The genetics of the opioid system and specific drug addictions.

paper Cited Public

Authors: Levran, Orna; Yuferov, Vadim; Kreek, Mary Jeanne
Year: 2012
Journal: Human genetics
PMID: 22547174
DOI: 10.1007/s00439-012-1172-4
PMCID: PMC3721349

#	Section	Preview
0	Introduction	Addiction to drugs is a chronic complex relapsing brain disease that causes major medical, social…
1	Introduction	ligand binding ability and signal transduction pathways (for figures see LaForge et al. 2000). The…
2	Introduction	Several comprehensive reviews describe the role of the endogenous opioid family of genes in…
3	Association studies	A vast number of studies have been reported the association of variants of the opioid system genes…
4	Association studies	The studies included a range of phenotypes, including heroin addiction, opioid dependence (OD);…
5	Association studies	Different studies have used different criteria for defining specific addictions or different…
6	Association studies	To allow a comprehensive and critical examination of the data, and to assist with planning future…
7	The mu opioid receptor gene (OPRM1)	The G protein-coupled mu opioid receptor (encoded by the OPRM1 gene) is the major site of action for…
8	The mu opioid receptor gene (OPRM1)	The OPRM1 gene is located at cytogenetic band 6q25.2. The major subtype contains 4 exons. A number…
9	The mu opioid receptor gene (OPRM1)	Only two SNPs out of the variants described in dbSNP in the OPRM1 coding sequence (17C>T (Ala6Val)…
10	The mu opioid receptor gene (OPRM1)	polymerase-1 (PARP-1) was shown to preferentially bind to the -172T allele and positively regulate…
11	The mu opioid receptor gene (OPRM1)	Functional evidence for a few coding variants was reported. The 118A>G SNP was the first variant…
12	118A>G (Asn40Asp, rs1799971)	The most studied OPRM1 variant is the non-synonymous (changing an amino acid) variant rs1799971…
13	118A>G (Asn40Asp, rs1799971)	The functionality of this variant was subject to numerous studies (e.g. Befort et al. 2001; Bond et…
14	118A>G (Asn40Asp, rs1799971)	Recently, in a positron emission tomography (PET) study of 22 smokers and 20 controls, the 118G…
15	Association studies of 118A>G	A large number of association studies of this SNP across various phenotypes were reported (for a…
16	Association studies of 118A>G	Several studies reported an association of the 118G allele with alcohol dependence (AD) in different…
17	Association studies of 118A>G	The SNP 118A>G was also associated with social hedonic capacity (Troisi et al. 2011) and with MAP…
18	Association studies of 118A>G	As the 118A>G SNP changes an amino acid, it has been generally assumed that it is the causative…
19	Animal models of 118A>G	Two mouse models of 118A>G with the equivalent amino acid substitution have been developed using two…

Name	Type
-1045A>G local	variant
118A>G (Asn40Asp) local	variant
118A>G SNP local	variant
118G local	variant
-1320A>G local	variant
-1565T>C local	variant
-1699insT local	variant
-172G>T local	variant
-172T allele local	variant
-1748G>A local	variant
-1793T>A local	variant
17C>T local	variant
17C>T polymorphism local	variant
17T allele local	variant
17TT genotype local	variant
-2044C>A local	variant
219 EA families local	cohort
540825 local	variant
562859 local	variant
63 kDa protein local	drug
779G>A (Arg260His) local	variant
77C>G (Pro26Arg) local	variant
794G>A (Arg265His) local	variant
802T>C (Ser268Pro) local	variant
80G allele local	variant
80G-allele local	variant
80T-allele local	variant
921C allele local	variant
AA	cohort
A allele	cohort
AA sample	cohort
Abstinent alcoholic individuals local	cohort
ACTH	drug
ACTH response to metyrapone local	phenotype
addiction	phenotype
adolescent alcohol use	phenotype
African	cohort
African American	cohort
