Multi-trait genome-wide association study of opioid addiction:<i>OPRM1</i>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.; Johnson, Emma C.; Martin, Nicholas G.; Degenhardt, Louisa; Montgomery, Grant W.; Wetherill, Leah; Lai, Dongbing; Bucholz, Kathleen K.; Foroud, Tatiana; Porjesz, Bernice; Webb, Bradley T.; Crist, Richard C.; Kranzler, Henry R.; 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.; Berrettini, Wade H.; Gelernter, Joel; Edenberg, Howard J.; Bierut, Laura J.; Hancock, Dana B.; Johnson, Eric O.

doi:10.1101/2021.09.13.21263503

Cited by 10 publications

(10 citation statements)

References 78 publications

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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: Validation Analysessupporting

confidence: 64%

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: Validation Analysessupporting

confidence: 64%

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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“…We also report 4 novel hits (rs951740, p =9.70E-10, PTPRF ; rs12713405, p =9.70E-09, BLC11A; rs67660520, p =7.60E-09, CADPS2; rs7128649, p =2.50E-09, NCAM1 ). Intriguingly, PTPRF has been recently associated with problematic prescription opioid use (25) and opioid use disorder (84), as well as smoking initiation/cessation (66), cognition (85), and educational attainment (9) ( Table S9 ). Variants in strong LD with rs67660520 have been associated with ADHD (86), smoking initiation (66), number of sexual partners (82) and BMI (69) ( Table S9 ).…”

Section: Resultsmentioning

confidence: 99%

CADM2is implicated in impulsive personality and numerous other traits by genome- and phenome-wide association studies in humans and mice

Sanchez‐Roige

Jennings

Thorpe

et al. 2022

Preprint

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Background: Impulsivity is a multidimensional heritable phenotype that broadly refers to the tendency to act prematurely and is associated with multiple forms of psychopathology. Methods: We performed genome-wide association studies (GWAS) of eight impulsive personality traits from the Barratt Impulsiveness Scale and the short UPPS-P Impulsive Personality Scale (N=123,509-133,517 23andMe research participants of European ancestry), and a measure of Drug Experimentation (N=130,684). Because these GWAS implicated the gene CADM2, we next performed a phenome-wide study (PheWAS) in a multi-ancestral 23andMe cohort (N=3,229,317, European; N=579,623, Latinx; N=199,663, African American). Finally, we produced Cadm2 knock-out mice and tested them using a battery of behavioral impulsivity tasks. Results: In humans, impulsive personality traits showed modest chip-heritability (~6-10%), and moderate genetic correlations (rg=.20-.50) with other personality traits, and various psychiatric and medical traits. We replicated associations from earlier GWAS of these traits and found novel associations including DRD2, CRHR1, FOXP2, TCF4, PTPRF. PheWAS for CADM2 identified associations with 378 traits in European participants, and 47 traits in Latinx participants, replicating associations with risky behaviors, and revealing novel associations including allergies, anxiety, irritable bowel syndrome, and migraine. Cadm2 knock-out mice showed reduced impulsivity in the 5-choice serial reaction time task, while heterozygote mice showed lower risky behavior in the mouse Iowa gambling task. Conclusions: Our results further establish the role of CADM2 in impulsivity and numerous other psychiatric and somatic traits across ancestries. Additionally, we demonstrate that deletion of Cadm2 in mice influences behavior in assays designed to measure impulsive and risky behavior.

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“…GWAS has taken the lead surpassing the previous candidate gene-driven approaches. GWAS has paved the way for the identification of common genetic variants such as single nucleotide variants (SNVs), rare variants, and structural variants [e.g., copy number variants (CNVs)] (Gaddis et al, 2021).…”

Section: Genome-wide Association Studies In Opioid Addictionmentioning

confidence: 99%

International Journal of KIU

2022

IJKIU

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International Journal of KIU is a peer-reviewed multidisciplinary open access journal published online and bi-annually in print version. The Journal provides a research platform for the researchers and practitioners in all regions of the world thus contributing new insights into current and emerging concepts, theories, research and practice through diverse disciplines. The Journal maintains high quality standards by exercising peer review and editorial quality control. Facts and opinions in articles published on International Journal of KIU are solely the personal statements of respective authors. Authors are responsible for all contents in their article(s) including accuracy of the facts, statements, citing resources, and so on. International Journal of KIU and editors disclaim any liability of violations of other parties’ rights, or any damage incurred therefore to use or apply any of the contents of the International Journal of KIU. Material submitted to International Journal of KIU considered to be original and not published or submitted for publication elsewhere. All rights reserved by International Journal of KIU. No part of this publication may be reproduced, stored or transmitted in any form or by any means without the prior permission in writing from the copyright holder. Special requests should be addressed to editor@kiu.ac.lk

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Multi-trait genome-wide association study of opioid addiction:OPRM1and Beyond

Cited by 10 publications

References 78 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

CADM2is implicated in impulsive personality and numerous other traits by genome- and phenome-wide association studies in humans and mice

International Journal of KIU

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