Partitioning the Genomic Components of Behavioral Disinhibition and Substance Use (Disorder) Using Genomic Structural...

Area of Science:

• Behavioral Genetics
• Psychiatric Genomics
• Addiction Research

Background:

• Externalizing behaviors, encompassing risk-taking and impulsivity, are studied alongside substance use (SU) and substance use disorder (SUD).
• Previous research indicates shared genetic architecture among SU, SUD, and behavioral disinhibition (BD) traits.
• Understanding the genetic basis of these overlapping yet distinct traits is crucial for developing targeted interventions.

Approach:

• Utilized European ancestry genome-wide association study (GWAS) statistics for SU, SUD, and BD traits.
• Developed single-factor measurement models for each trait category.
• Applied trivariate Cholesky decomposition to partition genetic covariance and identify BD-specific genomic variation.

Key Points:

• High genetic correlations were observed between SU, SUD, and BD latent factors (rg ≈ 0.80-0.86).
• BD-specific genetic variance accounted for 33% (initial) and 27% (refined) of total BD variance, indicating unique genetic underpinnings.
• The majority of genetic covariance between BD and SU/SUD was shared across all factors.

Conclusions:

• Behavioral disinhibition, substance use, and substance use disorder are highly genetically correlated.
• A significant, non-shared component of genomic variation underlies behavioral disinhibition.
• Further research into BD-specific genetic variation may reveal novel molecular correlates and therapeutic targets.