Association and ancestry analysis of sequence variants in ADH and ALDH using alcohol‐related phenotypes in a Native American community sample

Peng, Qian; Gizer, Ian R.; Libiger, Ondrej; Bizon, Chris; Wilhelmsen, Kirk C.; Schork, Nicholas J.; Ehlers, Cindy L.

doi:10.1002/ajmg.b.32272

Cited by 22 publications

(16 citation statements)

References 46 publications

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“…The analyses of changes in introns, e.g. studies conducted by Peng et al, which corroborated earlier results obtained by two study groups, indicate that changes within introns of the ADH7 gene frequently demonstrate a protective role against alcoholism [37].…”

Section: Archiwum Medycyny Sądowej I Kryminologii Archives Of Forensisupporting

confidence: 84%

See 1 more Smart Citation

Variation in gastric alcohol dehydrogenase and the risk of alcohol dependence

Całka¹,

Ciesielka²,

Buszewicz³

et al. 2016

amsik

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StreszczenieUzależnienie od alkoholu stanowi problem zarówno medyczny, jak i społeczno-ekonomiczny. Jest zaliczane do chorób o charakterze wieloczynnikowym, czyli takich, za które odpowiadają relacje gen-gen oraz gen-środo-wisko. Wieloośrodkowe badania nad genetycznym podłożem alkoholizmu podkreślają znaczenie genów kodujących enzymy szlaku rozkładu etanolu w organizmie ludzkim, szczególnie dehydrogenazy alkoholowej (ADH) w rozwoju choroby. Z pięciu klas dehydrogenaz alkoholowych związek z uzależnieniem od alkoholu wykazują izoenzymy klasy I i IV. Klasa IV jest szczególnie interesująca ze względu na jej występowanie w górnym odcinku przewodu pokarmowego, głównie w żołądku. Nie wykazano aktywności tego enzymu w wątrobie. Polimorfizm pojedynczych nukleotydów (SNP) genu kodującego tę klasę, czyli ADH7, wpływa na jej aktywność utleniającą etanol w świetle żołądka i tym samym na metabolizm pierwszego przejścia ( FPM) tej substancji. Opublikowane wyniki różnych ośrodków badawczych pokazują, że konkretne zmiany typu SNP w genie ADH7 mają odmienne znaczenie dla ryzyka uzależnienia od alkoholu w zależności od badanej populacji.Słowa kluczowe: ADH7, alkoholizm, metabolizm pierwszego przejścia. AbstractAlcohol dependence is both a medical and socioeconomic problem. The disease is multifactorial, i.e. its development is attributable to gene-gene and gene-environment interactions. Multi-centre studies investigating the genetic background of alcoholism stress the role of genes encoding enzymes of the ethanol decomposition pathway in the human body, particularly alcohol dehydrogenase (ADH), in the development of alcohol dependence. Among five classes of alcohol dehydrogenases, class I and IV isoenzymes have been found to be associated with alcohol dependence. Class IV is of particular interest due to its occurrence in the upper gastrointestinal tract, mainly in the stomach. No activity of the enzyme has been demonstrated in the liver. Single nucleotide polymorphism (SNP) of the gene encoding ADH class IV (ADH7) affects its ethanol-oxidizing activity in the gastric lumen, thereby influencing the first-pass metabolism (FPM) of the substance. The findings published by various research centres have demonstrated that specific SNP changes in the ADH7 gene are of different significance for the risk of alcohol dependence according to the population studied.

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Section: Archiwum Medycyny Sądowej I Kryminologii Archives Of Forensisupporting

confidence: 84%

“…Analizy zmian w obrębie intronów, m.in. badania Penga i wsp., które potwierdziły wcześniejsze wyniki dwóch grup badawczych, wskazują, że zmiany w obrębie intronów genu ADH7 często wykazują rolę ochronną przeciwko alkoholizmowi [37].…”

Section: Discussionunclassified

Variation in gastric alcohol dehydrogenase and the risk of alcohol dependence

Całka¹,

Ciesielka²,

Buszewicz³

et al. 2016

amsik

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“…The demographic information on the sample is provided in Table 1. A description of the sample has been reported previously (Ehlers et al 2004a(Ehlers et al ,2004bPeng et al 2014).…”

Section: Resultsmentioning

confidence: 99%

Single nucleotide polymorphisms in the REG‐CTNNA2 region of chromosome 2 and NEIL3 associated with impulsivity in a Native American sample

