Genome-Wide Association Study Finds Multiple Genes Associated With OUD, Substance Use Disorders

A new genome-wide association study (GWAS) has identified 19 possible genes associated with opioid and other substance use disorders. Prior genomic studies had found only one specific gene associated with opioid use disorder (OUD).

The value of genome-wide association and other genetic studies of psychiatric disorders is that they may provide more efficient ways to identify potential therapeutic agents. However, the value of genomic analysis in crafting more precise clinical approaches remains to be seen, observed lead author Joseph D. Deak, Ph.D., a postdoctoral fellow in the Psychiatry Division of Human Genetics at Yale University School of Medicine. “Time will tell on the value that genetic information will play in precision medicine efforts,” he commented, but “we aren’t there yet.”

The study incorporated data from numerous genome-wide association studies. It was led by a team of Yale scientists and published in Molecular Psychiatry. It employed a sample of 639,000 participants of European and African ancestry.

The data from the various studies were refined by examining the relationship between OUD-associated genes and other substance use disorders known to be genetically correlated with OUD.

Joel Gelernter, M.D., director of the Division of Human Genetics in the Department of Psychiatry at Yale University, was the study’s senior author. He told Psychiatric News that in the past, a good understanding of the mechanisms of action of many psychiatric (and other) medications was unknown. “In many cases psychiatric drugs came about by serendipitous observations—for example the tricyclic antidepressants were first proposed as antihistamines—but good clinicians noticed their antidepressant effects.”

In addition to amplifying the understanding of OUD’s genetic architecture by identifying many more genes correlated with OUD and other substance use disorders, the authors also looked at the overlapping association of various genes with a range of psychiatric and other disorders, in particular a gene called FURIN. This gene encodes an enzyme that plays a primary role in regulating synaptic neuronal activity.

In this study, FURIN was associated with OUD risk in both single-nucleotide polymorphism (SNP)-based analysis and gene-based analysis. A SNP is a variation in a single nucleotide—that is, in one of the building blocks that comprise DNA—and is the most common genetic variation found in humans.

Genetic variation in FURIN has been correlated with schizophrenia and bipolar disorder, while FURIN SNPs have been significantly associated with other traits including cardiovascular disease and hypertension, the authors observed.

The genetic relationship of OUD to a range of other traits including nonpsychiatric medical conditions means that “since they are genetically related, they are biologically related,” Gelernter said. “This has lots of implications in terms of our understanding of these disorders,” but it does not necessarily mean that treatments for different disorders would overlap, although that is possible. If GWAS and other genomic research ultimately facilitate the development of new treatments, whether and to what extent treatments may overlap “would require extensive clinical evaluation,” he added.

The advent of highly advanced gene editing technologies, particularly CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) has generated speculation that psychiatric disorders may someday be susceptible to gene editing. But this notion was strongly repudiated by Gelernter. “This is not likely to be applicable—ever—to a complex genetic trait like OUD, which involves hundreds to thousands of risk variants, each of individually modest effect,” he said.

A substantial body of research indicates that the genetic contribution to OUD is higher than that for other substance-use disorders. Further, a large proportion of research on substance use disorders has focused on opioid addiction because opioid dependence and abuse are associated with extremely high morbidity and mortality. Provisional data from the Centers for Disease Control and Prevention found that approximately 108,000 drug overdose deaths occurred in the United States during 2021, an overall increase of nearly 15% over 2020; deaths specifically linked to opioids increased from approximately 70,000 in 2020 to nearly 81,000 in 2021.

In their discussion, the authors highlighted some limitations of the study.

“Despite including all genotyped OUD subjects available, the OUD-only component of the present study is smaller than GWAS for other substance use behaviors because OUD cases are underrepresented in available datasets,” they noted.

Although the study included a significant cohort of African and non-European subjects, they were still underrepresented, limiting the ability to identify risk variants in non-European populations, they noted. Future research must address this issue by “purposeful recruitment of African and other non-European OUD subjects,” they concluded.

The study was funded in part by the National Institutes of Health and the Brain and Behavior Research Foundation. A complete list of funders appears in the study at the link given below. ■