Genetic architecture underlying alcohol and tobacco use

Have you ever questioned why some people can smoke cigarettes for a year before quitting simply, but others develop a lifelong addiction? Why are some people unable to stop consuming alcohol while others can do without it? A person's hereditary propensity to take drugs is one factor. Researchers at the UNC School of Medicine under the direction of Hyejung Won, PhD, are starting to comprehend these underlying genetic variations. The more they discover, the more likely it is that scientists can develop therapies to aid the millions of people who battle addiction.

Won, an assistant professor of genetics and a researcher at the UNC Neuroscience Center, and his team discovered genes connected to drinking alcohol and smoking cigarettes. The scientists discovered that certain types of neurons--brain cells that cause other cells to send chemical messages across the brain--have an excess of these genes.

The researchers, whose findings were published in the journal Molecular Psychiatry, also discovered that the genes associated with smoking were connected to the sensation of pain and how the body reacts to food, in addition to the consumption of other drugs like cocaine. Stress, learning, and the consumption of other drugs like morphine were also connected to other genes associated with alcohol use.

The researchers also performed assessments of a publicly accessible pharmacological database to find potential novel treatments for substance abuse because there are currently few alternatives for treating substance use disorder.

According to Nancy Sey, a graduate student in the Won lab and the paper's first author, "we discovered that antipsychotics and other mood stabilisers may be able to offer therapeutic treatment for people who are battling with substance misuse."

And we're certain that our research will serve as a solid platform for studies aimed at developing more effective drug addiction treatments.

Numerous prevalent illnesses and problems, including lung cancer, liver disease, and mental illnesses, have been related to long-term substance use and substance use disorders. However, there aren't many therapy choices, largely because we don't fully understand the underlying molecular mechanisms.

According to Won, "twin studies have shown that, in addition to contextual factors like family dynamics or personal trauma, genetics may also play a role in why certain people use and abuse drugs."

Won said that by comparing individuals who exhibit a trait against those who do not, researchers can use GWAS to pinpoint specific regions in the genome that contribute to that feature. However, genome-wide research cannot provide much insight into how the genes in those areas influence a trait. This is because these areas are frequently found in the genome's "non-coding" regions.

The term "non-coding" describes how the genes in these areas do not immediately transfer - or "code" - their genetic information into the production of proteins, which then carry out a recognised biological function. Therefore, it is still largely unknown what biological processes take place in these "non-coding" areas.

We wanted to find out what was going on in these areas, Won said. We, therefore, created Hi-C coupled MAGMA (H-MAGMA), a computational tool, to aid in our efforts to better understand the results of our genome-wide research.

In a previous study, Won's lab demonstrated how using H-MAGMA to study brain illnesses might reveal the genes that are connected with them as well as their underlying biology. Her lab also expanded the tool to include drinking alcohol and smoking cigarettes for this particular paper.

They created H-MAGMA frameworks from cortical neurons and dopaminergic neurons, two classes of brain cells that have been linked to substance abuse for a long time. Won's team, led by Sey, an HHMI Gilliam Fellow, focused on those two cell types and used H-MAGMA to analyse GWAS results related to heavy drinking, heavy smoking, nicotine dependence, and problematic alcohol use to determine the genes responsible for each feature.

Genes linked to alcohol consumption and cigarette smoking were also linked to genes for cocaine and morphine usage. Although the opioid epidemic has had a negative social impact, there are currently no well-powered GWAS on cocaine and opioid usage. Therefore, Won's team investigated if the genes linked to alcohol consumption and cigarette smoking can provide insight into the genetics that underlie general addiction behaviour, and genetic discoveries that could be generalised to other addictive drugs.

Our investigations revealed that other substances, such as cocaine, can affect the expression of genes associated with features related to cigarette smoking and alcohol use, according to Won. We will be able to determine the basic mechanisms behind addiction by describing the biological function of these genes, which might be generalised to different types of substance use disorders.

Won's team also discovered other cell types, such as cortical glutamatergic, midbrain dopaminergic, GABAergic, and serotonergic neurons that are connected to the risk genes, in addition to the various types of excitatory neurons.

With these results in hand, UNC researchers and others can now look into chemicals that greatly reduce the likelihood of addiction.