Article at a Glance
- Family-based studies have shown the highest heritability of up to 60% for alcoholism.
- In candidate gene studies, the strongest associations were for ADH and ALDH genes regulating alcohol metabolism. Those who metabolize alcohol poorly tend to avoid drinking and are less likely to develop alcoholism.
- More recently, large-scale GWAS studies show only 5-10% heritability for alcoholism, which means a lot is still undiscovered, and more research is needed.
- Genetics represents just one piece of the intricate puzzle that is alcoholism.
Alcohol Use Disorder (AUD), commonly known as alcoholism, is a pervasive global health concern. Individuals grappling with AUD often find themselves locked in a relentless battle against excessive and harmful alcohol consumption, impacting not only their own lives but also those of their loved ones and society at large. Despite its widespread prevalence, AUD remains an under-diagnosed and under-treated mental health condition.
In this blog post, we set out on a quest to explore the genetic underpinnings of alcoholism, aiming to shed light on the role genetics plays in this complex disorder.
Defining Alcoholism: The Diagnostic Puzzle
Before we delve into genetics, let’s understand how we diagnose alcoholism.
Genetic studies often rely on a formal diagnosis called Alcohol Dependence, as outlined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). According to this diagnostic framework, an individual is classified as having AUD when they meet three or more out of seven specific criteria indicative of severe alcohol-related problems.
Researchers also employ tools like the AUDIT scale to classify alcohol-related issues. The AUDIT scale comes in various forms, with the shorter AUDIT-C consisting of three questions that assess how often and how much someone drinks, as well as episodes of binge drinking.
The 7-item AUDIT-P, on the other hand, focuses on measuring alcohol-related problems. These tools serve as valuable instruments in the arsenal of researchers and healthcare professionals, aiding in the identification and understanding of different facets of alcohol-related concerns.
Genetic Insights from Family, Adoption, and Twin Studies
The genetic exploration of AUD is rooted in a long history of observing that alcohol-related problems tend to run in families.
Early research uncovered a significant increase in the risk of AUD among the relatives of individuals with alcohol issues, often three to four times higher. 1 Subsequent adoption studies further cemented this notion, revealing a heightened risk of AUD in the sons of alcoholics, even when raised by non-alcoholic families. 2
Another avenue of inquiry involved the use of twins, a valuable tool for dissecting the roles of genes and the environment in AUD risk. Identical (monozygotic or MZ) twins, who share 100% of their genes, were compared to fraternal (dizygotic or DZ) twins, who share around 50% of their genes, akin to regular siblings. This comparison was insightful because twins typically grow up in the same environment, experiencing similar life events. The consistent finding from twin studies was that genetics played a substantial role in alcoholism, explaining roughly 60% of the risk. 3 4
Genetic linkage studies explored the inheritance of AUD within extensive family trees by investigating whether specific genetic markers consistently correlated with the disorder among family members.
These studies pinpointed potential connections on chromosomes 1 and 7, as well as intriguing associations on chromosome 2 concerning alcohol dependence. 5 Additionally, a chromosome 2 locus, seemingly conferring protection against alcohol dependence, was discovered, located in proximity to the alcohol dehydrogenase genes.
Candidate gene association studies sought out tiny genetic variations known as single nucleotide polymorphisms (SNPs) that occurred more or less frequently in individuals with AUD compared to those without. Numerous genes were implicated in AUD, covering critical brain signaling systems like GABA, glutamate, serotonin, dopamine, and acetylcholine. Genes linked to neuropeptide signaling (such as NPY and CRH) and various cellular functions (like MPDZ and RSU1) also played a role. 6 7
Key functional SNPs in ADH1B resulting in different molecular forms of ADH1B gene such as ADH1B*2 (Arg48His or rs1229984) and ADH1B*3 (Arg370Cys or rs2066702) accelerate the breakdown of ethanol into acetaldehyde, while a functional variant in ALDH2 i.e. ALDH2*2 (Glu504Lys or rs671) essentially hampers its ability to eliminate acetaldehyde. 10
Presence of either of these alleles leads to build up of acetaldehyde. This causes symptoms like flushing (reddening of the skin), headache, sweating, fast heart rate, nausea, and vomiting. 11 These symptoms act as a natural deterrent against excessive drinking and can help protect against the development of AUDs.
Cracking the Genetic Code: Genome-Wide Association Studies
Genome-wide association studies (GWAS) enable researchers to identify and study millions of common genetic variations (SNPs) in our DNA all at once. Genome-wide association studies (GWAS) have proposed a polygenic model for Alcohol Use Disorder (AUD). In this model, a significant number of specific SNPs located at different positions throughout the genome each make a moderate contribution to the overall risk of developing AUD.
In 2019, a landmark GWAS, involving a staggering sample size of 274,424 individuals, uncovered over a dozen genetic locations linked to alcoholism. 12, these findings reaffirmed the importance of genes influencing alcohol metabolism (such as ADH1B and ADH1C) and genes regulating alcohol consumption (like KLB, encoding beta-klotho, and GCKR, encoding glucokinase regulatory protein). Intriguingly, five genetic locations were identified as risk factors in both AUD and AUDIT-C GWAS, including ADH1B, ADH1C, FTO (encoding FTO Alpha-Ketoglutarate Dependent Dioxygenase), GCKR, and SLC39A8 (encoding Solute Carrier Family 39 Member 8).
In contrast to findings from family studies, GWAS have so far been able to account for approximately 5-10% of the total heritability of AUD. 12 Discrepancy in explaining heritability is a recurrent issue in GWAS research. However, there is optimism that as sample sizes in GWAS studies grow larger, we may uncover new genetic associations that contribute to reducing the gap in the missing heritability.
The Genetics of Alcoholism is Complex
Despite these remarkable genetic discoveries, it’s crucial to recognize that genetics represents just one piece of the intricate puzzle that is alcoholism. Environmental factors, such as upbringing, social influences, access to alcohol, and stress, also play pivotal roles in the development of AUD. The interplay between genetics and the environment is a dynamic area of ongoing research, as scientists strive to unravel the multifaceted factors contributing to alcoholism.
In conclusion, understanding the genetics of alcoholism is a complex endeavor, one that holds the potential to transform our approach to diagnosis, treatment, and prevention. While genes indeed play a significant role, they do not act in isolation. Instead, they interact with a myriad of environmental factors, shaping the trajectory of this complex and challenging condition.
As researchers continue to decode the genetic and environmental components of alcoholism, we move closer to a more comprehensive understanding and more effective interventions for this critical public health issue.