Genetic Confounding in the Association Between Traumatic Brain Injury and Mental Disorder or Suicide

Traumatic brain injury is common and occurs across all ages. Observational studies have shown that traumatic brain injury is associated with a wide range of mental disorders and suicide. Whether these associations represent a causal effect is, however, difficult to establish, and confounding by genetic liability for mental disorder may play a substantial role.

To investigate whether observational associations between traumatic brain injury and mental disorder or suicide could be confounded by genetic liability for mental disorder.

This cohort study was conducted from October 2023 to January 2025. The study population consisted of the general population subcohort of the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH) sample, which is a representative sample of the Danish population born between 1981 and 2008 that has been genotyped.

Polygenic risk scores (PRSs) for schizophrenia, bipolar disorder, depression, and attention-deficit/hyperactivity disorder (ADHD) calculated from the genotypes and genome-wide association summary statistics.

The primary outcome was traumatic brain injury, operationalized via hospital diagnoses. The associations between PRSs for schizophrenia, bipolar disorder, depression, and ADHD, respectively, and traumatic brain injury were examined via Cox proportional hazards regression, yielding hazard rate ratios (HRRs) with 95% confidence intervals.

The final cohort consisted of a total of 40 274 individuals, of whom 19 802 (49.2%) were female. A total of 3341 (8.3%) of the cohort members (of whom 1464 [43.8%] were female and 1877 [56.2%] were male) experienced traumatic brain injury during follow-up. All 4 PRSs showed statistically significant positive associations with traumatic brain injury (PRS-schizophrenia: HRR, 1.06; 95% CI, 1.02-1.10; P = .002; PRS-bipolar disorder: HRR, 1.04; 95% CI, 1.00-1.08; P = .04; PRS-depression: HRR, 1.10; 95% CI, 1.06-1.14; P < .001; and PRS-ADHD: HRR, 1.12; 95% CI, 1.08-1.16; P < .001).

The results of this cohort study suggest that confounding by genetic liability for mental disorder could explain some of the association between traumatic brain injury and mental disorder or suicide. Consequently, genetic liability for mental disorder should be factored into future studies of these associations to avoid overestimation of causality.