Alcohol is a double-edged sword, capable of imparting both beneficial and detrimental effects on health, depending on the quantity and frequency of consumption. While moderated drinking can yield benefits such as stress alleviation, mood enhancement, and even prevention of certain cardiovascular diseases, excessive or problematic alcohol use (PAU) can inflict serious physical, psychological, and societal damage. PAU is defined as the consumption of alcohol that surpasses the World Health Organization's (WHO) recommended limits of 14 drinks per week for males and 7 drinks per week for females.
PAU is linked with an elevated risk of over 200 diseases and injuries, including cirrhosis of the liver, cancer, depression, violence, traffic accidents, and suicide. In fact, it is the leading cause of death for people aged 15-49, according to the WHO. This raises the question: what makes some individuals more prone to developing this condition than others? A multitude of factors come into play, with genetics being one of the most significant. It is estimated that 40-60% of individual variability in PAU is due to hereditary factors, i.e., the genes we inherit from our parents.
Recently, a team of researchers conducted the largest-ever study on PAU, analyzing the DNA of over a million people from around the globe. The study, published in Nature Communications, identified several new risk genes for PAU and discovered new biological mechanisms explaining how PAU impacts brain functioning.
Meta-analysis of Genetic Data Reveals Risk Genes for PAU
The research team, based at the VA Connecticut Healthcare Center/Yale, collaborated with numerous international research institutions to collect genetic and behavioral data from individuals with PAU. Data was sourced from several large genetic databases, including the Million Veteran Program (MVP), the UK Biobank, 23andMe, and the Psychiatric Genomics Consortium.
The researchers used a technique called meta-analysis, which combines the results of several studies to increase statistical power and precision. The aim of their study was to identify regions of the genome, known as loci, associated with PAU. These loci might contain one or more genes that impact PAU either directly or indirectly.
The researchers identified 110 loci associated with PAU, 99 of which were previously unknown. These loci contained 261 candidate genes for PAU, which are involved in various biological functions, such as alcohol metabolism, nerve transmission, brain development, immune system function, and the circadian cycle. Some of these genes are also associated with other psychiatric disorders, like schizophrenia, bipolar disorder, depression, and attention deficit hyperactivity disorder (ADHD).
How Genes Impact Brain Functioning in PAU
To better understand how the genes associated with PAU affect the brain, the researchers analyzed gene expression and chromatin interaction in the brain. Gene expression is the process by which genes produce proteins that carry out biological functions. Chromatin interaction refers to how genes organize themselves in the three-dimensional space of the cell nucleus, which influences their activation or deactivation.
The researchers found that many of the genes associated with PAU are expressed in various regions of the brain, particularly in the amygdala, hippocampus, nucleus accumbens, and prefrontal cortex. These areas are involved in the regulation of emotion, memory, reward, and impulse control.
Polygenic Risk Scores and PAU
One of the most significant outcomes of this research is the development of polygenic risk scores (PRS) for PAU. PRS are calculated by summing the effects of all genetic variants associated with PAU in an individual, weighting them according to their importance. A higher PRS indicates a greater genetic risk of developing PAU.
PRS for PAU could potentially be a valuable tool for prevention and treatment strategies, as they could help identify individuals at higher risk and tailor intervention strategies accordingly. However, it's important to note that the PRS calculated in this study are not yet ready for clinical use, as they have low predictive accuracy and are influenced by many other environmental and social factors that are not included in the genetic model.
Potential Drug Treatments for PAU
The study also identified several existing drugs that could potentially be repurposed to treat PAU, based on their action on the genes and biological mechanisms involved. These include naltrexone, an opioid antagonist that reduces alcohol cravings; baclofen, a muscle relaxant that modulates the GABAergic system; topiramate, an anticonvulsant that acts on the glutamatergic system; and disulfiram, an alcohol dehydrogenase inhibitor that causes adverse effects when taken with alcohol.
These drugs are already approved for other indications, but could be repurposed for the treatment of PAU, subject to further clinical validation.
Conclusion
The researchers' findings provide valuable insight into the genetic underpinnings of PAU, paving the way for improved prevention and treatment strategies. The study also demonstrates the value of collaboration among different research institutions and data sharing, which can enrich our understanding of human health and biodiversity.
Nonetheless, it's important to remember that while genetics play a significant role in PAU, they don't tell the whole story. Numerous environmental and social factors also contribute to the risk of developing PAU, and these must be taken into account when developing comprehensive strategies to address this complex condition.
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