Alcoholism
Population Genetics
Family Studies
A review of 39 studies on families of 6251 alcoholic subjects and 4083 nonalcoholic subjects reported a 27.0% prevalence of alcoholism in fathers of alcoholic subjects and a 4.9% prevalence in mothers; 30.8% of the alcoholic subjects had at least one alcoholic parent. The same preponderance of alcoholism was not seen in the parents of comparison groups of patients with other psychiatric disorders. The nonpsychiatric control subjects included in the same review showed a 5.2% prevalence of alcoholism in fathers and a 1.2% prevalence in mothers. A recent multicenter study confirmed familial aggregation of alcoholism, with more severe forms showing greater familiality.
Twin Studies
Twin studies tend to show heritability of drinking behavior and heritability of alcoholism. Heritability of alcohol consumption is about 40%, at least in males (ie, twin studies show that about 40% of the variance between members of a twin pair is due to genetic factors).
Twin studies of alcoholism itself have generally shown heritability. In a total of 205 twin pairs, in which at least one was alcoholic, probandwise concordance was 54.2% in MZ twins and 31.5% in DZ twins (P < .01). Concordance rates in MZ twins increased with the severity of the disturbance. Heritability appears to vary from 40% to 90%, and the more serious forms of alcoholism are more heritable.
In a population-based study of female twin pairs from the Virginia twin registry, personal interviews were completed on 1033 of 1176 pairs. MZ concordance varied from 26% to 47% (as the definition of alcoholism varied from narrow to broad); DZ concordance ranged from 12% to 32%. Calculated heritability was 50–61%. This observation suggests substantial genetic influence in alcoholism in women in the populations studied.
Adoption Studies
One study compared 55 adopted-away male children with an alcoholic parent to 78 adoptees without an alcoholic parent. The groups were matched by age, sex, and age at adoption. The principal finding was that 18% of the proband group were alcoholic compared to 5% of the control subjects (P < .02). Adopted-away sons with an alcoholic parent were also compared to sons whose alcoholic parent raised them. There was no difference in rates of alcoholism.
One investigation studied 2324 adoptees born in Stockholm between 1930 and 1949. Male adoptees whose fathers abused alcohol (excluding those who were also sociopathic) were more likely to be alcoholic themselves (39.4% vs 13.6%, P < .01) compared to adoptees without an alcoholic (or sociopathic) father. Cloninger postulated a familial distinction between types of alcoholism: milieu-limited (type I) and male-limited (type II). Individuals with type I alcoholism usually have onset after age 25, manifest problems with loss of control, and have a great deal of guilt and fear about alcohol use. Individuals with type II alcoholism have onset before age 25, are unable to abstain from alcohol, and have fights and arrests when drinking but less frequently show loss of control and guilt and fear about alcohol use. The Stockholm adoption data were reanalyzed using these specific categories. This analysis showed that the prevalence of type I alcoholism was increased significantly only among those adoptees with both genetic and environmental risk factors (ie, alcoholism in both biological and adoptive parents). Type I was the most common type of alcoholism and was present in 4.3% of the control subjects with no risk factors. Type II alcoholism was present in 1.9% of the control subjects and in 16.9–17.9% of adoptees with genetic risk factors; the presence or absence of environmental risk factors (alcoholism in adoptive parents) did not appear to make a difference.
Genetically Related Disorders
In some family studies, an increased prevalence of depression has been reported in the female relatives of alcoholic individuals, roughly comparable to the increased prevalence of alcoholism in male relatives. Some forms of illness may result from shared vulnerability factors. Recent studies suggest that alcoholism with comorbid affective illness may itself run in families. Adopted-away daughters of parents with type II alcoholism manifest no increase in alcoholism but show an increased prevalence of somatization disorder.
Some sociopathic alcoholic individuals may transmit both alcoholism and sociopathy as part of the same syndrome. However, it is not clear that a single genetic predisposing factor may be manifest as either alcoholism or sociopathy.
Various behavioral disorders (eg, ADHD, oppositional defiant disorder, conduct disorder, substance use disorders) are more common in offspring of alcoholic parents.