African descent	cohort
alcohol	phenotype
alcohol abuse	phenotype
alcohol dependence	phenotype
alcoholism	phenotype
alcohol preference	phenotype
alcohol sensitivity	phenotype
Alcohol Use	phenotype
Alcohol use disorder diagnoses during adolescence local	phenotype
alpha-neoendorphin local	drug
altered signal transduction local	phenotype
altered stress reactivity local	phenotype
Alzheimer's disease	phenotype
amphetamine	drug
Amphetamine-induced euphoria local	phenotype
amphetamine response (euphoria, energy, blood pressure) local	phenotype
Amphetamine use disorder	phenotype
amygdala	anatomy
anterior pituitary	anatomy
Antisocial drug dependence in adolescents local	phenotype
anxiety-like behavior	phenotype
anxiogenic role local	phenotype
AP-1	drug
AP-1 transcription complex local	drug
apomorphine	drug
Asian	cohort
Asian HapMap population local	cohort
attenuated cortisol levels during the maternal postpartum period local	phenotype
basal proenkephalin expression local	phenotype
beta-endorphin	drug
beta-neoendorphin local	drug
blood pressure	phenotype
blunted cortisol response to psychosocial stress local	phenotype
Blunted drug-context association formation local	phenotype
brain	anatomy
brain tissue	anatomy
buprenorphine	drug
Buprenorphine maintenance treatment local	cohort
C57BL/6J	cohort
Ca2+/calmodulin-dependent protein kinase local	drug
Ca2+ signaling regulation local	phenotype
cannabis dependence	phenotype
cannabis use	phenotype
caudate nucleus	anatomy
CCT local	variant
CD	phenotype
CD/AD local	phenotype
C/EBP local	gene
central amygdala	anatomy
CEU	cohort
CHB	cohort
Chinese	cohort
Chinese subjects local	cohort
cocaine	phenotype
Cocaine addiction/dependence local	phenotype
cocaine use disorder	phenotype
COGA sample	cohort
Collaborative Study on the Genetics of Alcoholism (COGA)	cohort
common drug liability local	phenotype
Common drug use disorders liability local	phenotype
controls	cohort
cortisol	drug
cortisol response	phenotype
craving	phenotype
CREB1	gene
CRH	gene
Cue-induced alcohol craving local	phenotype
DBA/2J	cohort
dopamine	drug
dopaminergic neurons	anatomy
Dopaminergic system	drug
dorsolateral prefrontal cortex	anatomy
drinking	phenotype
drug addiction-related phenotypes local	phenotype
drug dependence	phenotype
drug use disorder diagnosis local	phenotype
dynorphin	drug
dynorphin B local	drug
dynorphin peptides local	drug
EA	cohort
EA participants	cohort
EAs	cohort
Emotion	phenotype
endogenous opioids	drug
enhanced affinity for beta-endorphin local	phenotype
enkephalin	drug
euphoria	phenotype
Euphoric effects of alcohol	phenotype
European American drinkers local	cohort
European ancestry	cohort
European cohort (n=238) local	cohort
European population	cohort
exogenous opiates local	drug
family history of alcoholism	phenotype
fetal brain	anatomy
GATA	gene
general illicit drug dependence local	phenotype
German cohort	cohort
Germans	cohort
greater baseline plasma cortisol concentration local	phenotype
haplotype	variant
haplotype 80G-921C local	variant
haplotype_rs1022563_rs2235749_rs910080 local	variant
haplotype rs204055-rs2236857-rs2298896 local	variant
healthy controls	cohort
healthy EA subjects local	cohort
heavy drinking	phenotype
heroin-induced positive response on first use local	phenotype
Heroin-induced subjective response local	phenotype
hippocampus	anatomy
His	cohort
Hispanic	phenotype
HIV+ women local	cohort
HIV- women local	cohort
hMOR-1O local	variant
hMOR-1X local	variant
HPA axis	anatomy
HPA axis local	gene
HPA axis suppression by buprenorphine local	phenotype
human brain	anatomy
Humanized mice (118GG) local	cohort
hypothalamic-pituitary-adrenal axis	anatomy
hypothalamus	anatomy
illicit drug dependence	phenotype
illicit drugs	phenotype
increased alcohol preference following naltrexone treatment local	phenotype
