Genome-wide association study for circulating FGF21 in patients with alcohol use disorder: Molecular links between the SNHG16 locus and catecholamine metabolism

Ho, Ming‐Fen; Zhang, Cheng; Moon, Irene; Wei, Lixuan; Coombes, Brandon J.; Biernacka, Joanna M.; Skime, Michelle; Choi, Doo Sup; Frye, Mark A.; Schmidt, Kristen; Gliske, Kate; Braughton, Jacqueline; Ngo, Quyen; Skillon, Cedric; Seppala, Marvin; Oesterle, Tyler S.; Karpyak, Victor M.; Li, Hu; Weinshilboum, Richard M.

doi:10.1016/j.molmet.2022.101534

Cited by 8 publications

(11 citation statements)

References 41 publications

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“…Our previous studies suggested that craving intensity ( p : 9.36E-06) was the most significant predictor of acamprosate treatment outcome [ 23 , 24 ]. We set out in the present experiments to study the craving pathophysiology and anti-craving drugs’ effect.…”

Section: Resultsmentioning

confidence: 99%

“…The primary outcome of the clinical trial was acamprosate treatment response [ 21 , 22 ]. We previously identified alcohol craving as the most significant clinical phenotype associated with treatment outcomes [ 23 , 24 ]. Specifically, higher baseline craving intensity was associated with relapse to alcohol use during the three months of acamprosate treatment [ 22 , 23 , 25 ].…”

Section: Introductionmentioning

confidence: 99%

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Molecular mechanisms involved in alcohol craving, IRF3, and endoplasmic reticulum stress: a multi-omics study

Ho,

Zhang,

Moon

et al. 2024

Transl Psychiatry

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Alcohol use disorder (AUD) is the most prevalent substance use disorder worldwide. Acamprosate and naltrexone are anti-craving drugs used in AUD pharmacotherapy. However, molecular mechanisms underlying their anti-craving effect remain unclear. This study utilized a patient-derived induced pluripotent stem cell (iPSC)-based model system and anti-craving drugs that are used to treat AUD as “molecular probes” to identify possible mechanisms associated with alcohol craving. We examined the pathophysiology of craving and anti-craving drugs by performing functional genomics studies using iPSC-derived astrocytes and next-generation sequencing. Specifically, RNA sequencing performed using peripheral blood mononuclear cells from AUD patients with extreme values for alcohol craving intensity prior to treatment showed that inflammation-related pathways were highly associated with alcohol cravings. We then performed a genome-wide assessment of chromatin accessibility and gene expression profiles of induced iPSC-derived astrocytes in response to ethanol or anti-craving drugs. Those experiments identified drug-dependent epigenomic signatures, with IRF3 as the most significantly enriched motif in chromatin accessible regions. Furthermore, the activation of IRF3 was associated with ethanol-induced endoplasmic reticulum (ER) stress which could be attenuated by anti-craving drugs, suggesting that ER stress attenuation might be a target for anti-craving agents. In conclusion, we found that craving intensity was associated with alcohol consumption and treatment outcomes. Our functional genomic studies suggest possible relationships among craving, ER stress, IRF3 and the actions of anti-craving drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular mechanisms involved in alcohol craving, IRF3, and endoplasmic reticulum stress: a multi-omics study

Ho,

Zhang,

Moon

et al. 2024

Transl Psychiatry

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“…Nearly two-thirds of the patients were men, however, sex did not substantially influence acamprosate treatment response. Baseline alcohol craving scores, as determined by the PACS scale, were significantly higher in the relapse group than in the non-relapse group ( p = 9.36E-06) ( Table 1 ) ( Ho et al, 2022b ). The PACS is one of the most commonly used assessments for alcohol craving ( Flannery et al, 1999 ; Ray et al, 2013 ).…”

Section: Resultsmentioning

confidence: 99%

Plasma TNFSF10 levels associated with acamprosate treatment response in patients with alcohol use disorder

Zhang

Moon

et al. 2022

Front. Pharmacol.

