong genetic correlation between problematic alcohol use and 138 other conditions, including substance abuse disorders, depression, and schizophrenia. “AUD has many variants across the genome that are involved in the predisposition of this trait, but these variants are not only predisposing to AUD, they are predisposing to many things,” Polimanti said. “It can depend on where [risk variants] play a role, maybe in sensitivity to a substance, or to addiction pathways in the brain, or to reward systems.”
This research does not mean AUD is solely explained by genetics. Rather, in AUD, only about fifty percent of the risk appears to be attributed to our genes. This is relatively small in comparison to schizophrenia, where genetics can explain eighty percent of the disease predisposition. Therefore, as research progresses, consideration must still be made for the environment—the “nurture”—that individuals were raised and live in. “Genetic variants among individuals cannot explain everything. We need to spend more time in gene discovery before bringing it into patient care,” Zhou said.
Beyond addressing the nature versus nurture debate, this research has a broader aim. According to Polimanti and Zhou, geneticists hope to be able to bring their findings to human healthcare in order to help predict and treat certain illnesses. This is called precision medicine, wherein a person’s treatment plan can be specially tailored based on their unique genetic makeup.
Until we get there, research will continue focusing on identifying genetic variants and possible mechanisms behind risk. Polimanti explained that for certain illnesses like cardiovascular disease, the field of genetics is expected to transform treatments in the coming years. “We will keep doing gene discovery and use increasingly advanced technology to deliver this information and get a deeper understanding of the role genetics play in human health,” Zhou said.
The study of AUD has been marked by both successes and failures. Now, we enter an exciting time where genetic and environmental studies promise great strides for the understanding of our human genome and real changes in clinical care. Nature and nurture, instinctivists and environmentalists, the D2 dopamine receptor and twenty-nine other discovered genes, and, now, precision medicine, are all important themes in the long and evolving story of alcoholism and scientific discovery.