Causal Analyses of Associations Between Brain Structure and Suicide Attempt in Adulthood and Late Childhood.

Objective: Brain markers for suicide risk in adulthood may be detected during childhood and used for earlier detection and initiation of preventive interventions. Genetic instrumental variable analyses were used to determine whether there is evidence of lower brain total cortical surface area and thinner average cortical thickness (ACT) causing increased suicide risk in adults and whether lower measures of similar brain measures can cause increased risk of suicidality and related psychopathology in older children. Method: Two-sample Mendelian randomization (MR) was used with summary statistics from genome-wide association studies for total cortical surface area, ACT, and suicide attempt in adults to test causal hypotheses. In youth ages 9 to 10 years old, a combined MR and twin-based direction-of-causation approach was applied to the European twin sample (199 monozygotic, 257 dizygotic twin pairs), and a hybrid traditional twin direction-of-causation approach was applied to the full twin sample (308 monozygotic, 397 dizygotic twin pairs) from the Adolescent Brain Cognitive Development (ABCD) Study. Results: Two-sample MR analyses found a significant negative causal effect of total cortical surface area on suicide attempt risk in adults. MR-direction-of-causation analyses did not find a significant causal effect of any brain measure on suicidality in older children, but found significant negative causal effects of ACT on depression and internalizing psychopathology, and vice versa. Conclusion: Brain markers of suicide risk may be instantiated differently in adults compared with older children, though lower ACT may be causally related to psychopathology associated with suicidality in these youth.