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Acamprosate is an anti-craving drug used in alcohol use disorder (AUD) pharmacotherapy. However, only a subset of patients achieves optimal treatment outcomes. The identification of predictive biomarkers of acamprosate treatment response in patients with AUD would be a substantial advance in addiction medicine. We designed this study to use proteomics data as a quantitative biological trait as a step toward identifying inflammatory modulators that might be associated with acamprosate treatment outcomes. The NIAAA-funded Mayo Clinic Center for the Individualized Treatment of Alcoholism study had previously recruited 442 AUD patients who received 3 months of acamprosate treatment. However, only 267 subjects returned for the 3-month follow-up visit and, as a result, had treatment outcome information available. Baseline alcohol craving intensity was the most significant predictor of acamprosate treatment outcomes. We performed plasma proteomics using the Olink target 96 inflammation panel and identified that baseline plasma TNF superfamily member 10 (TNFSF10) concentration was associated with alcohol craving intensity and variation in acamprosate treatment outcomes among AUD patients. We also performed RNA sequencing using baseline peripheral blood mononuclear cells from AUD patients with known acamprosate treatment outcomes which revealed that inflammation-related pathways were highly associated with relapse to alcohol use during the 3 months of acamprosate treatment. These observations represent an important step toward advancing our understanding of the pathophysiology of AUD and molecular mechanisms associated with acamprosate treatment response. In conclusion, applying omics-based approaches may be a practical approach for identifying biologic markers that could potentially predict alcohol craving intensity and acamprosate treatment response.

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“…We investigated the effects of BDNF rs6265 and FGF21 rs11665896 on impulsivity with alcohol dependence during withdrawal. Previous studies showed that BDNF played a significant role in the processes of alcohol withdrawal syndrome ( 31 ), and FGF21 is related to AUD ( 32 ). The present study found no significant single-gene effect of BDNF rs6265 or FGF21 rs11665896 on AUD-related impulsivity.…”

Section: Discussionmentioning

confidence: 99%

“…Studies found that BDNF and FGF21 are associated with alcohol dependence and impulsivity ( 31 , 32 ). In addition, the link between BDNF SNP and AUD has been reported in some critical literature.…”

Section: Introductionmentioning

confidence: 99%

The effects of BDNF rs6265 and FGF21 rs11665896 polymorphisms on alcohol use disorder-related impulsivity in Han Chinese adults

Yang,

Wang,

Sun

et al. 2024

Front. Psychiatry

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IntroductionPatients with alcohol use disorder (AUD) often experience repeated withdrawal. Impulsivity is the most relevant factor influencing successful withdrawal. Brain-derived neurotrophic factor (BNDF) and fibroblast growth factor 21 (FGF21) are associated with impulsivity. Previous studies on the differential effects of BDNF or FGF21 on impulsivity have focused on single-gene effects and have inconsistent results. We aim to investigate the effects of BDNF rs6265 and FGF21 rs11665896, individually and together, on impulsivity during alcohol withdrawal in patients with AUD.MethodsWe recruited 482 adult Han Chinese males with AUD and assessed their impulsivity using the Barratt Impulsivity Scale. Genomic DNA was extracted and genotyped from peripheral blood samples. Statistical analysis was conducted on the data.ResultsThe T-test and 2 × 2 analysis of variance were used to investigate the effects of the genes on impulsivity. There was a significant BDNF × FGF21 interaction on no-planning impulsiveness (F = 9.15, p = 0.003, η2p = 0.03). Simple main effects analyses and planned comparisons showed that BDNF rs6265 A allele × FGF21 rs11665896 T allele was associated with higher no-planning impulsiveness. Finally, hierarchical regression analyses revealed that only the interaction of BDNF and FGF21 accounted for a significant portion of the variance in no-planning impulsiveness.Conclusion and significanceThe combination of BDNF rs6265 A allele and FGF21 rs11665896 T allele may increase impulsivity and discourage alcohol withdrawal. Our study provides a possible genetic explanation for the effects of associated impulsivity in patients with AUD from the perspective of gene-gene interactions.

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Genome-wide association study for circulating FGF21 in patients with alcohol use disorder: Molecular links between the SNHG16 locus and catecholamine metabolism

Cited by 8 publications

References 41 publications

Molecular mechanisms involved in alcohol craving, IRF3, and endoplasmic reticulum stress: a multi-omics study

Molecular mechanisms involved in alcohol craving, IRF3, and endoplasmic reticulum stress: a multi-omics study

Plasma TNFSF10 levels associated with acamprosate treatment response in patients with alcohol use disorder

The effects of BDNF rs6265 and FGF21 rs11665896 polymorphisms on alcohol use disorder-related impulsivity in Han Chinese adults

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