Summary: A new large-scale genome-wide study has identified 18 new genetic risk factors for opioid use disorder, raising the number of genes associated with OUD from 1 to 19.
Font: yale
A new human genomics study led by Yale scientists has identified genetic risk factors for opioid use disorder (OUD) and substance use disorders according to a new large-scale genome-wide association study, increasing the number of known risk genes from 1 to 19 .
This work comes as opioid-related overdoses have reached an all-time high in the United States and continue to rise worldwide. The findings, published in Molecular Psychiatry, address a pressing need as genetic discovery of OUD has been limited in recent years. Genetic discovery leads to a better understanding of biology.
Lead author Joel Gelernter, MD, a Foundations Fund professor of psychiatry and professor of genetics and neuroscience at Yale, said not much is known about the specific genetic factors that influence OUD risk.
In this study, researchers worked to increase our understanding of the genetics of OUD by completing a meta-analysis for OUD, that is, pooling data from many different studies, and then incorporating genetic information from other substance use disorders to learn more. gene seeking power. .
The researchers examined genetic data from more than 600,000 participants of European and African genetic descent, more information than previous studies on variation in OUD risk.
The scientists identified genetic variation in 19 genes that was associated with OUD risk; OPRM1 and FURIN were two genes identified in the OUD analysis alone, with many more genes identified in the analysis that incorporated OUD information along with cannabis use disorder and alcohol use disorder.
“OPRM1 is a gene that encodes mu-opioid receptors in the brain, making it a leading genetic possibility for OUD; Previous work showed that variation in this gene influences the risk of OUD. Our challenge was to go beyond OPRM1,” said Gelernter.
“Our effort brought in as much genome data as possible. We wanted to compile as many data sets and samples as we could,” said Joseph D. Deak, Ph.D., a postdoctoral fellow in the Yale Department of Psychiatry’s Division of Human Genetics and the paper’s first author.
“We believe that our findings have identified the specific genetic risk of OUD, as well as the genetic risk shared more broadly with other types of substance use disorders. That is consistent with previous studies showing specific genetic effects for certain drugs along with a shared genetic responsibility for substance use disorders in general.”
The findings also reveal genetic connections between the development of OUD and related conditions, such as chronic pain, inability to work due to illness or disability, and other psychiatric outcomes such as anxiety, depression, and post-traumatic stress disorder.
“These genetic findings align with common features often seen in the clinical presentation of people diagnosed with OUD. We found that genetic overlap,” Deak said.
We know that there are many factors that influence the risk of substance use disorders like OUD. These results don’t say that anyone with these specific genetic risk factors should or shouldn’t be prescribed opioids for pain control or anything like that; this work does not support that conclusion, but it might help explain some unanswered questions as we continue to build on these findings in hopes of helping to address opioid-related public health concerns.
About this research news on genetics and addictions
Author: Christopher Gardner
Font: yale
Contact: Christopher Gardner – Yale
Image: The image is in the public domain.
original research: Open access.
“Genome-Wide Association Study in Individuals of European and African Descent and Multitrait Analysis of Opioid Use Disorder Identifies 19 Independent Loci of Significant Genome-Wide Riskby Joseph D. Deak et al. Molecular Psychiatry
Summary
Genome-Wide Association Study in Individuals of European and African Descent and Multitrait Analysis of Opioid Use Disorder Identifies 19 Independent Loci of Significant Genome-Wide Risk
See also
Despite the large number of opioid use disorder (OUD) victims, genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci.
We performed a large-scale OUD GWAS on individuals of European (EUR) and African (AFR) descent, optimizing genetic information by performing MTAG (Multi-Trait Analysis of GWAS) with genetically correlated substance use disorders (SUD) .
The meta-analysis included seven cohorts: Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total north = 639,063 (northcases= 20.686;Neffective= 77,026) between ancestries. OUD cases were defined as those with a lifetime OUD diagnosis and controls as anyone who did not meet OUD criteria. We estimate the heritability of SNPs (htwoSNP ) and genetic correlations (rgram ).
Based on genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A one-exclusion polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status in Yale-Penn 3.
The EUR meta-analysis identified three significant genomes (GWS; p ≤ 5 × 10−8) lead SNPs-one in furin (rs11372849; p= 9.54 × 10−10) and two OPRM1variants (rs1799971, p= 4.92 × 10−09; rs79704991, p= 1.11 × 10−08; rtwo= 0.02). Rs 1,799,971 (p = 4.91 × 10−08) and other OPRM1variant (rs9478500; p= 1.95 × 10−08; rtwo= 0.03) were identified in the cross-ancestry meta-analysis. Estimated timetwoSNPwas 12.75%, with strong rgramwith CanUD (rgram= 0.82; p= 1.14 × 10−47) and AUD (rgram= 0.77; p= 6.36 × 10−78).
The OUD-MTAG resulted in a GWAS Nequivalent= 128,748 and 18 independent GWS loci, some mapped to genes or genetic regions that have been previously associated with psychiatric or addiction phenotypes.
The OUD-MTAG PRS accounted for 3.81% of the OUD variance (beta = 0.61, se = 0.066; p= 2.00 × 10−16) versus 2.41% (beta = 0.45; se = 0.058; p= 2.90 × 10−13) explained by the OUD PRS. The current study identified associations of OUD variants in OPRM1associations of a single variant with furinand 18 GWS associations in the OUD-MTAG.
The genetic architecture of OUD is likely influenced by both OUD-specific loci and loci shared between SUDs.