scholarly journals Genetic Variants Associated with Acamprosate Treatment Response in Alcohol Use Disorder Patients: A Multiple Omics Study

2022 ◽  
Author(s):  
Ming‐Fen Ho ◽  
Cheng Zhang ◽  
Lixuan Wei ◽  
Lingxin Zhang ◽  
Irene Moon ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Treatment Response ◽  
Genetic Variants ◽  
Alcohol Use Disorder

scholarly journals Prefrontal cortex eQTLs/mQTLs enriched in genetic variants associated with alcohol use disorder and other diseases

Epigenomics ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 789-800
Author(s):  
Honghuang Lin ◽  
Fan Wang ◽  
Andrew J Rosato ◽  
Lindsay A Farrer ◽  
David C Henderson ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Alcohol Use ◽  
Genetic Variants ◽  
Alcohol Use Disorder ◽  
Genome Wide Association Study ◽  
Disease Risk ◽  
Genome Wide ◽  
Morphine Addiction ◽  
Methylation Patterns ◽  
Methylation Quantitative Trait Loci

Aim: This study aimed to investigate the function of genome-wide association study (GWAS)-identified variants associated with alcohol use disorder (AUD)/comorbid psychiatric disorders. Materials & methods: Genome-wide genotype, transcriptome and DNA methylome data were obtained from postmortem prefrontal cortex (PFC) of 48 Caucasians (24 AUD cases/24 controls). Expression/methylation quantitative trait loci (eQTL/mQTL) were identified and their enrichment in GWAS signals for the above disorders were analyzed. Results: PFC cis-eQTLs (923 from cases+controls, 27 from cases and 98 from controls) and cis-mQTLs (9,932 from cases+controls, 264 from cases and 695 from controls) were enriched in GWAS-identified genetic variants for the above disorders. Cis-eQTLs from AUD cases were mapped to morphine addiction-related genes. Conclusion: PFC cis-eQTLs/ cis-mQTLs influence gene expression/DNA methylation patterns, thus increasing the disease risk.

scholarly journals Evidence of shared genetic influences underlying schizophrenia and alcohol use disorder, but not alcohol consumption

2020 ◽  
Author(s):  
Emma C. Johnson ◽  
Manav Kapoor ◽  
Alexander S. Hatoum ◽  
Hang Zhou ◽  
Renato Polimanti ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Alcohol Use ◽  
Genetic Variants ◽  
Alcohol Use Disorder ◽  
Association Studies ◽  
Genetic Correlations ◽  
Genome Wide Association Studies ◽  
Genetic Covariance ◽  
Genome Wide ◽  
Brain Tissues

AbstractBackgroundAlcohol use disorder (AUD) and schizophrenia (SCZ) frequently co-occur, and recent genome-wide association studies (GWAS) have identified significant genetic correlations between them. In parallel, mounting evidence from GWAS suggests that alcohol consumption is only weakly genetically correlated with SCZ, but this has not yet been systematically investigated.MethodsWe used the largest published GWAS for AUD (total cases = 77,822) and SCZ (total cases = 46,827) to systematically identify genetic variants that influence both disorders (in either the same or opposite direction of effect) as well as disorder-specific loci, and contrast our findings with GWAS data for drinks per week (DPW; N = 537,349) as a measure of alcohol consumption.ResultsWe identified 55 independent genome-wide significant SNPs with the same direction of effect on AUD and SCZ, 9 with robust opposite effects, and 99 with disorder-specific effects. We also found evidence for 12 genes whose pleiotropic associations with AUD and SCZ are consistent with mediation via gene expression in the prefrontal cortex. The genetic covariance between AUD and SCZ was concentrated in genomic regions functional in brain tissues (p = 0.001). The genetic correlation between DPW and SCZ (rg = 0.102, SE = 0.022) was significantly lower than that for AUD and SCZ (rg = 0.392, SE = 0.029; p-value of the difference = 9.3e-18), and the genetic covariance between DPW and SCZ was not enriched for any meaningful tissue-specific categories.ConclusionsOur findings provide a detailed view of genetic loci that influence risk of both AUD and SCZ, suggest that biological commonalities underlying genetic variants with an effect on both disorders are manifested in brain tissues, and provide further evidence that SCZ shares meaningful genetic overlap with AUD and not merely alcohol consumption.

scholarly journals Genetic variation within GRIN2B in adolescents with alcohol use disorder may be associated with larger left posterior cingulate cortex volume

2016 ◽  
Vol 29 (4) ◽  
pp. 252-258 ◽  
Author(s):  
Shareefa Dalvie ◽  
Samantha J. Brooks ◽  
Valerie Cardenas ◽  
George Fein ◽  
Raj Ramesar ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Genetic Variants ◽  
Alcohol Use Disorder ◽  
Brain Volume ◽  
Cingulate Cortex ◽  
Posterior Cingulate Cortex ◽  
Magnetic Resonance Images ◽  
Mixed Ancestry ◽  
Posterior Cingulate ◽  
Left Posterior

