Have you ever wondered why one person can smoke cigarettes for a year and quit easily, while another person becomes addicted for life? Why can’t some people stop abusing alcohol and others can take it or leave it? One of the reasons is a person’s genetic propensity to abuse substances. UNC School of Medicine researchers led by Hyejung Won, PhD, are beginning to understand these underlying genetic differences. The more they learn, the more likely they are to be able to create therapies to help the millions of people struggling with addiction.
Won, an assistant professor of genetics and a member of the UNC Neuroscience Center, and his colleagues have identified genes linked to smoking and alcohol consumption. The researchers found that these genes are overrepresented in certain types of neurons, brain cells that trigger other cells to send chemical signals throughout the brain.
The researchers, who published their work in the journal Molecular psychiatry, also found that the genes underlying smoking were linked to pain perception and response to food, as well as the abuse of other drugs, such as cocaine. Other genes associated with alcohol use were linked to stress and learning, as well as the abuse of other drugs, such as morphine.
Given the lack of current treatment options for substance use disorders, the researchers also conducted analyzes of a publicly available drug database to identify potential new treatments for substance abuse. .
“We found that antipsychotics and other mood stabilizers could potentially provide therapeutic relief for people struggling with addiction,” said Nancy Sey, graduate student at the Won Lab and first author of the paper. “And we believe our research provides a good foundation for research focused on creating better treatments for drug addiction.”
Analyze the genome
Long-term substance use and substance use disorders have been linked to many common diseases and conditions, such as lung cancer, liver disease, and mental illness. Yet few treatment options are available, largely due to gaps in our understanding of the biological processes involved.
“We know from twin studies that genetics may explain why some people use and abuse substances, aside from environmental factors, such as family issues or personal trauma,” Won said. “Genetic studies such as genome-wide association studies (GWAS) provide a way to identify genes associated with complex human traits, such as nicotine addiction or excessive alcohol consumption. “
Using GWAS, Won added, researchers can identify regions of the genome that play a role in particular traits, compared to individuals who don’t exhibit the trait. Yet genome-wide studies can’t tell us much about how genes in these regions affect a trait. This is because these regions are often found in “non-coding” regions of the genome.
“Non-coding” refers to the fact that the genes in these regions do not translate – or code – their genetic information directly into the creation of proteins, which then perform a known biological function. Therefore, what is actually happening biologically in these “non-coding” regions remains mostly unknown.
“We wanted to know what was going on in those areas,” Won said. “So we developed Hi-C coupled MAGMA (H-MAGMA), a computational tool to help us better understand what we see in genome-scale studies.”
In a previous publication, Won’s lab showed how applying H-MAGMA to brain disorders identifies their associated genes and describes their underlying biology. And for this current paper, his lab extended the tool to smoking and alcohol consumption.
They developed H-MAGMA frameworks from dopaminergic neurons and cortical neurons – types of brain cells that researchers have long implicated in substance use. Focusing on these two cell types, Won’s team – led by Sey, an HHMI Gilliam Fellow – applied H-MAGMA to GWAS findings related to heavy smoking, nicotine addiction, problematic drinking and heavy drinking to identify genes associated with each trait.
Genes associated with alcohol consumption and smoking were also associated with other types of substances, such as morphine and cocaine. While the opioid crisis has caused a detrimental social burden, potent GWAS on cocaine and opioid use are not currently available. Won’s team therefore set out to determine whether genes associated with alcohol consumption and smoking may reveal the genetics underlying general addictive behavior, genetic findings that could be extended to other substances of abuse. abuse.
“Our analyzes showed that the expression of genes shared between smoking and drinking traits can be altered by other types of substances such as cocaine,” Won said. “By characterizing the biological function of these genes, we will be able to identify the biological mechanisms underlying addiction, which could be generalized to various forms of substance use disorders.”
In addition to the different types of excitatory neurons, Won’s team also identified other cell types, including cortical glutamatergic, midbrain dopaminergic, GABAergic, and serotonergic neurons associated with risk genes.
With these discoveries in hand, it is now possible for researchers at UNC and others to study the molecules that make addiction much less likely.
This research was supported by grants from the National Institute on Drug Abuse (R21DA051921, U01DA048279); the National Institute of Mental Health (R00MH113823, DP2MH122403); the NARSAD Young Investigator Award from the Brain and Behavior Research Foundation; the National Science Foundation Graduate Fellowship Program (DGE-1650116); the University of North Carolina at Chapel Hill; Howard Hughes Medical Institute James H. Gilliam Fellowship for Advanced Study Program; and the National Institute of General Medical Sciences (5T32GM067553).