Genetic Association of Attention-Deficit/Hyperactivity Disorder and Major Depression With Suicidal Ideation and Attempts in Children: The Adolescent Brain Cognitive Development Study

Abstract

Background: Suicide is among the leading causes of death in children and adolescents. There are well-known risk factors of suicide, including childhood abuse, family conflicts, social adversity, and psychopathology. While suicide risk is also known to be heritable, few studies have investigated genetic risk in younger individuals.

Methods: Using polygenic risk score analysis, we examined whether genetic susceptibility to major psychiatric disorders is associated with suicidal behaviors among 11,878 children enrolled in the ABCD (Adolescent Brain Cognitive Development) Study. Suicidal ideation and suicide attempt data were assessed using the youth report of the Kiddie Schedule for Affective Disorders and Schizophrenia for DSM-5. After performing robust quality control of genotype data, unrelated individuals of European descent were included in analyses (n = 4344).

Results: Among 8 psychiatric disorders we examined, depression polygenic risk scores were associated with lifetime suicide attempts both in the baseline (odds ratio = 1.55, 95% CI = 1.10-2.18, p = 1.27 × 10^-2) and in the follow-up year (odds ratio = 1.38, 95% CI = 1.08-1.77, p = 1.05 × 10^-2), after adjusting for children's age, sex, socioeconomic backgrounds, family history of suicide, and psychopathology. In contrast, attention-deficit/hyperactivity disorder polygenic risk scores were associated with lifetime suicidal ideation (odds ratio = 1.15, 95% CI = 1.05-1.26, p = 3.71 × 10^-3), suggesting a distinct contribution of the genetic risk underlying attention-deficit/hyperactivity disorder and depression on suicidal behaviors of children.

Conclusions: The largest genetic sample of suicide risk data in U.S. children suggests a significant genetic basis of suicide risk related to attention-deficit/hyperactivity disorder and depression. Further research is warranted to examine whether incorporation of genomic risk may facilitate more targeted screening and intervention efforts.

Keywords: ADHD; Adolescents; Children; Depression; Polygenic risk score; Suicide.

Figure 1.

Study outline of the polygenic risk score (PRS) analyses. Our study used ABCD (Adolescent Brain Cognitive Development) Study data release 3.0, which included genetics and phenotypic data collected in the baseline and the first follow-up year for 11,877 participants. Suicidal data were collected using the youth version of the computerized Kiddie Schedule for Affective Disorders and Schizophrenia for DSM-5. Using the individual item data, we generated 3 lifetime suicide-related measures, encompassing nonsuicidal self-injury (NSSI), suicidal ideation (SI), and suicide attempt (SA). Well-known risk factors of suicide were included in the analysis using the ABCD Study survey data. For PRS data generation, 8 psychiatric disorder genome-wide association studies (GWASs) of the largest available sample size were applied to 4344 ABCD participants of European ancestry. SNP, single nucleotide polymorphism.

Figure 2.

Logistic regression analysis results for testing the association between 8 psychiatric disorder polygenic risk scores and lifetime suicide risk outcome measures. Odds ratio (OR) represents the exponential of the logistic regression estimates. Error bars represent 95% confidence intervals of ORs. ADHD, attention-deficit/hyperactivity disorder; PTSD, posttraumatic stress disorder; NSSI, nonsuicidal self-injury; SA, suicide attempt; SI, suicidal ideation.

Figure 3.

Association analysis results of major depression (MD) and attention-deficit/hyperactivity disorder (ADHD) polygenic risk scores (PRSs) with known risk factors of suicide. (A) Partial correlations were measured between PRSs and 11 Child Behavior Checklist items, conditioning on age, sex, and 10 genetic principal components to control for potential population substratification within Europeans. The y-axis represents the t-statistics of partial correlation measures. (B) The t-test results for comparing ADHD and MD PRSs between 2 groups of participants stratified by various risk factors. Participants were divided into two groups based on family history of suicide, parent college education, and poverty. Poverty was set at yes if the household income of the participants was less than $20,000 annually. The top panels display MD PRS scores on the y-axis, while the bottom panels show ADHD PRS scores. aggressive = aggressive behavior; anxdep = anxious/depressed; attention = attention problems; external = externalizing problems; internal = internalizing problems; rulebreak = rule-breaking behavior; social = social problems; somatic = somatic complaints; thought = thought problems; totprob = total problem score; withdep = withdrawn/depressed.