. 2022 Oct 7;12(1):16873.

doi: 10.1038/s41598-022-21003-y.

Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond

Nathan Gaddis^#¹, Ravi Mathur^#¹, Jesse Marks¹, Linran Zhou¹, Bryan Quach¹, Alex Waldrop¹, Orna Levran², Arpana Agrawal³, Matthew Randesi², Miriam Adelson⁴, Paul W Jeffries³, Nicholas G Martin⁵, Louisa Degenhardt⁶, Grant W Montgomery⁷, Leah Wetherill⁸, Dongbing Lai⁸, Kathleen Bucholz³, Tatiana Foroud⁸, Bernice Porjesz⁹, Valgerdur Runarsdottir¹⁰, Thorarinn Tyrfingsson¹⁰, Gudmundur Einarsson¹¹, Daniel F Gudbjartsson¹¹, Bradley Todd Webb¹, Richard C Crist¹², Henry R Kranzler¹², Richard Sherva¹³, Hang Zhou¹⁴, Gary Hulse¹⁵, Dieter Wildenauer¹⁵, Erin Kelty¹⁶, John Attia¹⁷, Elizabeth G Holliday^{17

18}, Mark McEvoy^{17

18}, Rodney J Scott¹⁹, Sibylle G Schwab²⁰, Brion S Maher²¹, Richard Gruza²², Mary Jeanne Kreek², Elliot C Nelson³, Thorgeir Thorgeirsson¹¹, Kari Stefansson^{11

23}, Wade H Berrettini¹², Joel Gelernter²⁴, Howard J Edenberg²⁵, Laura Bierut²⁶, Dana B Hancock¹, Eric Otto Johnson^#^{27

28}

Affiliations

¹ GenOmics, Bioinformatics, and Translational Research Center, Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, NC, USA.
² The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA.
³ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
⁴ Dr. Miriam and Sheldon G. Adelson Clinic for Drug Abuse, Treatment and Research, Las Vegas, NV, USA.
⁵ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁶ National Drug and Alcohol Research Centre, University of New South Wales, Randwick, NSW, Australia.
⁷ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
⁸ Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁹ Department of Psychiatry, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
¹⁰ SAA-National Center of Addiction Medicine, Vogur Hospital, Reykjavik, Iceland.
¹¹ deCODE Genetics/Amgen, Reykjavik, Iceland.
¹² Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
¹³ Genome Science Institute, Boston University, Boston, MA, USA.
¹⁴ Department of Psychiatry, Yale University School of Medicine, West Haven, CT, USA.
¹⁵ School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, WA, Australia.
¹⁶ School of Population and Global Health, Population and Public Health, The University of Western Australia, Perth, WA, Australia.
¹⁷ Hunter Medical Research Institute, Newcastle, Australia.
¹⁸ School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia.
¹⁹ School of Biomedical Sciences and Pharmacy College of Health, Medicine and Wellbeing, The University of Newcastle, New Lambton Heights, NSW, Australia.
²⁰ Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia.
²¹ Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
²² Department of Family and Community Medicine, Saint Louis University, Saint Louis, MO, USA.
²³ Faculty of Medicine, University of Iceland, Reyjavik, Iceland.
²⁴ Department of Psychiatry, Genetics, & Neuroscience, Yale University School of Medicine, West Haven, CT, USA.
²⁵ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
²⁶ Department of Psychiatry, Washington University, St. Louis, MO, USA.
²⁷ GenOmics, Bioinformatics, and Translational Research Center, Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, NC, USA. ejohnson@rti.org.
²⁸ Fellow Program, RTI International, Research Triangle Park, NC, USA. ejohnson@rti.org.

^# Contributed equally.

PMID: 36207451
PMCID: PMC9546890
DOI: 10.1038/s41598-022-21003-y

Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond

Nathan Gaddis et al. Sci Rep. 2022.

. 2022 Oct 7;12(1):16873.

doi: 10.1038/s41598-022-21003-y.

Authors

Affiliations

¹ GenOmics, Bioinformatics, and Translational Research Center, Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, NC, USA.
² The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, NY, USA.
³ Department of Psychiatry, Washington University School of Medicine, St. Louis, MO, USA.
⁴ Dr. Miriam and Sheldon G. Adelson Clinic for Drug Abuse, Treatment and Research, Las Vegas, NV, USA.
⁵ Genetic Epidemiology, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁶ National Drug and Alcohol Research Centre, University of New South Wales, Randwick, NSW, Australia.
⁷ Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia.
⁸ Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
⁹ Department of Psychiatry, State University of New York Downstate Medical Center, Brooklyn, NY, USA.
¹⁰ SAA-National Center of Addiction Medicine, Vogur Hospital, Reykjavik, Iceland.
¹¹ deCODE Genetics/Amgen, Reykjavik, Iceland.
¹² Department of Psychiatry, University of Pennsylvania, Philadelphia, PA, USA.
¹³ Genome Science Institute, Boston University, Boston, MA, USA.
¹⁴ Department of Psychiatry, Yale University School of Medicine, West Haven, CT, USA.
¹⁵ School of Psychiatry and Clinical Neurosciences, The University of Western Australia, Perth, WA, Australia.
¹⁶ School of Population and Global Health, Population and Public Health, The University of Western Australia, Perth, WA, Australia.
¹⁷ Hunter Medical Research Institute, Newcastle, Australia.
¹⁸ School of Medicine and Public Health, The University of Newcastle, Callaghan, NSW, Australia.
¹⁹ School of Biomedical Sciences and Pharmacy College of Health, Medicine and Wellbeing, The University of Newcastle, New Lambton Heights, NSW, Australia.
²⁰ Faculty of Science, Medicine and Health, University of Wollongong, Wollongong, NSW, Australia.
²¹ Department of Mental Health, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
²² Department of Family and Community Medicine, Saint Louis University, Saint Louis, MO, USA.
²³ Faculty of Medicine, University of Iceland, Reyjavik, Iceland.
²⁴ Department of Psychiatry, Genetics, & Neuroscience, Yale University School of Medicine, West Haven, CT, USA.
²⁵ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
²⁶ Department of Psychiatry, Washington University, St. Louis, MO, USA.
²⁷ GenOmics, Bioinformatics, and Translational Research Center, Biostatistics and Epidemiology Division, RTI International, Research Triangle Park, NC, USA. ejohnson@rti.org.
²⁸ Fellow Program, RTI International, Research Triangle Park, NC, USA. ejohnson@rti.org.