increased cue-elicited activation local	phenotype
Increased dopaminergic sensitivity local	phenotype
increased explorative behavior local	phenotype
increased frequency of alcohol consumption to intoxication local	phenotype
increased psychomotor stimulation in response to alcohol local	phenotype
Increased striatal dopamine response to alcohol local	phenotype
Indian	cohort
Indian males from Delhi local	cohort
Indian sample local	cohort
Italian sample local	cohort
Japanese	cohort
Japanese subjects local	cohort
kappa opioid receptor	drug
Knock-in mice (112G homozygous) local	cohort
larger cohort local	cohort
LD-tagging SNPs local	variant
left anterior cingulate cortex local	anatomy
left thalamus	anatomy
locomotor sensitization	phenotype
lower cell-surface receptor binding site availability local	phenotype
MAP psychosis local	phenotype
Maturation efficiency local	phenotype
MD	phenotype
Mesocorticolimbic system	anatomy
mesolimbic dopamine system	drug
mesolimbic–mesocortical system local	anatomy
Methadone	drug
Methadone maintenance treatment local	cohort
methamphetamine	drug
methamphetamine dependence	phenotype
methamphetamine dependence/psychosis local	phenotype
Methamphetamine dependence/psychosis local	phenotype
methamphetamine psychosis local	phenotype
Metyrapone local	drug
Middle Eastern subjects local	cohort
mixed populations local	cohort
MMT response local	phenotype
monkeys	cohort
morphine	drug
mu opioid receptor	drug
MZF local	gene
nalmefene	drug
naloxone	drug
naltrexone	drug
Native Americans	cohort
neurosteroids	drug
NF-κB	gene
nicotine	drug
nigrostriatal system	anatomy
nociceptin	drug
NTX	drug
nucleus accumbens	anatomy
OCT-1	drug
OD	phenotype
opiates	drug
opioid	drug
opioid analgesic drugs local	drug
opioid dependence	phenotype
opioid receptor	drug
opioid system local	gene
opioid system genes local	gene
opioid withdrawal	phenotype
Oprd1	cohort
OPRD1 921T>C local	variant
OPRD1 knockout mice local	cohort
OPRD1 rs2234918 local	variant
OPRD1 rs678849 local	variant
OPRK1	cohort
OPRK1 rs963549 local	variant
OPRL1	cohort
Oprl1 knockout mice local	cohort
Oprl1 knockout rats local	cohort
OPRM1	cohort
OPRM1 112G (Asn38Asp) local	variant
OPRM1 118A>G polymorphism local	variant
OPRM1 -1320A>G local	variant
OPRM1 -1565T>C local	variant
OPRM1 -1699insT local	variant
OPRM1 -172T local	variant
OPRM1 -1748G>A local	variant
OPRM1 -1793T>A local	variant
OPRM1 17C>T local	variant
OPRM1 -554G>A local	variant
OPRM1 77G local	variant
OPRM1 -995C>A local	variant
OPRM1 A118G	cohort
orphanin/nociceptin local	drug
pain perception	phenotype
PARP1	gene
Pdyn	gene
Pdyn knockout mice local	cohort
PENK	gene
pERK local	drug
personality traits	phenotype
pituitary gland	anatomy
PKA	drug
Plasma membrane stability local	phenotype
PNOC	gene
Pomc	gene
positive reinforcement	phenotype
positive subjective effect of alcohol local	phenotype
prodynorphin local	drug
Proenkephalin-derived peptides local	drug
receptor desensitization	phenotype
receptor signaling activity	phenotype
reduced cortisol response to acute alcohol exposure later in life local	phenotype
reduced cortisol response to maternal separation in infancy local	phenotype
Reduced morphine reward local	phenotype
reduced mRNA levels local	phenotype
Reduced OPRM1 expression local	phenotype
reduced receptor binding availability local	phenotype
response to naltrexone treatment	phenotype
reward	phenotype
reward and reinforcement local	phenotype
rewarding effects	phenotype
RGS19	gene
robust cortisol response to naloxone blockade local	phenotype
rs1009388 local	variant
rs1022563 local	variant
rs1042114 local	variant
rs1042571 local	variant
rs1051660 local	variant
rs1074287	variant
rs118175398 local	variant
rs12545109 local	variant
rs1381376	variant
rs1437277 local	variant
