NEW YORK – A National Institutes of Health-led team has identified brain proteins and cell type-related genes with ties to alcohol use disorders (AUD) and other problematic drinking behaviors ranging from alcohol use frequency to binge drinking. The findings appeared in Nature Human Behaviour on Monday.
"These findings provide insights into the genetic landscapes governing problematic alcohol use and alcohol consumption behaviors, highlighting promising therapeutic targets for future research," senior and corresponding author Falk Lohoff, a clinical genomics and experimental therapeutics researcher with the National Institute on Alcohol Abuse and Alcoholism, and his colleagues wrote.
In an effort to tease out AUD-related relationships between cortical protein variants and cell type-specific gene expression, the researchers considered expression quantitative loci profiles produced with post-mortem, single-cell expression data spanning 6,100 genes in eight brain cell types for 192 genotyped, European ancestry participants.
They also brought in published protein quantitative trait locus (pQTL) data based on expression patterns for nearly 7,400 proteins in three cortical brain regions in 722 European ancestry participants, along with summary-level data from published genome-wide association studies on four types of problem drinking: drinks per week (DPW), binge drinking, problematic alcohol use (PAU), and alcohol intake frequency (AIF).
"This multiomics approach is critical for uncovering the biological mechanisms behind neuropsychiatric outcomes identified in GWASs," the authors explained, "enhancing our understanding of AUD and alcohol consumption behaviors by revealing tissue- and cell type-specific relationships."
With a statistical framework centered on Mendelian randomization, the team used the multiomics data to track down 217 AUD- or problem drinking-related proteins in the brain's cortex, including three dozen proteins not implicated in alcohol use behaviors in the past. The search also highlighted 255 AUD- or problem drinking-associated genes with cell type-specific activity — a set that encompassed 37 cell type-related genes not flagged in prior studies.
"Our comparison between cortical proteome and cell type transcriptome results showed minimal overlap, consistent with previous findings that protein levels and gene expression are underpinned by different genetic factors," the authors reported. "This suggests that each data type provides unique biological insights important for variant-to-function studies."
In particular, the investigators tracked down contributors to neurotransmitter regulation, lysosomal storage, neurological conditions, and other psychiatric or neurodegeneration conditions. They noted that distinct sets of genes and proteins appeared to be involved in each of the alcohol use behaviors considered.
"Differences in the proteomic and transcriptomic architecture across alcohol behaviors, tissues, and omics levels underscore the need for comprehensive evaluation," the authors noted, adding that additional studies "will be important to further clarify the roles of the apparent differences in the biological underpinnings of genetically predisposed AUD and alcohol consumption."
Even so, they suggested that the current findings "will inform future work, including drug development and harm-reduction strategies, to reduce AUD and hazardous alcohol consumption."