Genetic risk factors for opioid use disorders have been identified

Summary: A new large-scale genome-wide study has identified 18 new genetic risk factors for opioid use disorder, bringing the number of genes associated with OUD to 1-19.

A source: Yale

A new human genomics study led by Yale has identified genetic risk factors for opioid use disorder (OUD) and related substance use disorders, increasing the number of known risk genes from 1 to 19, according to a new large-scale genome-wide association study. .

The case comes as opioid-related overdoses have reached an all-time high in the United States and are on the rise around the world. Results, published Molecular psychiatry, addressing the limited need for genetic discovery for OUD in recent years. Genetic discovery leads to better understanding of biology.

Senior author Joel Gelernter, MD, Foundation Professor of Psychiatry and Professor of Genetics and Neuroscience at Yale, said that not much is known about the specific genetic factors that influence the risk of OUD.

In this study, researchers worked to increase knowledge of the genetics of OUD by completing a meta-analysis for OUD, that is, pooling data from many different studies and then adding genetic information from other related substance use disorders to power the gene discovery. .

The researchers examined genetic data from more than 600,000 participants of European and African genetic ancestry, more information than any previous study on variation in OUD risk.

The researchers identified genetic variation in 19 genes that were associated with risk of OUD; OPRM1 and FURIN were the only two genes identified in the OUD analysis, with many more genes that included OUD data in the analysis including cannabis use disorder and alcohol use disorder.

“OPRM1 is the gene that encodes opioid receptors in the brain, making it a key genetic predisposition to OUD—previous work has shown that variation in this gene affects risk for OUD. Our challenge was to look beyond OPRM1,” Gelernter said.

The case comes as opioid-related overdoses have reached an all-time high in the United States and are on the rise around the world. Image is in the public domain

“Our effort brought as much information as possible about the genome. We wanted to create as many data sets and samples as possible,” said Joseph D. Dick, Ph.D., is a postdoctoral fellow in the Department of Psychiatry in Human Genetics at Yale and first author of the paper.

“Our findings have identified a genetic risk specific to OUD, and we believe that genetic risk is broadly shared with other forms of substance use. This is consistent with previous studies showing specific genetic effects for certain drugs, as well as a general genetic liability for substance use disorders.

Research also reveals genetic links between conditions associated with the development of OUD, such as chronic illness, inability to work due to illness or disability, and other psychiatric outcomes such as anxiety, depression, and PTSD.

“These genetic findings often correspond to common features observed in the clinical presentation of people diagnosed with OUD. We found a genetic match,” said Dick.

We know that there are many factors that influence the risk of substance use disorders, such as OUD. These findings do not mean that someone 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 that conclusion, but it does help clarify some unanswered questions as we continue to expand on these findings in hopes of helping to address opioid-related public health issues.

About it Genetics and Addiction Research News

Author: Christopher Gardner
A source: Yale
The connection: Christopher Gardner – Yale
Photo: Image is in the public domain

Original research: Open access.
“A genome-wide association study and multi-qualitative analysis of opioid use disorder identification in individuals of European and African ancestry at 19 independent genome-wide significant risk loci” Joseph D. Dick et al. Molecular psychiatry


Abstract

A genome-wide association study and multivariate analysis of opioid use disorder in individuals of European and African ancestry.

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Despite the high prevalence of opioid use disorder (OUD), genome-wide association studies (GWAS) of OUD to date have yielded few susceptibility loci.

We conducted a large-scale GWAS OUD in people of European (EUR) and African (AFR) descent to optimize genetic information by performing MTAG (multi-qualitative analysis of GWAS) with genetically linked substance use disorders (SUDs).

The meta-analysis included seven cohorts: the Million Veterans Program, the Psychiatric Genomics Consortium, iPSYCH, FinnGen, Partners Biobank, BioVU, and Yale-Penn 3, resulting in a total Do not = 639,063 (Do notcases= 20.686;Neffective= 77,026) by ancestry. OUD cases are controlled as those defined as having a lifetime diagnosis of OUD and not meeting criteria for OUD. We estimated the heritability of SNPs (htwoSNP ) and genetic correlations (rd ).

Based on genetic correlates, we conducted MTAG for OUD, alcohol use disorder (AUD), and cannabis use disorder (CanUD). A univariate polygenic risk score (PRS) analysis was performed to compare OUD and OUD-MTAG PRS as predictors of OUD event status at Yale-Penn 3.

In the EUR meta-analysis, three genome-wide significant (GWS; P ≤ 5 × 10-8) led by SNPs 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). Rs1799971 (p = 4.91 × 10-08) and so on OPRM1variant (rs9478500; P= 1.95 × 10-08; rtwo= 0.03) identified in a cross-sectional meta-analysis. approximate htwoSNPwas 12.75% with a strong rdwith CanUD(rd= 0.82; P= 1.14 × 10-47) and AUD (rd= 0.77; P= 6.36 × 10-78).

OUD-MTAG results from GWAS Nis equivalent= 128,748 and 18 independent GWS loci, some mapping to genes or gene regions previously associated with psychiatric or addiction phenotypes.

The OUD-MTAG PRS accounted for 3.81% of the variance in OUD (beta = 0.61; se = 0.066; P= 2.00 × 10-16) compared to 2.41% (beta = 0.45; se = 0.058; P= 2.90 × 10-13) explained by OUD PRS. The current study identified associations of OUD variants OPRM1with single-variant associations FURINand 18 GVS associations in OUD-MTAG.

The genetic architecture of OUD may be influenced by both OUD-specific loci and common loci across SUDs.

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