Heritability of Level of Response and Association with Recent Drinking History in Nonalcohol‐Dependent Drinkers

Kalu, Nnenna; Ramchandani, Vijay A.; Marshall, Vanessa; Scott, Denise M.; Ferguson, Clifford L.; Cain, Gloria; Taylor, Robert E.

doi:10.1111/j.1530-0277.2011.01699.x

Cited by 26 publications

(30 citation statements)

References 40 publications

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“…As summarized in a recent meta-analysis, populations at risk for AUD, such as individuals with a family history of alcoholism, typically have lower LR compared to other populations [45]. Heritability ( h 2 ) estimates for LR are approximately 60% [46, 47]. …”

Section: Evaluating the Weight Of Evidence For Aud Candidate Endophenmentioning

confidence: 99%

Endophenotypes for Alcohol Use Disorder: An Update on the Field

2015

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The endophenotype concept was first proposed as a strategy to use (purportedly) genetically simpler phenotypes in gene identification studies for psychiatric disorders, and is distinct from the closely related concept of intermediate phenotypes. In the area of alcohol use disorder (AUD) research, two candidate endophenotypes have produced replicable genetic associations: level of response to alcohol and neurophysiology markers (e.g., event-related oscillations and event-related potentials). Additional candidate endophenotypes from the cognitive, sensory, and neuroimaging literatures show promise, although more evidence is needed to fully evaluate their potential utility. Translational approaches to AUD endophenotypes have helped characterize the underlying neurobiology and genetics of AUD endophenotypes and identified relevant pharmacological interventions. Future research that capitalizes on the polygenic nature of endophenotypes and emphasizes endophenotypes that may change across development will enhance the usefulness of this concept to understand the genetically-influenced pathways toward AUD.

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Section: Evaluating the Weight Of Evidence For Aud Candidate Endophenmentioning

confidence: 99%

Endophenotypes for Alcohol Use Disorder: An Update on the Field

2015

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“…A study in young adult Australian twins showed that a composite alcohol sensitivity measure, combining subjective intoxication and increase in body-sway after alcohol challenge had a heritability of 0.60 (Heath et al, 1999). A sibling study in young adult social drinkers concluded that the heritability of the SRE was 0.67 (Kalu et al, 2012). Since the longitudinal studies described above have shown that a low LR to alcohol predicts the development of alcoholism, a low LR can be considered as an intermediate phenotype to search for candidate genes for alcoholism (Enoch et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

Genetic influences on response to alcohol and response to pharmacotherapies for alcoholism

Enoch

2014

Pharmacology Biochemistry and Behavior

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Although very many individuals drink alcohol at safe levels, a significant proportion escalates their consumption with addiction as the end result. Alcoholism is a common, moderately heritable, psychiatric disorder that is accompanied by considerable morbidity and mortality. Variation in clinical presentation suggests inter-individual variation in mechanisms of vulnerability including genetic risk factors. The development of addiction is likely to involve numerous functional genetic variants of small effects. The first part of this review will focus on genetic factors underlying inter-individual variability in response to alcohol consumption, including variants in alcohol metabolizing genes that produce an aversive response (the flushing syndrome) and variants that predict the level of subjective and physiological response to alcohol. The second part of this review will report on genetic variants that identify subgroups of alcoholics who are more likely to respond to pharmacotherapy to reduce levels of drinking or maintain abstinence. Genetic analyses of the level of response to alcohol, particularly of the functional OPRM1 A118G polymorphism and 5′ and 3′ functional polymorphisms in SLC6A4, are beginning to provide insights into the etiology of alcoholism and also genotype-stratified subgroup responses to naltrexone and SSRIs / ondansetron respectively. Because of large inter-ethnic variation in allele frequencies, the relevance of these functional polymorphisms will vary between ethnic groups. However there are relatively few published studies in this field, particularly with large sample sizes in pharmacogenetic studies, therefore it is premature to draw any conclusions at this stage.

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“…People with a low LR are more likely to become alcoholic than people with a high LR (5,6), and the LR phenotype is heavily genetically influenced (7). Therefore, determining the factors that contribute to LR is a promising approach for the identification of abuse liability loci.…”

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confidence: 99%

SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans

Mathies¹,

Blackwell²,

Austin³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Alcohol abuse is a widespread and serious problem. Understanding the factors that influence the likelihood of abuse is important for the development of effective therapies. There are both genetic and environmental influences on the development of abuse, but it has been difficult to identify specific liability factors, in part because of both the complex genetic architecture of liability and the influences of environmental stimuli on the expression of that genetic liability. Epigenetic modification of gene expression can underlie both genetic and environmentally sensitive variation in expression, and epigenetic regulation has been implicated in the progression to addiction. Here, we identify a role for the switching defective/sucrose nonfermenting (SWI/SNF) chromatin-remodeling complex in regulating the behavioral response to alcohol in the nematode Caenorhabditis elegans. We found that SWI/SNF components are required in adults for the normal behavioral response to ethanol and that different SWI/SNF complexes regulate different aspects of the acute response to ethanol. We showed that the SWI/SNF subunits SWSN-9 and SWSN-7 are required in neurons and muscle for the development of acute functional tolerance to ethanol. Examination of the members of the SWI/SNF complex for association with a diagnosis of alcohol dependence in a human population identified allelic variation in a member of the SWI/SNF complex, suggesting that variation in the regulation of SWI/SNF targets may influence the propensity to develop abuse disorders. Together, these data strongly implicate the chromatin remodeling associated with SWI/SNF complex members in the behavioral responses to alcohol across phyla.SWI/SNF | alcohol | C. elegans | chromatin remodeling | GWAS

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Heritability of Level of Response and Association with Recent Drinking History in Nonalcohol‐Dependent Drinkers

Cited by 26 publications

References 40 publications

Endophenotypes for Alcohol Use Disorder: An Update on the Field

Endophenotypes for Alcohol Use Disorder: An Update on the Field

Genetic influences on response to alcohol and response to pharmacotherapies for alcoholism

SWI/SNF chromatin remodeling regulates alcohol response behaviors in Caenorhabditis elegans and is associated with alcohol dependence in humans

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