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

Gaddis, Nathan; Mathur, Ravi; Marks, Jesse; Zhou, Linran; Quach, Bryan C.; Waldrop, Alex; Levran, Orna; Agrawal, Arpana; Randesi, Matthew; Adelson, Miriam; Jeffries, Paul W.; Martin, Nicholas G.; Degenhardt, Louisa; Montgomery, Grant W.; Wetherill, Leah; Lai, Dongbing; Bucholz, Kathleen K.; Foroud, Tatiana; Porjesz, Bernice; Rúnarsdóttir, Valgerður; Einarsson, Guðmundur; Guðbjartsson, Daníel F.; Webb, Bradley T.; Crist, Richard C.; Kranzler, Henry R.; Sherva, Richard; Zhou, Hang; Hulse, Gary Kenneth; Wildenauer, Dieter B.; Kelty, Erin; Attia, John; Holliday, Elizabeth G.; McEvoy, Mark; Scott, Rodney J.; Schwab, Sibylle G.; Maher, Brion S.; Gruza, Richard; Kreek, Mary Jeanne; Nelson, Elliot C.; Thorgeirsson, Thorgeir E.; Stefánsson, Kári; Berrettini, Wade H.; Gelernter, Joel; Edenberg, Howard J.; Bierut, Laura J.; Hancock, Dana B.; Johnson, Eric O.

doi:10.1038/s41598-022-21003-y

Cited by 50 publications

(62 citation statements)

References 71 publications

(104 reference statements)

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“…Finally, no lead variants in the shared loci for OUD and psychiatric disorders, had a p-value <0.05 in the independent AA GWAS dataset on OUD 21 . A total of four of the OUD risk loci identified by conjFDR were identified in recent larger GWAS on OUD, specifically the PPP6C 42 , NCAM1 39 , DRD2 39 and FURIN 39,42,43 loci, supporting the validity of the results.…”

Section: Resultssupporting

confidence: 64%

“…It has previously been associated with SCZ 40 , BD 27 and MD 41 . This locus was not identified in the original OUD GWAS 21 , but reached genome-wide significance in subsequent GWAS on OUD, validating this finding 39,42,43 . The lead SNP rs4702 is shown to influence the expression of its nearest gene FURIN in neurons derived from human induced pluripotent stem cells, and influence synaptic function in synergy with other SCZ risk variants 50 .…”

Section: Discussionmentioning

confidence: 69%

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Genome-wide analyses reveal novel opioid use disorder loci and genetic overlap with schizophrenia, bipolar disorder, and major depression

Holen

Shadrin

Icick

et al. 2022

Preprint

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Opioid use disorder (OUD) and mental disorders are often comorbid, with increased morbidity and mortality. The causes underlying this relationship are poorly understood. Although these conditions are highly heritable, their shared genetic vulnerabilities remain unaccounted for. We applied the conditional/conjunctional false discovery rate (cond/conjFDR) approach to analyse summary statistics from independent genome wide association studies of OUD, SCZ, BD and MD. Next, we characterized the identified shared loci using biological annotation resources. OUD data was obtained from the Million Veteran Program (15,756 cases 99,039 controls). SCZ (53,386 cases 77,258 controls), BD (41,917 cases 371,549 controls) and MD (170,756 cases 329,443 controls) data was provided by the Psychiatric Genomics Consortium. We discovered genetic enrichment for OUD conditional on associations with SCZ, BD, MD and vice versa, indicating polygenic overlap with identification of 14 novel OUD loci at condFDR<0.05 and 7 unique loci shared between OUD and SCZ (n=2), BD (n=2) and MD (n=7) at conjFDR<0.05 with concordant effect directions, in line with estimated positive genetic correlations. Two loci were novel for OUD, one for BD and one for MD. Three OUD risk loci were shared with more than one psychiatric disorder, at DRD2 on chromosome 11 (BD and MD), at FURIN on chromosome 15 (SCZ, BD and MD), and at the major histocompatibility complex region (SCZ and MD). Our findings provide new insights into the shared genetic architecture between OUD and SCZ, BD, and MD, indicating a complex genetic relationship, suggesting overlapping neurobiological pathways.

