Effects of polygenic risk for suicide attempt and risky behavior on brain structure in young people with familial risk of bipolar disorder

Abstract

Aims: Bipolar Disorder (BD) is associated with a 20-30 fold increased suicide risk compared to the general population. First-degree relatives of BD patients show inflated rates of psychopathology including suicidal behaviors. As reliable biomarkers of suicide attempts (SA) are lacking, we examined associations between suicide-related polygenic risk scores (PRS) - a quantitative index of genomic risk - and variability in brain structures implicated in SA. Methods: Participants (n=206; aged 12-30 years) were unrelated individuals of European ancestry and comprised three groups: 41 BD cases, 96 BD relatives ('high-risk'), and 69 controls. Genotyping employed PsychArray, followed by imputation. Three PRS were computed using genome-wide association data for SA in BD (SA-in-BD), SA in Major Depressive Disorder (SA-in-MDD) [Mullins et al., 2019], and risky behavior [Karlsson Linnér et al., 2019]. Structural MRI processing employed FreeSurfer v5.3.0. General linear models were constructed using 32 regions-of-interest identified from suicide neuroimaging literature, with false-discovery-rate correction. Results: SA-in-MDD and SA-in-BD PRS negatively predicted parahippocampal thickness, with the latter association modified by group membership. SA-in-BD and Risky Behavior PRS inversely predicted rostral and caudal anterior cingulate structure, respectively, with the latter effect driven by the 'high-risk' group. SA-in-MDD and SA-in-BD PRS positively predicted cuneus structure, irrespective of group. Conclusions: This study demonstrated associations between PRS for suicide-related phenotypes and structural variability in brain regions implicated in SA. Future exploration of extended PRS, in conjunction with a range of biological, phenotypic, environmental and experiential data in high-risk populations, may inform predictive models for suicidal behaviors.

Distinguish bipolar and major depressive disorder in adolescents based on multimodal neuroimaging: Results from the Adolescent Brain Cognitive Development study®

“…68 Some evidence suggests that individuals with or at risk for depression are associated with structural alterations in the cuneus. 69–71 Previous studies have reported that cuneus gray matter volume is associated with depression 72 and suicidal behavior 73,74 in MDD adults. Kim et al 75 found that MDD adolescents have a thinner cortical thickness in the cuneus.…”