Many New Genes Linked to Opioid Addiction Through GWAS

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Eighteen new genetic risk factors for opioid use disorder (OUD) and related substance use disorders have been found though a large-scale genome-wide association study. Previously, there was only one gene linked so far to these conditions.

The findings, published in Molecular Psychiatrywere made by a team of Yale scientists.

“Our effort brought in as much genome-wide data as possible. We wanted to compile as many datasets and samples as we could,” said Joseph D. Deak, PhD, postdoctoral fellow in the Yale Department of Psychiatry Division of Human Genetics and the paper’s first author. “We believe our findings have identified genetic risk specific to OUD as well as genetic risk shared more broadly with other kinds of substance use disorders. That is consistent with prior studies that show specific genetic effects for certain drugs along with shared genetic liability for substance use disorders more broadly.”

Drug overdose deaths in the US alone increased by 31% from 2019 to 2020, and opioid use accounts for about 75% of all these deaths. It is expected that this number will rise significantly over the next couple of years.

Not much is known yet about specific genetic risk factors for OUD. As these authors write, “Although opioid misuse and progression to OUD are influenced by heritable factors, discovery of OUD risk loci has been limited. Difficulties in advancing OUD genetic discovery are largely due to lack of adequately powered cohorts of genetically informative samples.”

In this study, researchers carried out a meta-analysis for OUD and then incorporated genetic information from other related substance use disorders.

The researchers analyzed data from over 600,000 participants of European and African genetic ancestry, more information, they say, than prior studies on OUD risk variation. The meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total of 639,063 samples across ancestries.

The scientists identified variation in 19 genes that were associated with OUD risk. OPRM1 and FURIN were two genes identified in the analysis of OUD alone. Additional genes were identified by incorporating information from cannabis and alcohol use disorders.

“OPRM1 is a gene that encodes mu opioid receptors in the brain making it a prime genetic possibility for OUD—prior work showed that variation in this gene influences OUD risk. Our challenge was to move beyond OPRM1,” said Senior author Joel Gelernter, MD, Foundations Fund Professor of Psychiatry and professor of genetics and of neuroscience at Yale.

The findings also reveal genetic connections between the development of OUD and related conditions such as chronic pain, disability, and other psychiatric conditions such as anxiety, depression, and PTSD. “These genetic findings line up with common features often seen in the clinical presentation of individuals diagnosed with OUD. We found that genetic overlap,” Deak said.

Many factors are known to influence the risk of substance use disorders. These authors note their results do not suggest anyone with these specific genetic risk factors should be denied opioids. The search for tests that can predict who has the highest risk of opioid addiction has been longstanding, but has so far not been delivered.

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