rs16918875 local	variant
rs17058952 local	variant
rs1799971	variant
rs1866146 local	variant
rs1975285 local	variant
rs1997794 local	variant
rs204055 local	variant
rs2075572	variant
rs2229205 local	variant
rs2234918 local	variant
rs2234918 C-allele local	variant
rs2235749 local	variant
rs2236857 local	variant
rs2236861	variant
rs2281617 local	variant
rs2295448 local	variant
rs2298896 local	variant
rs2576581 local	variant
rs2609997 local	variant
rs3138832 local	variant
rs3219515 local	variant
rs351779 local	variant
rs351784 local	variant
rs35286281 local	variant
rs35566036 local	variant
rs3766951 local	variant
rs3769671 local	variant
rs3778151	variant
rs4654327	variant
rs4732636 local	variant
rs483481 local	variant
rs510769	variant
rs534673 local	variant
rs563649	variant
rs569356 local	variant
rs6010718 local	variant
rs6045819 local	variant
rs6089789 local	variant
rs6090041 local	variant
rs6090043 local	variant
rs61761346 local	variant
rs6473797 local	variant
rs6512305 local	variant
rs6713532 local	variant
rs6719226 local	variant
rs6985606	variant
rs702764 local	variant
rs7271530 local	variant
rs76786693 local	variant
rs7815824 local	variant
rs910079 local	variant
rs910080 local	variant
rs934778 local	variant
rs997917	variant
single nucleotide polymorphism	variant
small subsample of 83 affected subjects local	cohort
smoking	phenotype
SNP	cohort
SNPs in opioid system genes local	variant
social hedonic capacity local	phenotype
Sp1	gene
specific drug addiction local	phenotype
STAT6 local	gene
stimulation	phenotype
stress response	phenotype
striatum	anatomy
substances	phenotype
substance use	phenotype
Swedish local	cohort
Swedish cohort	cohort
SWR local	cohort
T-A haplotype (rs934778 and rs3769671) local	variant
Taiwanese	cohort
Taiwanese Han local	cohort
Taiwanese sample local	cohort
tobacco use	phenotype
treatment response	phenotype
ventral tegmental area	anatomy
vulnerability to develop heroin addiction local	phenotype
Wild-type controls local	cohort
women	cohort
Yoruba (Nigeria) local	cohort
YRI	cohort
YY1 local	gene

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In this knowledge base

Title	Year	PMID
Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond.	2022	36207451
Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts.	2016	26392368

External

Title	Authors	Journal	Year	Link
Genomic Insights into Opioid Addiction: Identification of genomic variants from Gene Expression data	Ajmeriya S et al.	—	2025	—
Identification of variants from gene expression data of opioid-addicted patients.	Ajmeriya S et al.	—	2025	→
Genetic Variants in <i>KNDy</i> Pathway Lack Association with Premature Ovarian Insufficiency in Mexican Women: A Sequencing-Based Cohort Study.	Ruiz A et al.	—	2024	→
Investigating the neurobiology of maternal opioid use disorder and prenatal opioid exposure using brain organoid technology.	Dwivedi I et al.	—	2024	→
Annual Research Review: Prenatal opioid exposure - a two-generation approach to conceptualizing neurodevelopmental outcomes.	Conradt E et al.	—	2023	→
Analyses of polymorphisms of intron 2 of OPRK1 (kappa-opioid receptor gene) in association with opioid and cocaine dependence diagnoses in an African-American population.	Yuferov V et al.	—	2022	→
Looking beyond the opioid receptor: A desperate need for new treatments for opioid use disorder.	Lee YK et al.	—	2022	→
Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond.	Gaddis N et al.	—	2022	→
Current overview of opioids in progression of inflammatory bowel disease; pharmacological and clinical considerations.	Lashgari NA et al.	—	2021	→
Morphine Perinatal Exposure Induces Long-Lasting Negative Emotional States in Adult Offspring Rodents.	Castro NCF et al.	—	2021	→
