Genome-wide analyses reveal shared genetic architecture and novel risk loci between opioid use disorder and general cognitive ability

Børge Holen; Gleda Kutrolli; Alexey A Shadrin; Romain Icick; Guy Hindley; Linn Rødevand; Kevin S O'Connell; Oleksandr Frei; Nadine Parker; Markos Tesfaye; Joseph D Deak; Piotr Jahołkowski; Anders M Dale; Srdjan Djurovic; Ole A Andreassen; Olav B Smeland

doi:10.1016/j.drugalcdep.2023.111058

Genome-wide analyses reveal shared genetic architecture and novel risk loci between opioid use disorder and general cognitive ability

Drug Alcohol Depend. 2024 Mar 1:256:111058. doi: 10.1016/j.drugalcdep.2023.111058. Epub 2023 Dec 11.

Authors

Affiliations

¹ NORMENT, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0407, Norway. Electronic address: borge.holen@medisin.uio.no.
² NORMENT, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0407, Norway.
³ NORMENT, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0407, Norway; INSERM UMR-S1144, Université Paris Cité, F-75006, France.
⁴ NORMENT, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0407, Norway; NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.
⁵ Yale School of Medicine, New Haven, CT, USA; VA Connecticut Healthcare Center, West Haven, CT, USA.
⁶ Department of Radiology, University of California San Diego, La Jolla, CA 92093, USA; Multimodal Imaging Laboratory, University of California San Diego, La Jolla, CA 92093, USA; Department of Cognitive Science, University of California San Diego, La Jolla, CA, USA; Department of Psychiatry, University of California San Diego, La Jolla, CA, USA; Department of Neurosciences, University of California San Diego, La Jolla, CA 92093, USA.
⁷ Department of Medical Genetics, Oslo University Hospital, Oslo, Norway; NORMENT, Department of Clinical Science, University of Bergen, Bergen, Norway.
⁸ NORMENT, Institute of Clinical Medicine, University of Oslo and Division of Mental Health and Addiction, Oslo University Hospital, Oslo 0407, Norway. Electronic address: o.b.smeland@medisin.uio.no.

PMID: 38244365
DOI: 10.1016/j.drugalcdep.2023.111058

Abstract

Background: Opioid use disorder (OUD), a serious health burden worldwide, is associated with lower cognitive function. Recent studies have demonstrated a negative genetic correlation between OUD and general cognitive ability (COG), indicating a shared genetic basis. However, the specific genetic variants involved, and the underlying molecular mechanisms remain poorly understood. Here, we aimed to quantify and identify the genetic basis underlying OUD and COG.

Methods: We quantified the extent of genetic overlap between OUD and COG using a bivariate causal mixture model (MiXeR) and identified specific genetic loci applying conditional/conjunctional FDR. Finally, we investigated biological function and expression of implicated genes using available resources.

Results: We estimated that ~94% of OUD variants (4.8k out of 5.1k variants) also influence COG. We identified three novel OUD risk loci and one locus shared between OUD and COG. Loci identified implicated biological substrates in the basal ganglia.

Conclusion: We provide new insights into the complex genetic risk architecture of OUD and its genetic relationship with COG.

Keywords: Cognition; Genetic overlap; Genome-wide association study (GWAS); Opioid use disorder; Single nucleotide polymorphisms (SNPs).

MeSH terms

Cognition
Genome-Wide Association Study*
Humans
Opioid-Related Disorders* / genetics