Ehlers

Gizer

Bizon

et al. 2016

Genes Brain and Behavior

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Impulsivity is a multi-faceted construct that, while characterized by a set of correlated dimensions, is centered around a core definition that involves acting suddenly in an unplanned manner without consideration for the consequences of such behavior. Several psychiatric disorders include impulsivity as a criterion, and thus it has been suggested that it may link a number of different behavioral disorders, including substance abuse. Native Americans experience some of the highest rates of substance abuse of all US ethnic groups. The described analyses used data from a low coverage whole genome sequence scan to conduct a genome-wide association study of an impulsivity phenotype in an American Indian community sample (n=658). Demographic and clinical information were obtained using a semi-structured interview. Impulsivity was assessed using a scale derived from the Maudsley personality inventory that combines both novelty-seeking and lack of planning items. The impulsivity score was tested for association with each variant adjusted for demographic variables, and corrected for ancestry and kinship, using EMMAX. Simulations were conducted to calculate empirical p-values. Genome-wide significant findings were observed for a variant 50 kb upstream from catenin cadherin-associated protein, alpha 2 (CTNNA2), a neuronal specific catenin, in the REG gene cluster. A meta-analysis of genome-wide association studies had previously identified common variants in CTNNA2 as being associated with excitement seeking. A second locus upstream of NEIL3 on chromosome 4 also achieved genome-wide significance. The association between sequence variants in these regions suggests their potential roles in the genetic regulation of this phenotype in this population.

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“…While SFFS cohort is primarily composed of European Americans, most AI participants have an admixed ancestral background (Norden-Krichmar et al, 2014, Peng et al, 2014). Additionally, both cohorts have family structures.…”

Section: Methodsmentioning

confidence: 99%

“…The present report is part of a larger study exploring risk factors for substance dependence in an American Indian community (Ehlers et al, 2004b, Gilder et al, 2004, Gilder et al, 2008) and a nationwide study on genetics of alcoholism and other substance dependence in a primarily European American population (Seaton et al, 2004, Vieten et al, 2004, Gizer et al, 2011b). We previously evaluated effects of variants in the ADH and ALDH genes on alcohol dependence phenotypes in a subset of the AI cohort, and found significant evidence for association with a severity level of alcohol drinking-related dependence symptoms phenotype across the ADH gene cluster (Peng et al, 2014). Our study also suggested that a higher degree of AI ancestry was associated with higher frequencies of potential risk variants.…”

Section: Introductionmentioning

confidence: 99%

Associations Between Genomic Variants in Alcohol Dehydrogenase Genes and Alcohol Symptomatology in American Indians and European Americans: Distinctions and Convergence

Peng

Gizer

Wilhelmsen

et al. 2017

Alcohol Clin Exp Res

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Background Higher rates of alcohol use disorders (AUD) have been observed in some Native American (NA) populations than other ethnic groups such as Euro-Americans (EA) in the U.S. Previous studies have shown that variation in the alcohol dehydrogenase (ADH) genes may affect the risk for development of AUD, and that the prevalence of these variants differs depending on the ancestral origins of a population. Methods In the present study, we assessed sequencing variants in the ADH genomic region (ADH1-7) and tested for their associations with AUD phenotypes in two independent populations: an American Indian (AI) community sample and an EA cohort from the San Francisco Family Alcohol Study. Association tests were conducted for both common and rare variants using sequencing data for two phenotypes: the number of alcohol-related life events, and the count of alcohol dependence drinking symptoms. A regularized regression method was used to select the best set of ADH variants associated with phenotypes. Variance component model was incorporated in all analyses to leverage the admixture and relatedness. Results Two variants near ADH4 and two near ADH1C exhibited significant associations with AUD in AI; no variant was significant in EA. Common risk variants in AI were either absent from or much less frequent in EA. The feature selection method selected mostly distinct yet often co-located subsets of ADH variants to be associated with AUD phenotypes between the two cohorts. In the rare variant analyses, the only association was observed between the whole region and the alcohol-related life events in AI. Conclusions Our results suggest that ADH variants, both common and rare, are more likely to impact risk for alcohol-related symptomatology in this AI population than in this EA sample; and ADH variants that might affect AUD are likely different but convergent on similar regions between the two populations.

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Association and ancestry analysis of sequence variants in ADH and ALDH using alcohol‐related phenotypes in a Native American community sample

Cited by 22 publications

References 46 publications

Variation in gastric alcohol dehydrogenase and the risk of alcohol dependence

Variation in gastric alcohol dehydrogenase and the risk of alcohol dependence

Single nucleotide polymorphisms in the REG‐CTNNA2 region of chromosome 2 and NEIL3 associated with impulsivity in a Native American sample

Associations Between Genomic Variants in Alcohol Dehydrogenase Genes and Alcohol Symptomatology in American Indians and European Americans: Distinctions and Convergence

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