Population-specific genetic background for the OPRM1 variant rs1799971 (118A>G): implications for genomic medicine and functional analysis.	Levran O et al.	—	2021	→
Spinocerebellar ataxia type 23 (SCA23): a review.	Wu F et al.	—	2021	→
The OPRD1 rs678849 variant influences outcome of disulfiram treatment for cocaine dependency in methadone-maintained patients.	Thomas PS et al.	—	2021	→
A dopamine-induced gene expression signature regulates neuronal function and cocaine response.	Savell KE et al.	—	2020	→
Association of opioid receptor gene polymorphisms with drinking severity and impulsivity related to alcohol use disorder in a Korean population.	Park CI et al.	—	2020	→
Genetic Associations with Indoor Tanning Addiction among non-Hispanic White Young Adult Women.	Mays D et al.	—	2020	→
Opioid use disorder.	Strang J et al.	—	2020	→
Placental <i>OPRM1</i> DNA methylation and associations with neonatal opioid withdrawal syndrome, a pilot study.	Wachman EM et al.	—	2020	→
The multi-faceted impact of methamphetamine on Alzheimer's disease: From a triggering role to a possible therapeutic use.	Shukla M et al.	—	2020	→
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Association of variants of prodynorphin promoter 68-bp repeats in caucasians with opioid dependence diagnosis: Effect on age trajectory of heroin use.	Yuferov V et al.	—	2019	→
Association Study of OPRM1 Gene in a Sample of Schizophrenia Patients With Alcohol Dependence or Abuse.	Gendy MNS et al.	—	2019	→
Caenorhabditis elegans as a model system to identify therapeutics for alcohol use disorders.	Katner SN et al.	—	2019	→
Childhood adversities and 5-HTTLPR polymorphism as risk factors of substance use disorders: retrospective case-control study in Murcia (Spain).	Navarro-Mateu F et al.	—	2019	→
Enkephalinase inhibitors, potential therapeutics for the future treatment of diarrhea predominant functional gastrointestinal disorders.	Szymaszkiewicz A et al.	—	2019	→
Sex differences in neural mechanisms mediating reward and addiction.	Becker JB et al.	—	2019	→
The repertoire of family A-peptide GPCRs in archaic hominins.	Mata X et al.	—	2019	→
Chronic Oxycodone Self-administration Altered Reward-related Genes in the Ventral and Dorsal Striatum of C57BL/6J Mice: An RNA-seq Analysis.	Zhang Y et al.	—	2018	→
Dopaminergic and Opioid Pathways Associated with Impulse Control Disorders in Parkinson's Disease.	Erga AH et al.	—	2018	→
Downregulation of the neuronal opioid gene expression concomitantly with neuronal decline in dorsolateral prefrontal cortex of human alcoholics.	Bazov I et al.	—	2018	→
Elevated methylation of OPRM1 and OPRL1 genes in Alzheimer's disease.	Xu C et al.	—	2018	→
Opioid receptors: drivers to addiction?	Darcq E et al.	—	2018	→
Opioid system and human emotions.	Nummenmaa L et al.	—	2018	→
Association of maternal and infant variants in PNOC and COMT genes with neonatal abstinence syndrome severity.	Wachman EM et al.	—	2017	→
Delta-opioid receptor antagonism leads to excessive ethanol consumption in mice with enhanced activity of the endogenous opioid system.	Poznanski P et al.	—	2017	→
Effect of toad skin extracts on the pain behavior of cancer model mice and its peripheral mechanism of action.	Chen T et al.	—	2017	→
Transgenerational attenuation of opioid self-administration as a consequence of adolescent morphine exposure.	Vassoler FM et al.	—	2017	→
Variability in prescription opioid intake and reinforcement amongst 129 substrains.	Jimenez SM et al.	—	2017	→
Association of the OPRM1 Variant rs1799971 (A118G) with Non-Specific Liability to Substance Dependence in a Collaborative de novo Meta-Analysis of European-Ancestry Cohorts.	Schwantes-An TH et al.	—	2016	→
Etiological theories of addiction: A comprehensive update on neurobiological, genetic and behavioural vulnerability.	Ouzir M et al.	—	2016	→