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Section: Resultssupporting

confidence: 64%

Section: Discussionmentioning

confidence: 69%

Genome-wide analyses reveal novel opioid use disorder loci and genetic overlap with schizophrenia, bipolar disorder, and major depression

Holen

Shadrin

Icick

et al. 2022

Preprint

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“…Although these traits are known to be genetically correlated, it is unknown whether there is a shared genetic structure between OUD, other substance use, and psychiatric disorders. Negative r g 's were seen for educational attainment 13,15,16 , cognitive performance 13 and subjective wellbeing 16 . Causal effects on OUD for some of these traits were identi ed via Mendelian randomization (MR) analysis.…”

Section: Introductionmentioning

confidence: 98%

“…A GWAS of prescription opioid misuse in an EA sample from 23andMe (27,805 cases) identi ed 2 novel GWS loci 15 . A metaanalysis of European-ancestry individuals included 23,367 cases ascertained using either Diagnostic and Statistical Manual of Mental Disorders diagnoses (DSM) or frequency of opioid use (FOU) and 384,629 controls 16 . Using a latent trait [opioid addiction (OA)] generated from a genomic structural equation model to conduct GWAS, the group identi ed GWS SNPs in OPRM1 and, in gene-based analyses, PPP6C and FURIN.…”

Section: Introductionmentioning

confidence: 99%

“…These studies also identi ed signi cant genetic correlations (r g 's) with traits well known to co-occur with OUD, suggesting widespread pleiotropy. The strongest positive r g 's were with substance-related traits (e.g., alcohol dependence/use disorder, cannabis use disorder, drinks/week, cigarettes/day) 12,13,15,16 , and psychiatric disorders (e.g., attention de cit hyperactivity disorder (ADHD), posttraumatic stress disorder (PTSD), major depressive disorder (MDD), schizophrenia, bipolar disorder, neuroticism) 13,15,16 . Although these traits are known to be genetically correlated, it is unknown whether there is a shared genetic structure between OUD, other substance use, and psychiatric disorders.…”

Section: Introductionmentioning

confidence: 99%

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Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction

Kember

Vickers-Smith²,

Xu³

et al. 2022

Nat Neurosci

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Despite an estimated twin heritability of ~50%, genome-wide association studies (GWAS) of opioid use disorder (OUD) have revealed few genome-wide signi cant (GWS) loci, with replicated ndings only in European-ancestry individuals. To identify novel loci, including those in non-European ancestries, and improve our understanding of the biology of OUD, we conducted a cross-ancestry meta-analysis using the Million Veteran Program (MVP). OUD cases in MVP had at least 1 International Classi cation of Diseases (ICD)-9 or ICD-10 code for opioid abuse or dependence (N=31,473). Opioid-exposed controls (N=394,471) had one or more outpatient opioid prescription lls. We conducted GWAS for each major ancestral group in MVP: African Americans (AAs; N=88,498), European Americans (EAs; N=302,585), and Hispanic Americans (HAs; N=34,861), followed by a cross-ancestry meta-analysis. Ten loci were GWS in the cross-ancestry meta-analysis, 8 of them novel. In addition to the known coding variant rs1799971 in OPRM1, which was the lead SNP genome-wide (p=6.78x10 −10 ), and a recently reported exonic variant in FURIN, we identi ed intronic variants in RABEPK, FBXW4, NCAM1, and KCNN1. Ancestry-speci c analyses identi ed an additional novel locus for each of the 3 ancestry groups. A supplementary meta-analysis within EAs that included MVP and other samples identi ed a locus in TSNARE1, which was also GWS in the cross-ancestry meta-analysis of all datasets. Gene-based association analyses identi ed 1 gene in AAs (CHRM2) and 3 in EAs (OPRM1, DRD2, and FTO). Signi cant genetic correlations (r g 's) were identi ed for 127 traits, including positive correlations with schizophrenia, problematic alcohol use, and major depressive disorder. The most signi cantly enriched cell type group was the central nervous system with gene-expression enrichment identi ed in brain regions previously associated with substance use disorders. With a case sample 50% larger than that of the previous largest GWAS, we identi ed 14 loci for OUD, including 12 novel loci, some of which were ancestry speci c. These ndings increase our understanding of the biological pathways involved in OUD, which can inform preventive, diagnostic, and therapeutic efforts and thereby help to address the opioid epidemic. Revision (ICD-10) diagnosis of OUD and control subjects were opioid exposed. Further details on phenotyping are described below. This GWAS was used for all subsequent downstream analyses.In a supplementary analysis, we performed within-ancestry meta-analyses for AAs and EAs from the MVP, Yale-Penn