ObjectiveBrain structure differences and adolescent alcohol dependence both show substantial heritability. However, exactly which genes are responsible for brain volume variation in adolescents with substance abuse disorders are currently unknown. The aim of this investigation was to determine whether genetic variants previously implicated in psychiatric disorders are associated with variation in brain volume in adolescents with alcohol use disorder (AUD).MethodsThe cohort consisted of 58 adolescents with DSM-IV AUD and 58 age and gender-matched controls of mixed ancestry ethnicity. An Illumina Infinium iSelect custom 6000 bead chip was used to genotype 5348 single nucleotide polymorphisms (SNPs) in 378 candidate genes. Magnetic resonance images were acquired and volumes of global and regional structures were estimated using voxel-based morphometry. To determine whether any of the genetic variants were associated with brain volume, association analysis was conducted using linear regression in Plink.ResultsFrom the exploratory analysis, the GRIN2B SNP rs219927 was associated with brain volume in the left posterior cingulate cortex (p<0.05), whereby having a G-allele was associated with a bigger volume.ConclusionThe GRIN2B gene is involved in glutamatergic signalling and may be associated with developmental differences in AUD in brain regions such as the posterior cingulate cortex. Such differences may play a role in risk for AUD, and deserve more detailed investigation.

scholarly journals Genetic underpinnings of the transition from alcohol consumption to alcohol use disorder: shared and unique genetic architectures in a cross-ancestry sample

2021 ◽  
Author(s):  
Rachel L Kember ◽  
Rachel A. Vickers-Smith ◽  
Hang Zhou ◽  
Heng Xu ◽  
Cecilia Dao ◽  
...  
Keyword(s):  
Alcohol Consumption ◽  
Alcohol Use ◽  
Genetic Variants ◽  
Alcohol Use Disorder ◽  
Genetic Factors ◽  
Genetic Correlations ◽  
Heavy Drinking ◽  
Direct Effects ◽  
Heavy Alcohol Consumption ◽  
Program Sample

Recent GWAS of alcohol-related traits have uncovered key differences in the underlying genetic architectures of alcohol consumption and alcohol use disorder (AUD), with the two traits having opposite genetic correlations with psychiatric disorders. Understanding the genetic factors that underlie the transition from heavy drinking to AUD has important theoretical and clinical implications. We utilized longitudinal data from the cross-ancestry Million Veteran Program sample to identify 1) novel loci associated with AUD and alcohol consumption [measured by the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C)] and 2) genetic variants with direct effects on AUD not mediated through alcohol consumption. We identified 26 loci associated with AUD, including 5 ancestry-specific and 6 novel loci and 22 loci associated with AUDIT-C, including 3 ancestry-specific and 8 novel loci. In secondary GWAS that excluded individuals who report abstinence, we identify 7 additional loci for AUD and 8 additional loci for AUDIT-C. We demonstrate that, although the heterogeneity of the abstinent group biases the GWAS findings, unique variance between alcohol consumption and disorder remains after the group is excluded. Finally, using mediation analysis, we identified a set of variants with effects on AUD that are not mediated through alcohol consumption. The distinct genetic architectures of alcohol consumption and AUD suggest different biological contributions to the traits. Genetic variants with direct effects on AUD are potentially relevant to understanding the transition from heavy alcohol consumption to AUD and targets for translational prevention and treatment efforts.

TSPAN5 Regulates Serotonin and Kynurenine Levels: Pharmacogenomic Mechanisms Related to Alcohol Use Disorder and Acamprosate Treatment Response

2020 ◽  
Vol 87 (9) ◽  
pp. S342-S343
Author(s):  
Ming-Fen Ho ◽  
Cheng Zhang ◽  
Lingxin Zhang ◽  
Ying Zhou ◽  
Lixuan Wei ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Treatment Response ◽  
Alcohol Use Disorder

scholarly journals Genetic contributions to alcohol use disorder treatment outcomes: a genome-wide pharmacogenomics study

2021 ◽  
Author(s):  
Joanna M. Biernacka ◽  
Brandon J. Coombes ◽  
Anthony Batzler ◽  
Ada Man-Choi Ho ◽  
Jennifer R. Geske ◽  
...  
Keyword(s):  
Alcohol Use ◽  
Treatment Outcomes ◽  
Treatment Response ◽  
Alcohol Use Disorder ◽  
European Ancestry ◽  
Pharmacological Intervention ◽  
Polygenic Effect ◽  
Polygenic Risk Score ◽  
Genome Wide ◽  
A Genome

AbstractNaltrexone can aid in reducing alcohol consumption, while acamprosate supports abstinence; however, not all patients with alcohol use disorder (AUD) benefit from these treatments. Here we present the first genome-wide association study of AUD treatment outcomes based on data from the COMBINE and PREDICT studies of acamprosate and naltrexone, and the Mayo Clinic CITA study of acamprosate. Primary analyses focused on treatment outcomes regardless of pharmacological intervention and were followed by drug-stratified analyses to identify treatment-specific pharmacogenomic predictors of acamprosate and naltrexone response. Treatment outcomes were defined as: (1) time until relapse to any drinking (TR) and (2) time until relapse to heavy drinking (THR; ≥ 5 drinks for men, ≥4 drinks for women in a day), during the first 3 months of treatment. Analyses were performed within each dataset, followed by meta-analysis across the studies (N = 1083 European ancestry participants). Single nucleotide polymorphisms (SNPs) in the BRE gene were associated with THR (min p = 1.6E−8) in the entire sample, while two intergenic SNPs were associated with medication-specific outcomes (naltrexone THR: rs12749274, p = 3.9E−8; acamprosate TR: rs77583603, p = 3.1E−9). The top association signal for TR (p = 7.7E−8) and second strongest signal in the THR (p = 6.1E−8) analysis of naltrexone-treated patients maps to PTPRD, a gene previously implicated in addiction phenotypes in human and animal studies. Leave-one-out polygenic risk score analyses showed significant associations with TR (p = 3.7E−4) and THR (p = 2.6E−4). This study provides the first evidence of a polygenic effect on AUD treatment response, and identifies genetic variants associated with potentially medication-specific effects on AUD treatment response.

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