Cis-Expression Quantitative Trait Loci Mapping Reveals Replicable Associations with Heroin Addiction in OPRM1.
BACKGROUND
No opioid receptor, mu 1 (OPRM1) gene polymorphisms, including the functional single nucleotide polymorphism (SNP) rs1799971, have been conclusively associated with heroin/other opioid addiction, despite their biological plausibility. We used evidence of polymorphisms altering OPRM1 expression in normal human brain tissue to nominate and then test associations with heroin addiction.


METHODS
We tested 103 OPRM1 SNPs for association with OPRM1 messenger RNA expression in prefrontal cortex from 224 European Americans and African Americans of the BrainCloud cohort. We then tested the 16 putative cis-expression quantitative trait loci (cis-eQTL) SNPs for association with heroin addiction in the Urban Health Study and two replication cohorts, totaling 16,729 European Americans, African Americans, and Australians of European ancestry.


RESULTS
Four putative cis-eQTL SNPs were significantly associated with heroin addiction in the Urban Health Study (smallest p = 8.9 × 10(-5)): rs9478495, rs3778150, rs9384169, and rs562859. Rs3778150, located in OPRM1 intron 1, was significantly replicated (p = 6.3 × 10(-5)). Meta-analysis across all case-control cohorts resulted in p = 4.3 × 10(-8): the rs3778150-C allele (frequency = 16%-19%) being associated with increased heroin addiction risk. Importantly, the functional SNP allele rs1799971-A was associated with heroin addiction only in the presence of rs3778150-C (p = 1.48 × 10(-6) for rs1799971-A/rs3778150-C and p = .79 for rs1799971-A/rs3778150-T haplotypes). Lastly, replication was observed for six other intron 1 SNPs that had prior suggestive associations with heroin addiction (smallest p = 2.7 × 10(-8) for rs3823010).


CONCLUSIONS
Our findings show that common OPRM1 intron 1 SNPs have replicable associations with heroin addiction. The haplotype structure of rs3778150 and nearby SNPs may underlie the inconsistent associations between rs1799971 and heroin addiction.
Behavioral Health Epidemiology Program, Behavioral Health and Criminal Justice Division, Research Triangle Institute (RTI) International, St. Louis, Missouri.. Electronic address: dhancock@rti.org.
Dana B
DB
Hancock
Research Computing Division, RTI International, Research Triangle Park, North Carolina, St. Louis, Missouri.
Joshua L
JL
Levy
Research Computing Division, RTI International, Research Triangle Park, North Carolina, St. Louis, Missouri.
Nathan C
NC
Gaddis
Behavioral Health Epidemiology Program, Behavioral Health and Criminal Justice Division, Research Triangle Institute (RTI) International, St. Louis, Missouri.
Cristie
C
Glasheen
Department of Genetics, Washington University in St. Louis, St. Louis, Missouri.
Nancy L
NL
Saccone
Center for Public Health Genomics, RTI International, Atlanta, Georgia.
Grier P
GP
Page
School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, Western Australia, Australia.
Gary K
GK
Hulse
School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, Western Australia, Australia.
Dieter
D
Wildenauer
School of Psychiatry and Clinical Neurosciences, University of Western Australia, Crawley, Western Australia, Australia.
Erin A
EA
Kelty
Department of Psychiatry and Psychotherapy, University of Erlangen-Nuremberg, Erlangen, Germany.; Faculty of Science, Medicine, and Health, University of Wollongong, Wollongong, New South Wales.
Sibylle G
SG
Schwab
National Drug and Alcohol Research Centre, University of New South Wales, Sydney.
Louisa
L
Degenhardt
Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, Queensland.
Nicholas G
NG
Martin
Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, Queensland.
Grant W
GW
Montgomery
Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales.; Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, Newcastle, New South Wales.
John
J
Attia
Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales.; Clinical Research Design, IT and Statistical Support Unit, Hunter Medical Research Institute, Newcastle, New South Wales.
Elizabeth G
EG
Holliday
Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, Newcastle, New South Wales.; Public Health Research Program, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, Newcastle, New South Wales.
Mark
M
McEvoy
Center for Bioinformatics, Biomarker Discovery and Information-Based Medicine, Hunter Medical Research Institute, Newcastle, New South Wales.; School of Biomedical Sciences and Pharmacy, University of Newcastle, Newcastle, New South Wales.; Division of Genetics, Hunter Area Pathology Service, Newcastle, New South Wales, Australia.
Rodney J
RJ
Scott
Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri.
Laura J
LJ
Bierut
Department of Psychiatry, Washington University in St. Louis, St. Louis, Missouri.
Elliot C
EC
Nelson
Urban Health Program, Behavioral Health and Criminal Justice Division, RTI International, San Francisco, California.
Alex H
AH
Kral
Fellow Program and Behavioral Health and Criminal Justice Division, RTI International, Research Triangle Park, North Carolina.
Eric O
EO
Johnson
D000293:Adolescent; D000328:Adult; D001741:Black or African American / Q000235:genetics; D000368:Aged; D001315:Australia / Q000453:epidemiology; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D006556:Heroin Dependence / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D017397:Prefrontal Cortex / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000235:genetics* / Q000378:metabolism*; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics; D055815:Young Adult
C485764:OPRM1 protein, human; D012333:RNA, Messenger; D017450:Receptors, Opioid, mu
Genetic association study; Heroin; Multiancestry; OPRM1; Opioid; Prefrontal cortex