Association between <i>AUTS2</i> haplotypes and alcohol dependence in a Japanese population

Narita, Shin; Nagahori, Kaoru; Nishizawa, Daisuke; Yoshihara, Eiji; Kawai, Atsuko; Ikeda, Kazutaka; Iwahashi, Kazuhiko

doi:10.1017/neu.2015.70

Cited by 4 publications

(6 citation statements)

References 21 publications

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“… 11 17 Genotype and allele frequencies of this polymorphism in this study were not significantly different compared to that of our previous study (male: 23, female: 52, mean age: 35.36±9.06) (genotype: χ 2 (2)=0.271, p=0.873; allele: χ 2 (1)=0.557, p=0.455). 17 In addition, the A/A genotype (11.6%) and A allele frequencies (34.7%) in our subjects showed very little difference from those in Han Chinese subjects [Zhang et al: male: 192, female: 243, mean age: 37.6±10.8; Chen et al: male: 390 (genotyping in 373 males), mean age: 42.8±14.4; Dang et al: male: 355, female: 61, mean age: 37.13±5.23] (A/A genotype: 8.31–13.0%; A allele: 29.3–35.8%).10-12 On the other hand, in Polish Caucasian subjects (male: 1819, female: 2042, mean age: 45.72±14.91) the A/A genotype accounts for only 4.7% and the A allele 21%. 13 The genotype and allele frequencies of the polymorphism AUTS2 rs6943555 in Polish Caucasian subjects show significant differences from those in the Japanese population examined in this study [genotype: χ 2 (2)=39.4, p<0.01; allele: χ 2 (1)=40.1, p<0.01].…”

Section: Discussioncontrasting

confidence: 82%

“… 12 In addition, our previous study also reported that the haplotype consisting of the intronic polymorphisms rs6943555 and rs9886351 might affect the pathogenesis of alcohol dependence. 17 Thus, although an effect of the rs6943555-rs9886351 haplotypes on the development of personality traits was not observed in this study, it would be interesting for further analysis to be focused on AUTS2 haplotypes in future research.…”

Section: Discussionmentioning

confidence: 67%

“…In addition, our recent study reported that the AUTS2 haplotype consisting of the polymorphisms rs6943555 and rs9886351 might affect the pathogenesis of alcohol dependence. 17 Therefore, as a preliminary analysis, we also examined whether the AUTS2 haplotypes are related to personality traits.…”

Section: Introductionmentioning

confidence: 99%

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No Association between the Polymorphism rs6943555 in the AUTS2 Gene and Personality Traits in Japanese University Students

Narita

Ikeda

Nishizawa

et al. 2017

Psychiatry Investig

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ObjectiveThe autism susceptibility candidate 2 (AUTS2) gene has been implicated in multiple neurological disorders. Several recent studies have revealed that the polymorphism rs6943555 in the AUTS2 gene is broadly associated with human mental function and behavior. Therefore, in the present study we investigated whether the polymorphism rs6943555 is associated with human personality traits in Japanese university students. In addition, our previous study reported that the AUTS2 rs6943555-rs9886351 haplotype is associated with alcohol dependence. As a preliminary analysis, we also examined whether the AUTS2 haplotypes are related to personality traits.MethodsAfter written informed consent had been obtained from the participants, two AUTS2 polymorphisms were analyzed, and personality was assessed using the Temperament and Character Inventory (TCI) in 190 university students. In addition, in order to exclude the influence of the results for students with mental health problems, we gave the Patient Health Questionnaire-9 (PHQ-9) to all subjects.ResultsIn all the subjects, there was a main effect of the polymorphism rs6943555 genotype on reward dependence (p=0.038) and cooperativeness (p=0.031), although the significance was lost on Bonferroni correction. Similarly, on analysis that excluded the subjects with PHQ-9 scores≥10, no significant association with any TCI dimension score among the rs6943555 genotypes was seen. There was no effect of the rs6943555-rs9886351 haplotypes on the TCI dimension scores.ConclusionThis study suggests that the polymorphism AUTS2 rs6943555 is not associated with personality traits. Further large-scale studies with more subjects using other self-report questionnaires are needed.

