Assessment of suicide attempt and death in bipolar affective disorder: a combined clinical and genetic approach.

Bipolar disorder (BP) suicide death rates are 10-30 times greater than the general population, likely arising from environmental and genetic risk factors. Though suicidal behavior in BP has been investigated, studies have not addressed combined clinical and genetic factors specific to suicide death. To address this gap, a large, harmonized BP cohort was assessed to identify clinical risk factors for suicide death and attempt which then directed testing of underlying polygenic risks. 5901 individuals of European ancestry were assessed: 353 individuals with BP and 2498 without BP who died from suicide (BPS and NBPS, respectively) from a population-derived sample along with a volunteer-derived sample of 799 individuals with BP and a history of suicide attempt (BPSA), 824 individuals with BP and no prior attempts (BPNSA), and 1427 individuals without several common psychiatric illnesses per self-report (C). Clinical and subsequent directed genetic analyses utilized multivariable logistic models accounting for critical covariates and multiple testing. There was overrepresentation of diagnosis of PTSD (OR = 4.9, 95%CI: 3.1-7.6) in BPS versus BPSA, driven by female subjects. PRS assessments showed elevations in BPS including PTSD (OR = 1.3, 95%CI:1.1-1.5, versus C), female-derived ADHD (OR = 1.2, 95%CI:1.1-1.4, versus C), and male insomnia (OR = 1.4, 95%CI: 1.1-1.7, versus BPSA). The results provide support from genetic and clinical standpoints for dysregulated traumatic response particularly increasing risk of suicide death among individuals with BP of Northern European ancestry. Such findings may direct more aggressive treatment and prevention of trauma sequelae within at-risk bipolar individuals.