Association of OPRM1 Functional Coding Variant With Opioid Use Disorder

Abstract

doi: medRxiv preprint NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice.

Multivariate genomic analysis of 1.5 million people identifies genes related to addiction, antisocial behavior, and health

“…Polygenic scores for EXT explained significant variance (Δ R 2 ) in criteria counts of ADHD (mean Δ R 2 = 1.65%), conduct disorder (CD; mean Δ R 2 = 3.1%), and oppositional defiant disorder (ODD; Δ R 2 = 1.96%), as well as in phenotypes categorized as substance use initiation (mean Δ R 2 = 1.3–6.5%), substance use disorders (mean Δ R 2 = 0.8–1.7%), disinhibited behaviors (mean Δ R 2 = 1.5–2.5%), criminal justice system involvement (mean Δ R 2 = 1.0–3.0%), reproductive health (mean Δ R 2 = 0.3–3.7%), and socioeconomic attainment (mean Δ R 2 = 0.1–2.3%). Many of the phenotypes – such as opioid use disorder criteria count, conduct disorder and antisocial personality disorder criteria count, lifetime history of arrest or incarceration, and lifetime history of being fired from work, were not included in our Genomic SEM analyses; however, our EXT polygenic score is notable in capturing appreciable variance in phenotypes that are still lacking large GWAS samples (a striking example being opioid use disorder 8 ). The associations between the EXT polygenic score and this broad range of phenotypes represents an affirmative test of the hypothesis that genetic variants associated with externalizing liability generalize to a wide variety of behavioral and social outcomes related to behavioral undercontrol.…”

“…Externalizing disorders and behaviors are a widely prevalent cause of human suffering, but understanding of the molecular genetic underpinnings of externalizing has lagged considerably behind progress made in other areas of medical and psychiatric genetics. For example, dozens of associated genetic loci have been discovered for schizophrenia (>100 loci) 54 , bipolar disorder (30 loci) 55 , and major depressive disorders (44 loci) 56 , whereas recent GWASs of antisocial behavior 57 , alcohol use disorders 58 , and opioid use disorders 8 have identified only a very small number of significantly associated loci, if any at all. Here, we used multivariate genomic analyses to accelerate genetic discovery, identifying 579 genome-wide significant loci associated with a predisposition toward externalizing disorders and behaviors, 121 of which are entirely novel discoveries for any of the seven phenotypes analyzed.…”

“…To date, however, there have been no large-scale molecular genetic studies that utilize the extensive degree of genetic overlap among externalizing traits to aid gene discovery, as most studies have focused on individual disorders or diseases 7 . But for many high-cost, high-risk externalizing behaviors – opioid use disorder and suicide attempts being salient examples – there are too few cases available with genome-wide data to yield sufficient power for gene discovery 8,9 .…”

Multi-environment gene interactions linked to the interplay between polysubstance dependence and suicidality

“…Further, the previous meta-analysis focused on varying degrees of cannabis use (any, chronic, and heavy cannabis use), while our analysis investigated CaD. The genetic basis of substance use, substance abuse, and SDs appears to be partially distinct 39 – 42 and these differences may affect their associations with suicidality. With respect to this issue, an interesting approach for future investigations would be to investigate the association of SD and SUD diagnostic criteria with suicidality.…”

“…We combined genetic and phenotypic data from two large cohorts, but the sample size investigated is not large enough to investigate the polygenic architecture of complex traits like polysubstance dependence and suicidality. To date, there is limited availability of large cohorts informative to investigate SD genetics, especially when considering illegal drugs 39 , 41 . Although information from Yale-Penn and Army STARRS cohorts were previously combined to replicate genetic associations related to SD and suicidality 8 , 11 , the limited availability of information regarding polysubstance dependence in Army STARRS participants likely prevented us from replicating the findings observed in the Yale-Penn participants.…”