^# Contributed equally.

PMID: 36207451
PMCID: PMC9546890
DOI: 10.1038/s41598-022-21003-y

Abstract

Opioid addiction (OA) is moderately heritable, yet only rs1799971, the A118G variant in OPRM1, has been identified as a genome-wide significant association with OA and independently replicated. We applied genomic structural equation modeling to conduct a GWAS of the new Genetics of Opioid Addiction Consortium (GENOA) data together with published studies (Psychiatric Genomics Consortium, Million Veteran Program, and Partners Health), comprising 23,367 cases and effective sample size of 88,114 individuals of European ancestry. Genetic correlations among the various OA phenotypes were uniformly high (r_g > 0.9). We observed the strongest evidence to date for OPRM1: lead SNP rs9478500 (p = 2.56 × 10^-9). Gene-based analyses identified novel genome-wide significant associations with PPP6C and FURIN. Variants within these loci appear to be pleiotropic for addiction and related traits.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Figure 1**
Genomic SEM model and Manhattan plot. (a) A common factor (p_g) gSEM model (using GenomicSEM) is fit with summary statistics from GENOA, MVP12-YP-SAGE, PGC, and Partners Health cohorts. Standardized estimates and standard errors are shown for each free parameter. Model fit is shown by a non-significant chi-square test, high Akaike information criterion (AIC, higher is better) and comparative fit index (CFI) equal to 1.0, and low standardized root mean squared root (SRMR) values (ideally < 0.05). (b) Manhattan plot for gSEM results with summary statistics from GWAS from each cohort. Bonferroni correction was used to correct for multiple comparisons; associations with P < 2 × 10^–8 (indicated by horizontal black bar) were genome-wide significant (top SNP highlighted in red).

**Figure 2**
Association of major haplotypes for genome-wide significant *OPRM1* variants with OA. (a) The 3 major haplotypes for genome-wide significant *OPRM1* variants. Haplotype A is the predominant haplotype (frequency ~ 0.69 among contributing cohorts) and consists of major alleles for all variants. Haplotype B (frequency ~ 0.13 among contributing cohorts) consists of the minor allele for rs1799971 and the major allele for all other variants. Haplotype C (frequency ~ 0.16 among contributing cohorts) consists of the major allele for rs1799971 and minor allele for all other variants. The cohorts for whom we had the raw data to conduct the haplotype analyses were: UHS, VIDUS, ODB, Yale-Penn, CATS and Kreek (Supplementary Table 1). (b) Association of *OPRM1* haplotypes with OA. Haplotype C is associated with increased risk of OA when compared to Haplotype A or Haplotype B, whereas Haplotype B does not have a significant impact on OA relative to Haplotype A. The single variant results using the cohorts contributing to the haplotype analyses were: rs1799971 beta = -– 0.058, p = 0.135; rs9478500 beta = 0.205, p = 2.43 × 10^–9.

**Figure 3**
Genetic correlations of opioid addiction (OA) with 38 other brain-related phenotypes. Correlations were calculated using linkage disequilibrium (LD) score regression with the gSEM OA GWAS meta-analysis results, compared with results made available via LD Hub or study investigators (see Supplementary Table 24 for original references). Phenotypes were grouped by disease/trait or measurement category, as indicated by different colorings. Dots indicate the mean values for genetic correlation (r_g); error bars show the 95% confidence intervals; the dashed vertical black line corresponds to r_g = 0 (no correlation with OA), and the solid vertical black line corresponds to r_g = 1.0 (complete correlation with OA). Phenotypes with significant correlation with OA are bolded (1 degree of freedom Chi-square test; Bonferroni adjusted p-value < 0.05 after accounting for 38 independent tests). Exact p-values are provided in Supplementary Table 10). CUD, Cannabis use disorder; DPW, drinks per week; FTND, Fagerström test for nicotine dependence; HSI, heaviness of smoking index; CPD, cigarettes per day; ADHD, attention deficit hyperactivity disorder; PTSD, post-traumatic stress disorder; MDD, major depressive disorder; ASD, autism spectrum disorder; ICV, intracranial volume.

**Figure 4**
Gene-level Manhattan Plot. GWAS results were summarized at the gene-level using MAGMA. Bonferroni correction was used to correct for multiple comparisons; associations with P < 3 × 10^–6 (indicated by horizontal red dotted line) were genome-wide significant.

**Figure 5**
Colocalization of GWAS loci and QTLs for selected genes across 10 brain tissues. Posterior probabilities of supporting hypotheses regarding the association of each trait with SNPs in a region were calculated using coloc. For *OPRM1*, SNP-gene cis-eQTL associations were reported in GTEx Analysis v8 for only 6 of the 10 tissues.

See this image and copyright information in PMC

References

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Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond

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Multi-trait genome-wide association study of opioid addiction: OPRM1 and beyond

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Conflict of interest statement

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