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Institutional and Regional Variation in Opioid Prescribing for Hospitalized Infants in the US

Keane,

Ourshalimian,

Lakshmanan

et al. 2024

JAMA Netw Open

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ImportanceHigh-risk infants, defined as newborns with substantial neonatal-perinatal morbidities, often undergo multiple procedures and require prolonged intubation, resulting in extended opioid exposure that is associated with poor outcomes. Understanding variation in opioid prescribing can inform quality improvement and best-practice initiatives.ObjectiveTo examine regional and institutional variation in opioid prescribing, including short- and long-acting agents, in high-risk hospitalized infants.Design, Setting, and ParticipantsThis retrospective cohort study assessed high-risk infants younger than 1 year from January 1, 2016, to December 31, 2022, at 47 children’s hospitals participating in the Pediatric Health Information System (PHIS). The cohort was stratified by US Census region (Northeast, South, Midwest, and West). Variation in cumulative days of opioid exposure and methadone treatment was examined among institutions using a hierarchical generalized linear model. High-risk infants were identified by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes for congenital heart disease surgery, medical and surgical necrotizing enterocolitis, extremely low birth weight, very low birth weight, hypoxemic ischemic encephalopathy, extracorporeal membrane oxygenation, and other abdominal surgery. Infants with neonatal opioid withdrawal syndrome, in utero substance exposure, or malignant tumors were excluded.ExposureAny opioid exposure and methadone treatment.Main Outcomes and MeasuresRegional and institutional variations in opioid exposure.ResultsOverall, 132 658 high-risk infants were identified (median [IQR] gestational age, 34 [28-38] weeks; 54.5% male). Prematurity occurred in 30.3%, and 55.3% underwent surgery. During hospitalization, 76.5% of high-risk infants were exposed to opioids and 7.9% received methadone. Median (IQR) length of any opioid exposure was 5 (2-12) cumulative days, and median (IQR) length of methadone treatment was 19 (7-46) cumulative days. There was significant hospital-level variation in opioid and methadone exposure and cumulative days of exposure within each US region. The computed intraclass correlation coefficient estimated that 16% of the variability in overall opioid prescribing and 20% of the variability in methadone treatment was attributed to the individual hospital.Conclusions and RelevanceIn this retrospective cohort study of high-risk hospitalized infants, institution-level variation in overall opioid exposure and methadone treatment persisted across the US. These findings highlight the need for standardization of opioid prescribing in this vulnerable population.

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

Cited by 50 publications

References 71 publications

Genome-wide analyses reveal novel opioid use disorder loci and genetic overlap with schizophrenia, bipolar disorder, and major depression

Genome-wide analyses reveal novel opioid use disorder loci and genetic overlap with schizophrenia, bipolar disorder, and major depression

Cross-ancestry meta-analysis of opioid use disorder uncovers novel loci with predominant effects in brain regions associated with addiction

Institutional and Regional Variation in Opioid Prescribing for Hospitalized Infants in the US

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