Study with a million-plus subjects finds shared genetic susceptibility to tobacco, alcohol, opioid and cannabis addictions.

A polygenic risk score gauging overall susceptibility to addiction has been developed by Vanderbilt University Medical Center in conjunction with other national research institutions.

The scoring tool draws on data from over a million study participants, a process explained in the publication Nature Mental Health.

Because addictive substances such as alcohol and opioids act similarly in triggering the brain’s reward circuitry, some common genomic variations have been found to increase or decrease overall addiction likelihood. Evidence of risks based on substance-specific sets of genes have also emerged, but these studies raise further questions.

A Common Genetic Basis

“They left this question about whether the genes that increase risk for substance abuse depend on the specific substance or whether there are some genes that increase risk regardless of the exposure,” said study coauthor Lea K. Davis, Ph.D., an associate professor in the Department of Psychiatry and Behavioral Sciences at Vanderbilt University Medical Center.

“And if there is a common vulnerability, does that mean it’s mostly shared or entirely shared – or are there some genetic aspects that are specific to particular substances?”

Genetic susceptibility in general was examined with respect to identifiable risk factors for four substance-use disorders: addiction to alcohol, tobacco, cannabis, and opioids.

Several locations within the human genome were together found to play a significant role in a person’s generalized risk for addiction.

Generalized Risk is Foundational

One set of genetic variations found among risk factors for all four substances was the brain’s response to rewards, Davis said.

“The shared-addiction risk factor we identified reflects the brain’s general reward circuitry – its capacity for responding to rewards and the intensity with which it responds.”

In seeking to identify genetic variations impacting individual substances, they pinpointed 27 substance-specific loci, most related to how the drugs are metabolized.

Overall, a person’s general genetic susceptibility to addiction acts as a foundation, Davis said.

“Built on that foundation are the genetic variations that are responsible for the body’s response to specific substances.”

Associations with Other Disorders

Other health conditions were also tied to the generalized addiction-risk score, including metabolic disorders and behavioral health conditions, including ADHD, known to have some basis in reward biology. Elevated scores also were associated with psychiatric conditions such as self-harming behavior, and physical conditions resulting from or leading to substance use, such chronic airway obstruction or chronic pain, Davis explained.

“We also studied the generalized risk score in drug-naïve young children to get a view of the biology involved in later addiction,” Davis said.

Among 9- and 10-year-olds, higher generalized addiction risk factors were correlated with impulsivity, disruptive behaviors, aggression, thought problems and neighborhood deprivation.

Beyond Individual Substances

“In the last decade or so, we’ve seen a lot of advancement in mapping the individual genetic variation in our genome that increases the likelihood of developing a substance-use disorder when you are exposed to a given substance, such as tobacco, alcohol, or opioids,” Davis said.

Many people try these substances, she pointed out, without developing addictions.

“We’ve learned that there are a lot of genes involved in substance-use disorders, and each of them contributes a small amount to the overall risk,” she said.

In fact, many genes are involved in every complex human health condition, from type 2 diabetes and cardiovascular disease, to depression, schizophrenia and bipolar disorder: each of these has a polygenic profile, she explained.

Davis previously used polygenic risk scores to study the biological roots of depression.

“We think that understanding the biological contributions to one person developing an addiction while another person does not may eventually help us develop better treatments for addictions,” she said.

“What parts of the brain are really susceptible and what are the critical time windows for addictions to develop?”

Using a Complex Modeling Method

The researchers employed a method called genomic structural equation modeling to carry out the work.

“Instead of modeling the relationships between genetic variants and one substance-use disorder at a time, we modeled the relationships between genetic variations and four different substance-use disorders at the same time,” Davis said.

The team reanalyzed existing data from genome-wide association studies from the past decade within a multivariate framework including four substances. The data reflected the experiences of 1,025,550 people with substance-use disorders.

Not for Individual Use

“At the population level, we’ve gained important knowledge about the biology of addiction and how these disorders relate to one another, but when it comes to extrapolating to an individual patient, we’re not there yet,” Davis said.

“There’s still a lot of work to be done to put these findings to work so we can better treat patients with these disorders. We’re really just starting to pave the way in terms of understanding the actual architecture of addiction.”

About the Expert

Lea K. Davis, Ph.D.

Lea K. Davis, Ph.D., is an associate professor of genetic medicine, biomedical informatics, physiology and biophysics and psychiatry and behavioral sciences at Vanderbilt University Medical Center. Her lab focuses on understanding how polygenic risk, rare-variant risk and environmental factors interact to result in complex traits, including psychiatric and endocrine phenotypes.