BETHESDA, MD — While it is understood that problematic alcohol use (PAU) and anxiety disorders (ANX) often co-occur, suggesting some type of shared genetic and neurobiological foundations, the directionality of potential causal relationships and the specific mechanisms have remained unclear.
That led to the investigation of the shared genetic architecture and neurobiological pathways between PAU and ANX using a multimethod genomic approach. The research was led by the Uniformed Services University in Bethesda, MD. Other federal medicine investigators were from the Henry M. Jackson Foundation for the Advancement of Military Medicine Inc. in Bethesda, MD,the Crescenz VAMC in Philadelphia and the VA Connecticut Healthcare System in West Haven, CT.
The study team analyzed summary statistics from genome-wide association studies (GWAS) of PAU and ANX using Mendelian Randomization to assess causal associations between ANX and PAU. MiXeR was employed to assess the overall shared genomic architecture, Local Analysis of (co)Variant Association to estimate regional genetic correlations, and conjunctional false discovery rate (conjFDR) to identify individual overlapping loci. The researchers said they also Functional Mapping and Annotation (FUMA) to map single-nucleotide polymorphisms (SNPs) to independent loci, conduct differential gene expression analyses across 30 general and 54 specific tissue types and perform cell-type specificity analyses using a human brain cell atlas. Druggability of identified targets also 1was evaluated, they said.
In results published in the journal Neuropsychopharmacology, Mendelian Randomization analyses indicated bidirectional causal associations between ANX and PAU. In addition, MiXeR identified moderate polygenic overlap (52.5%) and genetic correlation (rg = 0.44) between the traits, with high effect direction concordance among shared estimated causal variants (86.4%). The study team explained that ConjFDR identified 97 shared lead SNPs, of which 89 had concordant and 8 discordant effects on PAU and ANX.
“These loci mapped to 97 genes, including DRD2 and PDE4B, genes linked to dopaminergic and cAMP signaling pathways, respectively,” according to the authors. “Concordant gene expression was enriched in brain, nerve, adrenal gland, esophagus, stomach, and colon, with enriched expression specifically in the prefrontal cortex, anterior cingulate cortex, hippocampus, hypothalamus, substantia nigra and amygdala. FUMA cell-type enrichment analysis identified associations predominantly in neurons from the cerebral cortex, hippocampus, and thalamus.”
The researchers concluded, “We found substantial genetic and neurobiological overlap between PAU and ANX, highlighting reciprocal, causal relationships between the traits, with differentially expressed genes enriched in addiction- and anxiety-relevant brain regions. These findings support shared genetic and neurobiological mechanisms linking PAU and ANX, while acknowledging that some signals may reflect broader internalizing or psychiatric liability.”
- Shi M, Gunawan T, Malone SG, Setzer M, et. al. Shared genetic architecture and neurobiological pathways of problematic alcohol use and anxiety disorders. Neuropsychopharmacology. 2026 Jul 13. doi: 10.1038/s41386-026-02494-z. Epub ahead of print. PMID: 42443535.
