Pathways from Polygenic Risk to Suicidality: Effects of Alcohol Use Disorder and Childhood Adversity.

Area of Science:

• Genetics
• Psychiatry
• Epidemiology

Background:

• Suicidal ideation (SI) and suicide attempts (SA) are complex, influenced by genetic, behavioral, and environmental factors.
• Alcohol use disorder (AUD) and adverse childhood experiences (ACEs) may play a role in the genetic predisposition to suicidality.

Purpose of the Study:

• To investigate the predictive value of polygenic scores (PGS) for SI and SA on lifetime suicidality.
• To examine the mediating role of AUD and the moderating role of ACEs in the genetic liability to suicidality.

Main Methods:

• Utilized data from 10,275 participants (African-like and European-like genetic ancestry).
• Tested PGS for SI and SA against lifetime SI and SA.
• Evaluated mediation by AUD and moderation by ACEs score.

Main Results:

• The SA PGS significantly predicted SA in both ancestry groups (p < 2e-16).
• The SI PGS did not predict SI (p > 0.55).
• AUD mediated the genetic risk for SA (p < 2e-16), with indirect effects attenuated by ACEs score (p < 2e-16 for AFR, p = 0.03 for EUR).

Conclusions:

• Genetic liability to SA is partly mediated by AUD, particularly in individuals with lower childhood adversity.
• Distinct etiological pathways contribute to suicidality, highlighting AUD as a potential target for intervention in genetically at-risk individuals.