Genes and Alcohol Consumption: Studies with Mutant Mice.	Mayfield J et al.	—	2016	→
Genome-Wide Association of Heroin Dependence in Han Chinese.	Kalsi G et al.	—	2016	→
Regulation and Functional Implications of Opioid Receptor Splicing in Opioid Pharmacology and HIV Pathogenesis.	Regan PM et al.	—	2016	→
Stress psychobiology in the context of addiction medicine: from drugs of abuse to behavioral addictions.	Lemieux A et al.	—	2016	→
Variants of opioid system genes are associated with non-dependent opioid use and heroin dependence.	Randesi M et al.	—	2016	→
Association between VNTR Polymorphism in Promoter Region of Prodynorphin (PDYN) Gene and Methamphetamine Dependence.	Saify K et al.	—	2015	→
Effects of an opioid (proenkephalin) polymorphism on neural response to errors in health and cocaine use disorder.	Moeller SJ et al.	—	2015	→
The epigenetic regulation of the opioid system: new individualized prompt prevention and treatment strategies.	Muñoa I et al.	—	2015	→
Variations in opioid receptor genes in neonatal abstinence syndrome.	Wachman EM et al.	—	2015	→
A commonly carried genetic variant in the delta opioid receptor gene, OPRD1, is associated with smaller regional brain volumes: replication in elderly and young populations.	Roussotte FF et al.	—	2014	→
Alcohol: a stimulant activating brain stress responsive systems with persistent neuroadaptation.	Zhou Y et al.	—	2014	→
Drug addiction in pregnancy: disease not moral failure.	Maguire D	—	2014	→
Epigenetic variation in the mu-opioid receptor gene in infants with neonatal abstinence syndrome.	Wachman EM et al.	—	2014	→
Introduction to deep sequencing and its application to drug addiction research with a focus on rare variants.	Wang S et al.	—	2014	→
Neuroimaging and genetic risk for Alzheimer's disease and addiction-related degenerative brain disorders.	Roussotte FF et al.	—	2014	→
Novel approaches for the treatment of psychostimulant and opioid abuse - focus on opioid receptor-based therapies.	Bailey CP et al.	—	2014	→
Pharmacogenomics of methadone maintenance treatment.	Somogyi AA et al.	—	2014	→
Physiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectives.	Sobczak M et al.	—	2014	→
The heritability of oxycodone reward and concomitant phenotypes in a LG/J × SM/J mouse advanced intercross line.	Bryant CD et al.	—	2014	→
Association of genetic variation in pharmacodynamic factors with methadone dose required for effective treatment of opioid addiction.	Levran O et al.	—	2013	→
Association of polymorphisms in pharmacogenetic candidate genes (OPRD1, GAL, ABCB1, OPRM1) with opioid dependence in European population: a case-control study.	Beer B et al.	—	2013	→
A systems medicine research approach for studying alcohol addiction.	Spanagel R et al.	—	2013	→
Convergent functional genomics in addiction research - a translational approach to study candidate genes and gene networks.	Spanagel R	—	2013	→
Genotyping the Mu-opioid receptor A118G polymorphism using the real-time amplification refractory mutation system: allele frequency distribution among Brazilians.	Daher M et al.	—	2013	→
Long-term effects of cocaine experience on neuroplasticity in the nucleus accumbens core of addiction-prone rats.	Waselus M et al.	—	2013	→
Opioid maintenance, weaning and detoxification techniques: where we have been, where we are now and what the future holds.	Plunkett A et al.	—	2013	→
Opioid system genes in alcoholism: a case-control study in Croatian population.	Cupic B et al.	—	2013	→
Current perspectives on the neurobiology of drug addiction: a focus on genetics and factors regulating gene expression.	Duncan JR	—	2012	→
Opiate addiction and cocaine addiction: underlying molecular neurobiology and genetics.	Kreek MJ et al.	—	2012	→
The genetics of addiction.	Volkow ND et al.	—	2012	→