Wilson’s disease (WD) is a rare genetic disorder that affects copper metabolism, primarily presenting with hepatic and central nervous system symptoms. Early detection can be challenging due to its variable presentation. In this case, we discuss a 44-year-old female with a six-year history of chronic neurogenic pain, migraines, alcohol use disorder, major depressive disorder, and recent unexplained abdominal pain. She presented to the emergency room with ascites, fulminant hepatic failure, and acute kidney injury. Despite her previously stable health, her condition rapidly decompensated over a month with the onset of hepatic failure. Decompensated cirrhosis secondary to non-alcoholic steatohepatitis or alcoholic hepatitis was suspected. Still, a positive ceruloplasmin study and the presence of Kayser-Fleischer rings observed on slit-lamp examination ruled in WD. This case highlights a late-onset presentation of WD. With early diagnosis and treatment, the fatal sequelae of WD can be prevented. Along with this case, the classifications of WD, its common and unique features, and the diagnostic criteria were reviewed.

Background/Objectives: Substance use behaviors share a complex, overlapping polygenic architecture, yet translating genome-wide association study (GWAS) findings into actionable biological mechanisms remains challenging. This study aimed to characterize the genetic architecture of five substance use traits (alcohol consumption, alcohol dependence, nicotine use, illicit drug use, and behavioral disinhibition) and identify shared and distinct gene expression signatures within the neural circuits governing addiction. Methods: We reanalyzed 7188 individuals from the Minnesota Center for Twin and Family Research (MCTFR) cohort utilizing longitudinal composite phenotypes spanning five substance-use domains and general behavioral disinhibition. Post-QC, 6874 individuals were retained for downstream analysis. Following genomic imputation and linear mixed model GWAS (GEMMA), we utilized the SNipar framework to partition polygenic risk scores (PRS) into direct and indirect genetic effects, investigating intergenerational shifts in genetic penetrance and effects of assortative mating. Finally, we integrated our summary statistics with brain tissue reference panels to perform a transcriptome-wide association study (TWAS) modeling genetically regulated gene expression within neural circuits relevant to addiction. Results: Partitioning of polygenic risk revealed that while surface-level parental DNA correlations were modest (r = 0.08), underlying latent genetic correlations approached unity (R_δ ≈ 0.99), indicating that addiction risk clustering in families is driven by intense assortive mating and concentrated biological inheritance. Multi-phenotype TWAS identified several significant gene–phenotype associations—notably ADAM32 and SLC9A3, which demonstrated pleiotropic effects across multiple substance use categories. Crucially, these significant TWAS signals were enriched in striatal structures (caudate, putamen, substantia nigra) and frontal cortical regions. Conclusions: Our findings support a model of shared genetic liability across diverse substance use behaviors, mediated by specific gene expression patterns in the mesolimbic dopamine system and frontal cortex. By integrating multi-phenotype GWAS and TWAS, this study highlights pleiotropic candidate genes and provides critical insights into the tissue-specific neurobiological pathways underlying addiction vulnerability.