Unraveling the complex genetics behind alcohol, cigarette and substance addiction

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 help themselves to abuse alcohol and others can take it or leave it? One of the reasons is a person’s genetic tendency 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 can develop therapies to help the millions of people struggling with addiction.

Won, assistant professor of genetics and member of the UNC Neuroscience Center, and colleagues identified genes associated with smoking and drinking cigarettes. The researchers found that these genes are overrepresented in certain types of neurons — brain cells that prompt other cells to send chemical signals through the brain.

The researchers, who their work published in the news Molecular Psychiatry, also found that the genes underlying cigarette smoking are linked to the perception of pain and response to food, as well as the abuse of other drugs, such as cocaine. Other genes linked to alcohol use were linked to stress and learning, as well as 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 substance abuse,” said first author Nancy Sey, a graduate student in the Won lab. “And we believe our research provides a good foundation for research aimed at creating better treatments to tackle drug addiction.”

parsing the genome

Long-term substance use and substance use disorders have been linked to common diseases and conditions, such as lung cancer, liver disease, and mental illness. Still, 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 problems 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 heavy drinking.”

Through GWAS, Won added, researchers can identify regions in the genome that play a role in certain traits, compared to individuals that don’t exhibit the trait. Still, genome-wide studies can’t tell us much about how genes in those regions influence a trait. That’s because these regions are often in “noncoding” regions of the genome.

“Noncoding” refers to the fact that the genes in these regions do not directly translate – or encode – their genetic information into the production of proteins, which then perform a known biological function. Therefore, what actually happens biologically in these “noncoding” regions remains largely unknown.

“We wanted to know what’s happening in these regions,” Won said. “So we developed Hi-C-linked MAGMA (H-MAGMA), a computational tool to help us better understand what we see in genome-wide studies.”

In a previous publicationWon’s lab showed how applying H-MAGMA to brain disorders identifies associated genes and described their underlying biology. And for this current paper, her lab expanded the tool to include smoking and drinking cigarettes.

They developed H-MAGMA frameworks of dopaminergic neurons and cortical neurons — brain cell types that researchers have long implicated in substance use. Focusing on those two cell types, Won’s team – led by Sey, and HHMI Gilliam Fellow – H-MAGMA applied to GWAS findings related to heavy smoking, nicotine dependence, problematic alcohol use and heavy drinking to identify genes associated with each trait.

Genes associated with alcohol consumption and cigarette smoking were also associated with other types of substances, such as morphine and cocaine. Although the opioid crisis has created an adverse social burden, potent GWAS for cocaine and opioid use are not currently available. Won’s team therefore sought to determine whether the genes linked to alcohol use and cigarette smoking could reveal the genetics underlying general addiction behavior, genetic findings that could be extended to other means of abuse.

“Our analyzes showed that the expression of genes shared between cigarette smoking and alcohol use can be altered by other types of substances such as cocaine,” Won said. “By characterizing the biological function of these genes, we can identify the biological mechanisms underlying addiction, which can be generalized to various forms of substance use disorders.”

In addition to the different types of excitatory neurons, Won’s team also identified additional cell types, including cortical glutamatergic, midbrain dopaminergic, GABAergic and serotonergic neurons associated with the risk genes.

With these findings in hand, it is now possible for the UNC researchers and others to investigate molecules that make addiction much less likely.

Reference: Sey NYA, Hu B, Iskhakova M, et al. Chromatin architecture in addiction circuitry identifies risk genes and potential biological mechanisms underlying cigarette smoking and alcohol use. Mol Psychiatry. 2022;27(7):3085-3094. bye: 10.1038/s41380-022-01558-y

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