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

Nathan Gaddis; Ravi Mathur; Jesse Marks; Linran Zhou; Bryan Quach; Alex Waldrop; Orna Levran; Arpana Agrawal; Matthew Randesi; Miriam Adelson; Paul W Jeffries; Nicholas G Martin; Louisa Degenhardt; Grant W Montgomery; Leah Wetherill; Dongbing Lai; Kathleen Bucholz; Tatiana Foroud; Bernice Porjesz; Valgerdur Runarsdottir; Thorarinn Tyrfingsson; Gudmundur Einarsson; Daniel F Gudbjartsson; Bradley Todd Webb; Richard C Crist; Henry R Kranzler; Richard Sherva; Hang Zhou; Gary Hulse; Dieter Wildenauer; Erin Kelty; John Attia; Elizabeth G Holliday; Mark McEvoy; Rodney J Scott; Sibylle G Schwab; Brion S Maher; Richard Gruza; Mary Jeanne Kreek; Elliot C Nelson; Thorgeir Thorgeirsson; Kari Stefansson; Wade H Berrettini; Joel Gelernter; Howard J Edenberg; Laura Bierut; Dana B Hancock; Eric Otto Johnson

doi:10.1038/s41598-022-21003-y

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

Sci Rep. 2022 Oct 7;12(1):16873. doi: 10.1038/s41598-022-21003-y.

Authors

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.

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Furin / genetics
Genetic Predisposition to Disease
Genome-Wide Association Study*
Humans
Opioid-Related Disorders* / genetics
Phenotype
Polymorphism, Single Nucleotide
Receptors, Opioid, mu / genetics

Substances

OPRM1 protein, human
Receptors, Opioid, mu
Furin

Abstract

Publication types

MeSH terms

Substances

Grants and funding