Genetic Architecture of Suicidal Ideation Continuum: Latent Profile Analysis of Data using the Million Veteran Program Cohort

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Abstract
Suicidal ideation (SI) and behavior are complex phenotypes, with multiple contributing risk-factors. This study used longitudinal data from the Million Veteran Program Mental Health Survey to identify SI profiles among Veterans based on trajectories of ideation and depression severity, and compared them to a non-suicidal (no-SI) control group. Latent profile analysis (LPA) was performed to identify SI profiles using data from Veterans (n = 34,322) endorsing SI in their electronic health record. LPA identified four highly reproducible SI profiles: mild ideators with and without depression, variable ideators, and persistent ideators. Veterans across the SI profiles were significantly more likely to have diagnoses of suicidal ideation or behavior, mental disorders, and TBI compared to Veterans with no-SI. The variable ideators showed higher rates of comorbid conditions. The mild ideators without depression and persistent ideators had a significantly higher proportion of deaths by suicide than the no-SI Veterans. European and African American GWAS and pan-ancestry meta-analyses of SI profiles compared to no-SI controls were also performed, which identified genome-wide significant loci across all SI profiles proximal to genes implicated in auditory and vestibular functioning, Alzheimer’s, Diabetes, and Asthma. In summary, SI profiles identified were associated with novel genetic variants not identified by previous suicide GWAS studies. Additionally, Veterans within the mild SI profile that did not present with high-risk comorbidities had the highest rate of suicide deaths, indicating the need for upstream suicide risk prevention interventions across the SI risk continuum.

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