Some genetic risk factors for alcohol use disorder overlap with those for neurodegenerative diseases like Alzheimer’s, scientists reported in Nature Communications on August 20. The study, which relied on a combination of genetic, transcriptomic, and epigenetic data, also offers insight into the molecular commonalities among these disorders, and their connections to immune disfunction.
“By meshing findings from genome wide association studies . . . with gene expression in brain and other tissues, this new study has prioritized genes likely to harbor regulatory variants influencing risk of Alcohol Use Disorder,” writes David Goldman, a neurogenetics researcher at the National Institute on Alcohol Abuse and Alcoholism (NIAAA), in an email to The Scientist. “Several of these genes are also associated with neurodegenerative disorders—an intriguing connection because of alcohol’s ability to prematurely age the brain.”
Over the past several years, researchers have published a handful of massive genome-wide association studies (GWAS) studies identifying loci—regions of the genome that can contain 10 or more individual genes—that likely influence a person’s risk of developing an alcohol use disorder (AUD).
In a study published two years ago, Manav Kapoor, a neuroscientist and geneticist at the Icahn School of Medicine at Mount Sinai and first author on the new paper, and his team found evidence that the immune system might be overactive in people with AUD, but the finding left him with more questions. The first was whether excessive drinking directly causes immune dysfunction, or if instead some people’s genetic makeup puts them at risk for both simultaneously. The second was which of the dozen or so genes at each previous GWAS-identified locus actually influences drinking behaviors. Lastly, he wanted to know if there is a genetic difference between people who consume higher numbers of alcoholic beverages per week but are not diagnosed with AUD and those who have received the diagnosis.
To answer these questions, Kapoor and his team looked at genetic data from about 700,000 families involved in the NIAAA’s Collaborative Studies on the Genetics of Alcoholism (COGA), as well as genetic variants and surveys about drinks per week from the UK Biobank dataset, then compared those to data from analyses of adult and fetal brains that determined how much RNA was transcribed from particular genes, and which genes were epigenetically silenced or expressed.
This multi-omic approach enabled the researchers to map to the level of changes in a single base pair, “which was amazing,” says Kapoor.
To make full biological use of GWAS results, we need to understand the biology underlying the statistical association signals. This paper describes a substantial move forward in that direction.—Joel Gelernter, Yale University School of Medicine
While the study’s meta-analysis of mutations revealed many genes associated with alcohol use, the team zeroed in on two genes associated with high alcohol consumption (measured in drinks per week), SPI1 and MAPT, because previous studies had linked them to neurodegenerative diseases. SPI1 encodes a transcription factor that modulates the activity of immune cells, and MAPT produces tau, a protein found throughout the nervous system.
Some of Kapoor’s colleagues were interested in SPI1 because, in previous research, it was shown to influence the likelihood of a person developing Alzheimer’s disease, likely because it influences the activity of immune cells in the brain known as microglia. That might help explain Kapoor’s earlier findings of an association between immune overactivity and AUDs, and additionally, in the new analysis, the gene was associated with both heavy drinking and an AUD diagnosis.
Alcoholism is associated with immune disfunction on its own, but the team found that SPI1 expression is enriched in some fetal brains, suggesting that people who are genetically predisposed to AUD and heavy drinking are also predisposed to developing an overactive immune system, says Kapoor. If that’s the case, then when people with certain versions of this gene drink heavily, their immune system is likely to become overactivated. That, in turn, could cause microglia to start altering neuronal connections, Kapoor suggests, pointing to a study in mice that found binge drinking activated microglia, which selectively pruned excitatory synapses, causing the animals to display anxiety-like behaviors.
Potentially, the microglia prune connections to neurons the produce dopamine, the chemical responsible for the “rewarding” feeling of drinking alcohol. All this means that if people with certain versions of SPI1 start drinking regularly, “they’d have to drink more and more to get the same level of reward,” says Kapoor. “And their immune system will get more activated,” pruning more synapses. “It will become a vicious cycle.”
MAPT isn’t associated with alcohol use disorder, but it is associated with consuming more drinks per week. The tau protein it codes for is thought to play a large role in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, frontotemporal dementia, and supranuclear palsy. It’s not yet clear how tau might factor into alcohol consumption.
Joel Gelernter, a geneticist and neurobiologist at Yale University School of Medicine who was not involved in the work, tells The Scientist in an email that the study is “a really necessary step in unraveling the biology of alcohol intake and alcohol use disorder.”
“To make full biological use of GWAS results, we need to understand the biology underlying the statistical association signals. This paper describes a substantial move forward in that direction,” he writes.
While the study focused primarily on SPI1 and MAPT, the scientists created a publicly available, searchable database of all the genetic, transcriptomic, and epigenetic data from the study.
Kapoor says the findings could help people in two ways. First, they suggest that drugs currently in development for neurodegenerative diseases might be repurposed to help people reduce or stop drinking. Second, “if we can identify some group of people that are more at risk of Alzheimer’s disease, we can ask them to reduce their drinking,” he says. “That might be beneficial to them.”