Twin studies reveal consistently the existence of shared genetic influences between alcoholism and externalizing disorders 17-20. Longitudinal studies have shown that externalizing disorders of childhood such as CD and ADHD are important risk factors for the subsequent development of alcoholism 21. Evidence from twin studies for shared genetic influences between alcoholism and internalizing disorders are more controversial 18,22,23. However, longitudinal studies have shown that anxiety disorders such as panic disorder and social phobia predict subsequent alcohol problems in adolescents and young adults 24. The accompanying review (3. Brain Function) covers the available brain function data and resulting findings in detail.
IDENTIFYING AN INTEGRATED APPROACH FOR AUD RESEARCH
One such successful study performed exon-focused sequencing of impulsive individuals derived from a Finnish population isolate and identified a stop codon in HTR2B (1% frequency) that was unique to Finns. The stop codon carriers performed violently impulsive acts, but only whilst intoxicated with alcohol 85. Risk ratios using estimates of lifetime alcoholism prevalence in the general population are unchanged in men but become 2.0 and 3.0 for adopted and non-adopted daughters of alcoholics based on Goodwin’s estimated 1-percent prevalence for alcoholism in women. According to these findings, rates of alcoholism are significantly elevated in both the adopted and nonadopted sons of alcoholics, results which are consistent with a genetic influence on alcoholism risk in men. With rapid advances over the past 10 years in technologies for discovering and analyzing the functions of genes, researchers are now increasingly able to get at the biological roots of complex disorders such as substance abuse and addiction.
The Collaborative Study on the Genetics of Alcoholism: Overview
This has been done through the examination of neuropsychological tests and noninvasively recorded brain electrical activity during resting state and cognitive tasks, and more recently, by deriving measures of neural synchrony and connectivity (3. Brain Function). About 80% of those with brain function data have more than one assessment, yielding a relatively large longitudinal cohort with these data. While the D2 dopamine receptor gene did not have the effect expected on alcoholism, the study contributed to moving forward genetic research. “We know now that it was only a first step of a very long road of complex genetics,” said Renato Polimanti, a colleague of Gelernter at the Yale School of Medicine.
BEHAVIORAL AND CLINICAL DATA
Such isolated populations, and large families within them, are likely to confer the advantage of reduced genetic heterogeneity. A non-exhaustive list of convergent findings across studies includes a region on chromosome 4q, that contains the alcohol dehydrogenase (ADH) gene cluster 96,97,99,100, and a chromosome 4p region near the centromere containing a γ-aminobutyric acid receptor (GABAA) gene cluster 96,99. In the COGA sample there was also evidence for linkage to chromosomes 1 and 7, and to chromosome 2 at the location of an opioid receptor gene 96. A region on chromosome 1 was linked to alcoholism and affective disorder in the COGA data set 102, supporting further the existence of a genetic overlap between alcoholism and internalizing disorders. Since then, there have been significant advances in techniques available for mapping genes and as a result considerable changes in outlook have occurred. It is now generally accepted that genetic risk for alcoholism is likely to be due to common variants in numerous genes, each of small effect, however rare variants with large effects might also play a role.
However, there is a need for a framework to unify the findings and provide the data to the community for additional analysis and discovery. The initiative will facilitate identification of therapeutic targets and development of prevention strategies for AUD, supported by data generation, curation and bioinformatic analyses. The establishment of the NIAAA Data Archive and the Final NIH Data Management and Sharing Policy (NOT-OD ) provide an ecosystem and structure for the sharing of future and past (legacy) data from the COGA studies. While the adult data in COGA are extensive, two family cohorts, adolescent and young adults in Prospective Study and older participants in Lifespan Study, will benefit from additional participants and data collection. The COGA initiative is focused on optimizing the use of the past COGA data and completing data collection across the lifespan. Awareness of the need for large sample sizes for GWAS has resulted in the formation of large scale collaborations for sharing data, such as the Psychiatric Genomics Consortium 82.
Addressing Alcoholism: Prevention and Treatment
- Hrubec and Omenn (1981) identified alcoholism cases in a followup of a series of male same-sex twin pairs born between 1917 and 1927, identified originally from birth records, in which both twins engaged in military service during World War II.
- By using archival records, the Stockholm study was able to obtain data on the entire sample of adoptees.
- Living in a household where you’re regularly exposed to parental alcohol use can also increase your chances of AUD, regardless of your genetic predisposition.
- According to these findings, rates of alcoholism are significantly elevated in both the adopted and nonadopted sons of alcoholics, results which are consistent with a genetic influence on alcoholism risk in men.
These genetic variants have a high prevalence in East Asians and protect against the development of alcoholism. Here, the control adoptees have been assigned a risk of 1 because they are the group against which the other groups in the study are measured. A risk ratio of 3.6 for adopted-away sons of alcoholics thus means that that group is 3.6 times as likely as the control adoptees to become alcoholic. Cloninger and colleagues (1985) reported no significant association between adoptee alcoholism and Temperance Board registration in the adoptive parents. However, one cannot conclude from this finding that rearing environment in general has little impact on alcoholism risk.
In most cases, studiesrecruited families having multiple members with alcohol dependence; such familiesare likely to segregate variants that affect the risk of alcohol dependence. Themost common initial approach was linkage analysis, in which markers throughout thegenome were measured to identify chromosomal regions that appeared to segregate withdisease across many families. Linkage studies are relatively robust to populationdifferences in allele frequencies (because they test within-family inheritance), andcan find a signal even if different variants in the same gene or region areresponsible for the risk in different families. The drawback to this approach isthat linkage studies find broad regions of the genome, often containing manyhundreds of genes.
According to Polimanti and Zhou, geneticists hope to be able to bring their findings to human healthcare in order to help predict and treat certain illnesses. This is called precision medicine, wherein a person’s treatment plan can be specially tailored based on their unique genetic makeup. 5 Key Differences Between Crack and Cocaine Recognizing alcoholism as a disease promotes early intervention, access to appropriate healthcare services, and ongoing support for people struggling with AUD.
In addition, broad regions of the genome generally are inherited within a family, increasing the sensitivity of the approach to detect an effect; however, the tradeoff is that for the same reason, family studies have less resolution to identify the specific allele(s) involved. When both types of studies point to the same genes, however, it provides additional evidence for the involvement of these genes. Alcoholism has a substantial heritability yet the detection of specific genetic influences has largely proved elusive.
Fourth, an apparent cross-cultural difference in the importance of genetic influences on alcoholism risk is evident from these data, which, if confirmed, would be an important example of gene-environment interaction. The data raise the possibility that, at least in men, genetic factors may have a reduced impact on alcoholism risk in some environments (e.g., Scandinavian) compared with other environments (e.g., U.S.). However, this could be an artifact of differences in research methodology, as no studies led by the same investigators and using a common research methodology have been conducted in both Scandinavia and the United States. Using as a criterion the requirement of at least one Temperance Board registration, the proportion of registered twins whose co-twins were also registered was significantly higher for the MZ than for the DZ pairs. Approximately 61 percent of MZ co-twins of twins with an alcohol problem and a significantly lower fraction (39 percent) of DZ co-twins of twins with an alcohol problem were registered.