Revealing the genetic architecture underlying substance abuse

Monday, 22 August, 2022

Revealing the genetic architecture underlying substance abuse

Why is it that some people can’t help themselves from abusing alcohol and others can take it or leave it? One reason is a person’s genetic proclivity to abuse substances.

Researchers from the University of North Carolina at Chapel Hill (UNC), led by Dr Hyejung Won, are now beginning to understand these underlying genetic differences — and the more they learn, the better chance they will be able to create therapies to help the millions of people who struggle with addiction.

“We know from twin studies that genetics may account for why some people use and abuse substances, aside from environmental factors such as family issues or personal trauma,” said Won, an assistant professor of genetics and member of the UNC Neuroscience Center. “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 drinking heavily.”

Through GWAS, Won said, researchers can identify regions in the genome that play roles in particular traits. Yet genome-wide studies cannot tell us much about how genes in those regions affect a trait, because these regions are often 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, so what actually happens biologically in these regions remains mostly unknown.

“We wanted to learn what’s happening in these regions,” Won said. “So we developed Hi-C coupled MAGMA (H-MAGMA), a computational tool to help us make more sense of what we’re seeing in genome-wide studies.”

Won’s lab has previously shown how applying H-MAGMA to brain disorders identifies their associated genes and described their underlying biology. For their current study, published in the journal Molecular Psychiatry, they expanded the tool to cigarette smoking and drinking.

The team developed H-MAGMA frameworks from dopaminergic neurons and cortical neurons — brain cell types that researchers have long implicated in substance use. Focusing on those two cell types, they applied H-MAGMA to GWAS findings related to heaviness of smoking, nicotine dependence, problematic alcohol use and heaviness of drinking to identify genes associated with each trait.

The colleagues identified genes linked to cigarette smoking and drinking, and sought to determine whether these could reveal the genetics underlying general addiction behaviour and be extended to other substances of abuse. They found that the genes underlying cigarette smoking were linked to the perception of pain 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 abuse of drugs such as morphine.

“Our analyses showed that expression of genes shared between cigarette smoking and alcohol use traits can be altered by other types of substances such as cocaine,” Won said. “By characterising the biological function of these genes, we will be able to identify the biological mechanisms underlying addiction, which could be generalised to various forms of substance use disorder.”

In addition to various types of excitatory neurons, Won’s team also identified additional cell types, including cortical glutamatergic, midbrain dopaminergic, GABAergic and serotonergic neurons, that are associated with the risk genes. The researchers also conducted analyses of a publicly available drug database to identify potential new treatments for substance abuse.

“We found that antipsychotics and other mood stabilisers could potentially provide therapeutic relief for individuals struggling with substance abuse,” said first author Nancy Sey, a graduate student in the Won lab. “And we’re confident our research provides a good foundation for research focused on creating better treatments to address drug dependency.”

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