Opioid use disorder and brain health: observational and genetic associations DOI
Sara Javidnia, James M. Roe, Ville Karhunen

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 19, 2024

Abstract Background The long-term impact of opioid use disorder (OUD) on brain health has been little explored although potentially high public importance. Objectives To investigate the potential causal OUD later life outcomes, including dementia, stroke and structure. Methods Observational Mendelian randomization (MR) analyses were conducted. Participants included in observational enrolled US Million Veteran Program (MVP). Cox proportional hazards used to examine association between electronic record (EHR)-derived diagnoses incident dementia European African ancestry populations. Two-sample MR was applied explore genetic predisposition as well key endophenotypes Several for insight into aetiological pathways, cis-MR assess genetically-proxied receptor perturbation, Bayesian colocalization, polygenic risk score longitudinal changes non-opioid users from Lifebrain project (n=229). Results Amongst 222,518 MVP participants, 8397 developed during follow up. with (n=9,399) younger more likely be male. In analyses, associated a higher all-cause (hazard ratio [HR]=1.56, 95% confidence interval [CI] [1.39,1.76];p=2.23×10 -13 ), Alzheimer’s [HR=1.40[1.04,1.87]; p=0.02) vascular (HR=1.49[1.19,1.86];p=0.0004). analysis, also risk. A doubling prevalence 77% increase odds (IVW OR=1.77[1.43,2.19];p=1.69×10 ⁻⁷ ). Variation μ-opioid genes strongly No significant associations observed structure users, nor lower powered non-European groups. Conclusions These findings suggest dementia. Genetic supported an role pathways. Further pharmacovigilance investigation effects opioids are warranted.

Language: Английский

Brain-wide pleiotropy investigation of alcohol drinking and tobacco smoking behaviors DOI Creative Commons
Giovanni Deiana, Jun He, Brenda Cabrera‐Mendoza

et al.

Translational Psychiatry, Journal Year: 2025, Volume and Issue: 15(1)

Published: Feb. 20, 2025

To investigate the pleiotropic mechanisms linking brain structure and function to alcohol drinking tobacco smoking, we integrated genome-wide data generated by GWAS Sequencing Consortium of Alcohol Nicotine use (GSCAN; up 805,431 participants) with information related 3935 imaging-derived phenotypes (IDPs) available from UK Biobank (N = 33,224). We observed global genetic correlation smoking behaviors white matter hyperintensities, morphology superior longitudinal fasciculus, mean thickness pole-occipital. With respect latter IDP, identified a local age at which individual began regularly (hg38 chr2:35,895,678-36,640,246: rho 1, p 1.01 × 10-5). This region has been previously associated initiation, educational attainment, chronotype, cortical thickness. Our genetically informed causal inference analysis using both latent variable approach Mendelian randomization linked activity prefrontal premotor cortex that inferior precentral sulci, cingulate sulci number alcoholic drinks per week (genetic causality proportion, gcp 0.38, 8.9 10-4, -0.18 ± 0.07; inverse variance weighting, IVW beta -0.04, 95%CI -0.07--0.01). relationship could be role these regions in modulation reward-seeking motivation processing social cues. Overall, our brain-wide investigation highlighted different likely contribute suggesting decision-making activities chemosensory as modulators propensity towards consumption.

Language: Английский

Citations

0
Gene discovery and pleiotropic architecture of Chronic Pain in a Genome-wide Association Study of >1.2 million Individuals DOI Creative Commons
Sylvanus Toikumo, Christal N. Davis, Zeal Jinwala

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 5, 2025

ABSTRACT Chronic pain is highly prevalent worldwide, and genome-wide association studies (GWAS) have identified a growing number of chronic loci. To further elucidate its genetic architecture, we leveraged data from 1,235,695 European ancestry individuals across three biobanks. In meta-analytic GWAS, 343 independent loci for pain, 92 which were new. Sex-specific meta-analyses revealed 115 (12 new) males (N = 583,066) 12 (two females 241,266). Multi-omics gene prioritization analyses highlighted 490 genes associated with through their effects on brain- blood-specific regulation. Loci increased risk also multiple other traits, Mendelian randomization showing that was causally psychiatric disorders, substance use C-reactive protein levels. variants exhibited pleiotropic associations cortical area brain structures. This study expands our knowledge the genetics pathogenesis, highlighting importance pleiotropy disorders elucidating multi-omic pathophysiology.

Language: Английский

Citations

0
Alcohol use disorder and body mass index show genetic pleiotropy and shared neural associations DOI
Samantha G. Malone, Christal N. Davis,

Zachary Piserchia

et al.