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Section: Discussioncontrasting

confidence: 82%

Section: Discussionmentioning

confidence: 67%

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No Association between the Polymorphism rs6943555 in the AUTS2 Gene and Personality Traits in Japanese University Students

Narita

Ikeda

Nishizawa

et al. 2017

Psychiatry Investig

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“…We observed that several proteins identified in our GWAS for baseline ethanolamine concentration might display protein–protein interactions based on the STRING database. It should also be pointed out that several genes involved in the protein interactive network have been implicated in substance use disorders (Narita et al, 2016; Uhl et al, 2008; Yeung et al, 2017). For example, the autism susceptibility candidate 2 ( AUTS2 ) gene has implications for alcohol consumption (Narita et al, 2016).…”

Section: Discussionmentioning

confidence: 99%

Genetic variants associated with acamprosate treatment response in alcohol use disorder patients: A multiple omics study

Ho¹,

Zhang²,

Wei³

et al. 2022

British J Pharmacology

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Background and Purpose Acamprosate is an anti‐craving drug used for the pharmacotherapy of alcohol use disorder (AUD). However, only some patients achieve optimal therapeutic outcomes. This study was designed to explore differences in metabolomic profiles between patients who maintained sobriety and those who relapsed, to determine whether those differences provide insight into variation in acamprosate treatment response phenotypes. Experimental Approach We previously conducted an acamprosate trial involving 442 AUD patients, and 267 of these subjects presented themselves for a 3‐month follow‐up. The primary outcome was abstinence. Clinical information, genomic data and metabolomics data were collected. Baseline plasma samples were assayed using targeted metabolomics. Key Results Baseline plasma arginine, threonine, α‐aminoadipic acid and ethanolamine concentrations were associated with acamprosate treatment outcomes and baseline craving intensity, a measure that has been associated with acamprosate treatment response. We next applied a pharmacometabolomics‐informed genome‐wide association study (GWAS) strategy to identify genetic variants that might contribute to variations in plasma metabolomic profiles that were associated with craving and/or acamprosate treatment outcome. Gene expression data for induced pluripotent stem cell‐derived forebrain astrocytes showed that a series of genes identified during the metabolomics‐informed GWAS were ethanol responsive. Furthermore, a large number of those genes could be regulated by acamprosate. Finally, we identified a series of single nucleotide polymorphisms that were associated with acamprosate treatment outcomes. Conclusion and Implications These results serve as an important step towards advancing our understanding of disease pathophysiology and drug action responsible for variation in acamprosate response and alcohol craving in AUD patients.

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“…They then found increased AUTS2 expression in the human prefrontal cortex from carriers of a minor AUTS2 allele, as well as altered expression between various high alcohol-preferring and low-alcohol-preferring mouse lines. The human importance of AUTS2 is further supported by another GWAS of alcohol consumption, a GWA meta-analysis of the maximum number of drinks consumed in 24 h, and a biased haplotype analysis [38,39,155]. Lastly, Schumann et al showed that reduced expression of the fly ortholog tay reduces EtOH sensitivity.…”

Section: Human Genome-wide Association Studies (Gwas)mentioning

confidence: 96%

Flying Together: Drosophila as a Tool to Understand the Genetics of Human Alcoholism

Lathen

Merrill

Rothenfluh

2020

IJMS

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Alcohol use disorder (AUD) exacts an immense toll on individuals, families, and society. Genetic factors determine up to 60% of an individual’s risk of developing problematic alcohol habits. Effective AUD prevention and treatment requires knowledge of the genes that predispose people to alcoholism, play a role in alcohol responses, and/or contribute to the development of addiction. As a highly tractable and translatable genetic and behavioral model organism, Drosophila melanogaster has proven valuable to uncover important genes and mechanistic pathways that have obvious orthologs in humans and that help explain the complexities of addiction. Vinegar flies exhibit remarkably strong face and mechanistic validity as a model for AUDs, permitting many advancements in the quest to understand human genetic involvement in this disease. These advancements occur via approaches that essentially fall into one of two categories: (1) discovering candidate genes via human genome-wide association studies (GWAS), transcriptomics on post-mortem tissue from AUD patients, or relevant physiological connections, then using reverse genetics in flies to validate candidate genes’ roles and investigate their molecular function in the context of alcohol. (2) Utilizing flies to discover candidate genes through unbiased screens, GWAS, quantitative trait locus analyses, transcriptomics, or single-gene studies, then validating their translational role in human genetic surveys. In this review, we highlight the utility of Drosophila as a model for alcoholism by surveying recent advances in our understanding of human AUDs that resulted from these various approaches. We summarize the genes that are conserved in alcohol-related function between humans and flies. We also provide insight into some advantages and limitations of these approaches. Overall, this review demonstrates how Drosophila have and can be used to answer important genetic questions about alcohol addiction.

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Association between AUTS2 haplotypes and alcohol dependence in a Japanese population

Abstract: This suggests that the rs6943555 and rs9886351 A-A haplotype might affect the vulnerability to alcohol dependence pathogenesis. Further studies are needed to confirm the reproducibility of the results of this study with increased numbers of subjects.

Cited by 4 publications

References 21 publications

No Association between the Polymorphism rs6943555 in the AUTS2 Gene and Personality Traits in Japanese University Students

No Association between the Polymorphism rs6943555 in the AUTS2 Gene and Personality Traits in Japanese University Students

Genetic variants associated with acamprosate treatment response in alcohol use disorder patients: A multiple omics study

Flying Together: Drosophila as a Tool to Understand the Genetics of Human Alcoholism

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