Single OPRM1 Gene Variant Tied to Risk of Opioid Use Disorder

By Marilynn Larkin

June 12, 2020

NEW YORK (Reuters Health) - A single variant in the OPRM1 gene, the main target for opioid drugs, was significantly associated with opioid use disorder (OUD) in a genome-wide association study.

"These findings don't have immediate clinical relevance," Dr. Joel Gelernter of the Veterans Affairs Connecticut Healthcare System in West Haven told Reuters Health by email. "We identified only one significant risk locus. This reflects the limited power of the study compared to others where more loci have been identified - for example, our problematic alcohol use genome-wide association study (GWAS) that came out in Nature Neuroscience identified 29 risk loci.( We need more OUD subjects to study!"

"That said," he noted, "this is the first GWAS study of OUD that was large enough to permit us to perform substantial post-GWAS analyses: to look at the SNP heritability of OUD; to look at genetic correlations with other genetic traits; etc. In so doing, we showed that if we can put together a decent-sized sample to study, we can start to account for the genetic basis of OUD in (we think) a believable way."

Future studies will incorporate our results by meta-analysis to obtain better power and map more risk genes," he added.

The team's GWAS of electronic health record-defined OUD included close to 115,000 individuals (mean age, 60; 88% men) from two large U.S. databases: 10,544 OUD cases among European-American individuals, plus 72,163 opioid-exposed controls; and 5,212 African-American cases and 26,876 controls.

As reported in JAMA Psychiatry, among the European-American individuals, a functional coding variant (rs1799971, encoding Asn40Asp) in OPRM1 - the mu-opioid receptor gene, the main biological target for opioid drugs (OMIM 600018) - reached genome-wide significance.

The finding was replicated in two independent samples, and the mean single-nucleotide polymorphism (SNP)-based heritability of OUD was 11.3%.

Further, OUD was genetically correlated with 83 traits, including multiple substance use traits, psychiatric illnesses, cognitive performance, risk-taking behavior, insomnia, and others.

Mendelian randomization analysis revealed multiple associations with OUD: risk of tobacco smoking, depression, neuroticism, worry neuroticism subcluster, and cognitive performance.

By contrast, no genome-wide significant association was detected for African-American individuals or in transpopulation meta-analysis.

The authors state, "Recruitment of additional individuals with OUD for future studies - especially those of non-European ancestry - is a crucial next step in identifying additional significant risk loci."

Joe Olechowski, genetics research and development supervisor at Addiction Labs of American Addiction Centers in Brentwood, Tennessee, commented in an email to Reuters Health, "Along with the correlation between OPRM1 and OUD, the study also indicates several traits that are genetically associated with OUD. This is important because the more we understand about the link between certain traits and the genes that influence them, the better we will be able to understand the genetic mechanisms behind OUD."

"This OPRM1 variant is a single piece to a much larger puzzle," he noted. "As more studies like this continue to reveal additional genetic variants that are associated with OUD, genetic tests can become a powerful tool not only for treatment, but possibly even prevention."

Dr. Patrice Malone, Assistant Professor of Psychiatry at Columbia University Irving Medical Center, also commented by email, "Prevention could be a key benefit of identifying associated SNPs for offspring, for instance, of an individual with severe substance use disorder(s). In that setting, the ability to provide psychoeducation and perhaps guard against the development of illness is critical information."

"Moreover, as there is significant stigma associated with substance use disorders, a better understanding of the biological etiology may aid in shifting the community perception from moral failure to medical illness," she said.

Like Olechowski, she noted that the OPRM1 variant also correlated with comorbid psychiatric traits. "Of course, it is not clear if the substance use disorder(s) developed first or the other psychiatric illnesses."

"A few limitations, which the authors mention and hold true, are the undiagnosed status of the control sample, smaller sample size as compared to studies conducted on substances that are legal and the need to improve on sample sizes for non-European Americans," Dr. Malone concluded.

SOURCE: JAMA Psychiatry, online June 3, 2020.