A new study, published in Nature Communications, has used a multi-omics systems approach to identify genes underlying alcohol use disorders. This is the first study of its kind in the field of addiction genetics and the findings suggest a potential overlap between alcoholism and neurodegenerative diseases. The results could influence how alcohol disorders are treated in the future.
Genes underlying alcohol use disorders
Alcohol use disorders (AUDs) are complex, moderately heritable, psychiatric disorders with negative physiological and psychological consequences for affected individuals. AUDs are associated with both heightened morbidity and mortality. Risk for AUD can be measured using drinks per week (DPW), which is a measure that assesses typical alcohol intake. Uncovering the causal genes driving AUD and DPW will aid the diagnosis and treatment of such disorders.
Previous genome-wide association studies (GWASs) of AUD and DPW have pinpointed multiple risk loci associated with alcohol consumption. However, the causal variants and genes underlying the loci have not been identified. This current study aimed to discover them.
“Identification of causal variants and genes underlying genome-wide association study loci is essential to understand the biology of alcohol use disorder and to improve its treatment,” first author Manav Kapoor said.
Multi-omics systems approach
Most genome-wide variants associated with AUD and DPW are intergenic, meaning that they cannot be directly mapped to a specific gene. This makes the discovery of causal genes more difficult.
To overcome this problem, researchers from the Icahn School of Medicine at Mount Sinai applied a multi-omics systems approach to uncover a list of causal candidate genes associated with AUD and DPW. They used Mendelian randomisation-based methods on the largest available transcriptomic and epigenomic datasets for brain tissues and myeloid cells.
Using this multi-omics approach, the team were able to fine-map AUD and DPW associations at single SNP resolution to predict causal genes.
Using multi-omics to identify causal genes
First, the researchers performed a meta-analysis on the AUD GWAS summary statistics. Using this data, the researchers tested which tissues the GWAS variants were found in. They found that variants for AUD and DPW were enriched in promoter regions of the foetal and adult brain.
Next, the team carried out fine mapping of the complex loci. The mapping identified MAPT as a candidate causal gene specifically associated with DPW. Further investigation also confirmed that increased MAPT expression was associated with increased alcohol consumption.
MAPT encodes a protein called tau, which is found in cells throughout the nervous system. Tau proteins are best known for their role in neuropsychiatric and neurodegenerative disorders, such as Alzheimer’s disease and frontotemporal dementia. In fact, more than 40 mutations in the MAPT gene have been associated with causing a specific subtype of frontotemporal dementia. These findings highlight a potential link between alcoholism and neurodegenerative disorders.
Further connections with neurodegenerative disease
In addition, SPI1, a gene primarily expressed in myeloid cells, was found to be associated with both DPW and AUD. Increased expression of the gene correlated with a higher DPW and higher AUD risk.
SPI1 encodes a transcription factor, PU.1, that regulates gene expression during myeloid cell and B-lymphoid cell development. Once again, a connection with neuropsychiatric diseases was found. Previous studies have reported that increased levels of SPI1 expression are associated with an increased risk of Alzheimer’s disease. Additionally, significantly higher expression levels of SPI1 have also been found in individuals with major depressive disorder and schizophrenia.
In the brain, SPI1 is specifically expressed in microglia, where PU.1 contributes to immune activation. Previous studies have found that immune networks contribute to drinking behaviours, yet these observations have not been consistent with previous GWASs of AUD and DPW. However, the identification of SPI1 in this study suggests that increased SPI1 expression is the reason behind the immune pathway enrichment seen in brains of individuals with increased drinking behaviour.
Conclusion and future work
The multi-omic analysis of human genetic and expression data carried out in this study has led to the identification of genes not previously known to influence AUD and DPW. The observation that these AUD-related variants also have roles in other brain disorders highlights a potential link between alcoholism and neurodegenerative diseases.
Future work on larger data sets will be required to validate the results. However, the genes identified will be able to guide subsequent research into potential therapies. The database of multi-omics analysis used by this study has also been made available, to provide a starting point for further elucidation of the biological mechanisms underlying AUD.
“This work could lead to novel therapeutics for the treatment for alcohol use disorders,” senior author Alison Goate said. “A number of anti-tau therapeutics are being developed for treatment of tauopathies including Alzheimer’s disease, these should also be tested in AUD models.”
