biomarkers of risk for alcoholism

Stress and emotional dysregulation are markers of later risk of alcoholism.

The offspring of alcohol dependent individuals are at increased risk for alcohol and drug dependence in young adulthood over that seen in the general population (1-4). Twin and adoption studies reveal that the heritability for alcohol dependence is between 40–60% (5-8).   The substantial heritability of alcohol dependence also implies a need to search for mechanisms of transmission across generations.

Some structural and functional differences in affective circuitry have been found in adolescents with AUDs compared to controls, and may precede alcoholism onset and thus constitute markers of precursive risk. Thus, it is reasonable to hypothesize that pre-alcoholic differences in the functioning of relevant neural systems will be related to risk for alcoholism (9).

Components of what has also been termed the cerebellothalamocortical system and the extended limbic network (Fig 1) may provide the underpinnings for the behavioral and emotional dysfunction observed in individuals at heightened risk for alcohol use disorders (AUD) . This figure shows two “types” of pathways into alcoholism; the “externalising” which implicates lack of inhibition over impulsive behaviours, sensation seeking, risky behaviours and conduct problems and “internalizing” which is posited as involving affective dysregulation with drinking to medicate anxiety like symptoms – both also posited to be linked to the “warrior” and the “worrier” of the dopamine COMT  gene variants, Val158 and Met158 respectively.

Fig 1.


In addition, abnormalities in these structures appear to be altered in individuals with the predisposition for other psychiatric conditions that may share a similar genetic diathesis (9).

This is very important as the so-called “co-morbidities” which are said to co-occur with later alcoholism may either be present in adolescence, or, alcoholism develops from these vulnerabilities and which, via chronic alcohol abuse, appear very similar to these co-morbidities.

These brain regions, involved in affective regulation, executive function, and autonomic reactivity, suggest a primary role for the limbic, cerebellothalamocortical, and HPA systems, playing an important role as neural underpinnings of risk for alcohol use disorder (AUD).

In terms of inherent stress regulation, offspring of alcoholics tend to have higher baseline heart rates (10,11)   and show increased cardiovascular reactivity to aversive stimuli (12-15)

In simple terms those at risk have inherent difficulties in stress regulation, they react more than those not at risk,  studies have shown that cortisol response to psychosocial stress is significantly increased in offspring with a family history of AUD compared to those with no family history of AUD (16,17).

Interestingly, this dysregulation may potentiate the rewarding properties of alcohol, not purely dopaminergic either, as  offspring from families with alcohol dependent (AD) individuals may be hypersensitive to the effects of alcohol on cardiovascular activity (12, 14, 18,19). Alcohol may serve to dampen heart rate and electrodermal reactivity to stress more in young adults with a family history of alcoholism than in offspring without a family history (13,14,15) . Slowing of heart rate may be associated with increased perception of relaxation making alcohol more rewarding to high risk offspring.

In offspring of alcohol dependent individuals, ethanol consumption results in significantly lower adrenocorticotropic hormone (ACTH) and cortisol levels compared to control subjects that are predictive of future AUD (19-21).

Also morphological differences in brain regions implicated in emotional processing and regulation may illustrate how symptoms frequently precede the addictive process and constitute a predisposing psychological background on which substance effects and addictive processes interact, leading to a full-fledged psychiatric disorder.

Brain regions involved in affective regulation, executive function, and autonomic reactivity such as the cerebellum, thalamus, hypothalamus, and regions of the prefrontal cortex are particularly susceptible to alcohol (22, reviewed by 23 ).

Slower reduction in grey matter volumes among the offspring of alcoholics that may indicate a delay in grey matter pruning or slower maturational increases in white matter. Benegal et al. (2007) also found differences in cerebellar volume in high risk alcohol-naive subjects (24). Compared to controls, high risk subjects also had decreased grey matter volume in the thalamus, superior frontal gyrus, and cingulate gyrus all implicated in emotional regulation.

Reduced grey matter has been reported for the amygdala and hippocampus in offspring from an Indian population of multigenerational families of alcoholics (24), two important brain regions implicated in stress regulation. These regions are also involved in emotion regulation and inhibition, corresponding to the behavioural and affective dysfunction often observed in these individuals.

Also offspring from multiplex families of alcoholic individuals with minimal prior exposure to alcohol have decreased volume of the orbitofrontal cortex in the right hemisphere (25) another important brain region implicated in emotional regulation.

Volumetric differences in adolescents at high risk for AUD appear to be limited to the right OFC (25) functionally important in behavioral and emotional regulation.

Taken together these, and other findings, strongly suggest a vulnerability to later alcohol dependence involves impairments in brain regions implicated in stress and emotional regulation.  Identifying these regulation difficulties in prevention strategies  (26) would greatly help in “treating” these disorders much earlier in their aetiology and make arguments over definitions and labels more redundant.


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25. Hill SY, Wang S, Kostelnik B, Carter H, Holmes B, McDermott M, et al. Disruption of orbitofrontal cortex laterality in offspring from multiplex alcohol dependence families. Biological Psychiatry.2009a;65(2):129–136.

26.  Hill SY, Steinhauer S,R, Locke-Wellman J, Ulrich R. Childhood risk factors for young adult substance dependence in offspring from multiplex alcohol dependence families: A prospective study. 2009b doi:10.1016/j.biopsych.2009.04.030. [PMC free article]



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