Linkage Studies
No linkages are confirmed in alcoholism at this time. A multicenter study of alcoholic families recently reported loci for vulnerability on chromosomes 1, 7, and 2, with a possible protective locus on chromosome 4.
Association Studies
An association between alcoholism and an allele at the D2 receptor locus has been reported. This finding has caused much controversy. It has been very difficult to separate the effects of ethnicity from those of alcoholism. A family-based control study that took ethnicity into account was not encouraging.
Potential Biological Vulnerability Markers
The search for a potential biological trait marker of alcoholism has focused on (1) enzymes of alcohol metabolism and other enzymes, (2) electroencephalogram (EEG) and evoked potentials before and after alcohol consumption, and (3) behavioral and neuroendocrine responses to alcohol.
Alcohol is metabolized primarily in the liver by the enzymes alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). Four isozymes of ALDH are known. Three are found in the cytoplasm and one (ALDH2) in the mitochondria. ALDH2 is probably responsible for most acetaldehyde metabolism in vivo. The ALDH2 enzyme is lacking in about 50% of Japanese subjects tested and apparently in other Asian groups. Such individuals are subject to a so-called flushing reaction caused by alcohol (similar to a reaction seen in patients receiving disulfiram treatment for alcoholism). The rate of alcoholism is significantly lower in those individuals who lack ALDH2.
Monoamine oxidase (MAO), a primary catabolic enzyme for dopamine, norepinephrine, and serotonin (among other substrates), has been found in lower levels in alcoholic subjects in comparison to control subjects. Perhaps most interesting are several reports suggesting that a low MAO level is related only to type II alcoholism. However, recent data suggest that the effect of cigarette smoking in lowering MAO levels may explain many of the findings in studies of alcoholism.
A poorly synchronized resting EEG (ie, decreased time of alpha rhythm) may be related to a predisposition for alcoholism. The change in alpha rhythm following alcohol consumption was found to be more concordant in MZ twins than in DZ twins (as are many other EEG parameters). A relationship was noted between the resting EEG of the unselected twins and drinking behavior (less alpha in the twins who were heavier drinkers). In subsequent studies, relatives of alcoholic individuals with poorly synchronized resting EEGs demonstrated the same characteristic themselves. A change in alpha rhythm following alcohol consumption has also been found to differentiate young adult subjects at high risk for alcoholism from control subjects.
Measurements of event-related potentials (ERPs) have shown smaller P300 waves following visual stimuli in 7- to 13-year-old sons of alcoholic parents compared to sons of control subjects; the age range studied lessens the likelihood of previous alcohol exposure. Similar findings using an auditory stimulus have been reported in older groups, both before and after alcohol administration. Other researchers have found a significant increase in P300 latency in adolescent and adult relatives of alcoholic individuals compared to control subjects. The EEG/ERP area remains one of the more promising in the field of pathophysiologic markers for alcoholism.
A study of behavioral and neuroendocrine responses to alcohol infusion in a series of high-risk populations found that sons of alcoholic parents displayed less subjective intoxication than did sons of control subjects. A follow-up study showed that decreased subjective intoxication is correlated with later development of alcoholism.
Summary
Hereditary factors appear to operate in normal drinking behavior and in individual vulnerability to alcohol abuse. The flushing reaction to acetaldehyde is a clear instance of a pharmacogenetic variant that influences human behavior. Alcoholism runs in families and is manifest in men more often than in women. The familial preponderance is related primarily to genetic factors, and the differentiation by gender is primarily the result of sociocultural factors. There may be two distinct types of alcoholism with different patterns of inheritance: type I (or milieu-limited) and type II (or male-limited). Type II alcoholism is more severe and more likely to be influenced strongly by major gene effects. Genetic markers for the vulnerability to alcoholism have yet to be verified. Of most interest are studies suggesting EEG/ERP differences in those at risk and studies showing decreased responsiveness to alcohol in those at risk. The neurochemical investigation of animal models of alcoholism is showing links to the serotonin system, as are recent genetic studies. Genetic linkages to areas on chromosomes 1, 2, 4, and 7 and elsewhere are being explored in ongoing studies.