Nature Human Behaviour, Journal Year: 2025, Volume and Issue: unknown

Published: March 31, 2025

Language: Английский

Citations

0
Alcohol use disorder and body mass index show genetic pleiotropy and shared neural associations DOI Creative Commons

Samantha G. Malone,

Christal N. Davis,

Zachary Piserchia

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 5, 2024

Abstract Despite neurobiological overlap, alcohol use disorder (AUD) and body mass index (BMI) show minimal genetic correlation (r g ), possibly due to mixed directions of shared variants. We applied MiXeR investigate architecture between AUD BMI, conjunctional false discovery rate (conjFDR) detect loci their directional effect, Local Analysis (co)Variant Association (LAVA) for local r , Functional Mapping Annotation (FUMA) identify lead single nucleotide polymorphisms (SNPs), Genotype-Tissue Expression (GTEx) examine tissue enrichment, BrainXcan assess associations with brain phenotypes. indicated 82.2% polygenic despite a −.03. ConjFDR identified 132 SNPs, 53 novel, showing both concordant discordant effects. GTEx analyses overexpression in multiple regions. Amygdala caudate nucleus volumes were associated BMI. Opposing variant effects explain the rg implicated regions involved executive function reward, clarifying overlap mechanisms.

Language: Английский

Citations

0
Brain-wide pleiotropy investigation of alcohol drinking and tobacco smoking behaviors DOI Open Access
Giovanni Deiana, Jun He, Brenda Cabrera‐Mendoza

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: May 28, 2024

ABSTRACT To investigate the pleiotropic mechanisms linking brain structure and function to alcohol drinking tobacco smoking, we integrated genome-wide data generated by GWAS Sequencing Consortium of Alcohol Nicotine use (GSCAN; up 805,431 participants) with information related 3,935 imaging-derived phenotypes (IDPs) available from UK Biobank (N=33,224). We observed global genetic correlation smoking behaviors white matter hyperintensities, morphology superior longitudinal fasciculus, mean thickness pole-occipital. With respect latter IDP, identified a local age at which individual began regularly (hg38 chr2:35,895,678-36,640,246: rho=1, p=1.01×10 −5 ). This region has been previously associated initiation, educational attainment, chronotype, cortical thickness. Our genetically informed causal inference analysis using both latent variable approach Mendelian randomization linked activity prefrontal premotor cortex that inferior precentral sulci, cingulate sulci number alcoholic drinks per week (genetic causality proportion, gcp=0.38, p=8.9×10 −4 , rho=-0.18±0.07; inverse variance weighting, IVW beta=-0.04, 95%CI=-0.07 – −0.01). relationship could be role these regions in modulation reward-seeking motivation processing social cues. Overall, our brain-wide investigation highlighted different likely contribute suggesting decision-making activities chemosensory as modulators propensity towards consumption.

Language: Английский

Citations

0
Opioid use disorder and brain health: observational and genetic associations DOI
Sara Javidnia, James M. Roe, Ville Karhunen

et al.

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Dec. 19, 2024

Abstract Background The long-term impact of opioid use disorder (OUD) on brain health has been little explored although potentially high public importance. Objectives To investigate the potential causal OUD later life outcomes, including dementia, stroke and structure. Methods Observational Mendelian randomization (MR) analyses were conducted. Participants included in observational enrolled US Million Veteran Program (MVP). Cox proportional hazards used to examine association between electronic record (EHR)-derived diagnoses incident dementia European African ancestry populations. Two-sample MR was applied explore genetic predisposition as well key endophenotypes Several for insight into aetiological pathways, cis-MR assess genetically-proxied receptor perturbation, Bayesian colocalization, polygenic risk score longitudinal changes non-opioid users from Lifebrain project (n=229). Results Amongst 222,518 MVP participants, 8397 developed during follow up. with (n=9,399) younger more likely be male. In analyses, associated a higher all-cause (hazard ratio [HR]=1.56, 95% confidence interval [CI] [1.39,1.76];p=2.23×10 -13 ), Alzheimer’s [HR=1.40[1.04,1.87]; p=0.02) vascular (HR=1.49[1.19,1.86];p=0.0004). analysis, also risk. A doubling prevalence 77% increase odds (IVW OR=1.77[1.43,2.19];p=1.69×10 ⁻⁷ ). Variation μ-opioid genes strongly No significant associations observed structure users, nor lower powered non-European groups. Conclusions These findings suggest dementia. Genetic supported an role pathways. Further pharmacovigilance investigation effects opioids are warranted.

Language: Английский

Citations

0