YSM Issue 96.4

Medicine
FOCUS
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.
www.yalescientific.org
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 followup
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.”
Moving Forward
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
ABOUT THE
AUTHORS
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. ■
MATTHEW BLAIR
LEA PAPA
MATTHEW BLAIR is a sophomore in Benjamin Franklin College from Manchester, NH, majoring in
the History of Science, Medicine, and Public Health. In addition to copy editing for YSM, Matthew
conducts lung cancer research in the Schalper Lab at the Yale School of Medicine and plays for the
club ice hockey team.
LEA PAPA is a sophomore in Ezra Stiles College from South Milwaukee, WI, studying neuroscience.
Outside of YSM, Lea is involved in Yale’s Questbridge Chapter, is working towards becoming an EMT,
and recently joined the Yale Undergraduate Research Journal Humanities Committee.
THE AUTHORS WOULD LIKE TO THANK Renato Polimanti and Hang Zhou for their time and expertise.
December 2023 Yale Scientific Magazine 15