Convergent Pathways Identified for Cannabis Use Disorder Across Diverse Ancestry Populations

Area of Science:

• Genetics
• Psychiatry
• Population Health

Background:

• Cannabis Use Disorder (CUD) prevalence varies significantly across U.S. ethnic groups.
• Genome-Wide Association Studies (GWAS) have identified CUD loci primarily in European descent populations.
• Rare and low-frequency functional variants may explain genetic contributions to CUD in understudied groups.

Purpose of the Study:

• To investigate the role of rare and low-frequency functional variants in CUD severity across three diverse populations: European Americans (EA), American Indians (AI), and Mexican Americans (MA).
• To identify specific genes and biological pathways associated with CUD severity in these distinct ethnic groups.

Main Methods:

• Association analysis focused on rare and low-frequency functional variants within genes and biological pathways.
• Examined three populations: EA, AI, and MA.
• Analyzed CUD severity as the primary phenotype.

Main Results:

• Identified 10 significant loci in AI and the *ARSA* gene in MA associated with CUD severity.
• Discovered three significant pathways in MA and one in EA related to CUD severity.
• Found overlapping pathways (arylsulfatase activation, heparan sulfate degradation, p38-gamma/delta signaling) across populations, alongside unique pathways (integrin beta-1 in MA, autoimmune in MA/EA).

Conclusions:

• Distinct genetic pathways contribute to CUD severity across EA, AI, and MA populations.
• Rare functional variants play a significant role in CUD heritability across diverse groups.
• Shared genetic factors exist, underscoring the importance of including diverse populations in CUD genetic research.