Summary: A new large-scale, genome-wide study has identified 18 novel genetic risk factors for opioid use disorder, bringing the number of OUD-associated genes from 1 to 19.
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 association study on a genome-wide scale – 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 around the world. The findings, published in Molecular psychiatry, fill a pressing need, as genetic discovery of TULO 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 a Yale professor of genetics and neuroscience, said not much is known about the specific genetic factors that influence risk for TOU.
In this study, the researchers worked to increase knowledge about the genetics of OUD by performing a meta-analysis of OUD, that is, bringing together data from many different studies and then incorporating genetic information from other substance use disorders for more gene research power. .
Researchers examined genetic data from more than 600,000 participants of European and African genetic ancestry, more information than previous studies on variation in OUD risk.
Scientists identified genetic variation in 19 genes that was associated with OUD risk; OPRM1 and FURIN were two genes identified in the analysis of OUD alone, with many other genes identified in the analysis that incorporated information from OUD as well as cannabis use disorder and cannabis use disorder. alcohol.
“OPRM1 is a gene that codes for mu opioid receptors in the brain, making it a prime genetic possibility for UDO. Previous work has shown that variation in this gene influences the risk of UDO. Our challenge was to go beyond OPRM1,” Gelernter said.
“Our effort has resulted in as much genome-wide data as possible. We wanted to compile as many datasets and samples as possible,” said Joseph D. Deak, Ph.D., postdoctoral fellow in the Yale Department of Psychiatry, Division of Human Genetics and first author of the paper. .
“We believe that our findings have identified a genetic risk specific to OUD as well as a genetic risk shared more broadly with other types of substance use disorders. This is consistent with previous studies that show specific genetic effects for certain drugs as well as shared genetic responsibility for substance use disorders more broadly.
The findings also reveal genetic links 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 PTSD.
“These genetic findings correspond to common features often seen in the clinical presentation of people diagnosed with OUD. We found this genetic overlap,” Deak said.
We know that there are many factors that influence the risk of substance use disorders such as OUSD. These results do not say that anyone with these specific genetic risk factors should or should not be prescribed opioids to manage pain or anything like that; this work does not support this conclusion, but it may help explain some unanswered questions as we continue to develop these findings in hopes of helping to address public health concerns related to opioids.
About this genetics and addictions research news
Author: Christopher Gardner
Contact: Christopher Gardner-Yale
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Original research: Free access.
“A genome-wide association study in people of European and African ancestry and a multi-trait analysis of opioid use disorder identify 19 independent significant genome-wide risk loci by Joseph D. Deak et al. Molecular psychiatry
Genome-wide association study in people of European and African ancestry and multi-trait analysis of opioid use disorder identify 19 independent significant genome-wide risk loci
Despite the large number of opioid use disorders (OUD), genome-wide association studies (GWAS) of OUD have so far yielded few susceptibility loci.
We performed large-scale GWAS of OUD in individuals of European (EUR) and African (AFR) ancestry, optimizing genetic informativeness by performing MTAG (multi-trait analysis of GWAS) with disorders related to genetically correlated substance use (SUD).
The meta-analysis included seven cohorts: the Million Veteran Program, Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, giving a total NOT = 639063 (NOTcase= 20,686;Nefficient= 77,026) through thermals. OUD cases were defined as having a lifetime OUD diagnosis and controls as anyone who was not known to meet the criteria for OUD. We estimated the heritability of SNPs (h2SNP ) and genetic correlations (rg ).
Based on the genetic correlation, we performed MTAG on OUD, alcohol use disorder (AUD) and cannabis use disorder (CanUD). A single-item polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD case status at Yale-Penn 3.
The EUR meta-analysis identified three genome-wide significant (GWS; p ≤5×10−8) major SNPs—one to FURIN (rs11372849; p= 9.54 × 10−10) And two OPRM1variants (rs1799971, p= 4.92 × 10−09; rs79704991, p= 1.11 × 10−08; r2= 0.02). Rs1799971 (p=4.91×10−08) and another OPRM1variant (rs9478500; p= 1.95 × 10−08; r2= 0.03) were identified in the cross-ancestry meta-analysis. estimated hours2SNPwas 12.75%, with a strong rgwith CanUD(rg= 0.82; p= 1.14 × 10−47) and AUD (rg= 0.77; p= 6.36 × 10−78).
The OUD-MTAG resulted in a GWAS Nequivalent= 128,748 and 18 independent GWS loci, some mapping genes or regions of genes that have previously been associated with psychiatric or addiction phenotypes.
The OUD-MTAG PRS accounted for 3.81% of the variance of the OUD (beta=0.61; se=0.066; p= 2.00 × 10−16) against 2.41% (beta = 0.45; se = 0.058; p= 2.90 × 10−13) explained by the PRS OUD. The current study identified associations of OUD variants to OPRM1single-variant associations 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 among SUDs.