Smaller volumes of the cornu ammonis (CA1 and CA3) may be a biological endophenotype for suicide risk in mood disorders

Mood disorders and suicidal behavior have moderate heritability and are associated with smaller hippocampal volumes. However, it is unclear whether these alterations reflect heritable risk or epigenetic effects of childhood, compensatory mechanisms, or illness-related changes. We sought to separate effects on hippocampal substructure volumes due to mood disorder, suicidal behavior, and risk and resilience to both by examining high familial risk individuals (HR) who have passed through the age of greatest risk for psychopathology onset. Structural brain imaging and advanced hippocampal substructure segmentation quantified cornu ammonis (CA1-4), dentate gyrus, and subiculum volumes in healthy volunteers (HV, N=25) and three groups with one or more relatives with early-onset mood disorder and suicide attempt: 1. unaffected HR (N=20); 2. HR with lifetime mood disorder and no suicide attempt (HR-MOOD, N=25); and 3. HR-MOOD+SA with mood disorder and a previous suicide attempt (N=18). Findings were tested in two independent cohorts not selected for family history (HV, MOOD, and MOOD+SA, total N=199). Lower CA1 and CA3 volumes were found in both HR-MOOD+SA and in HR as compared to HV, suggesting a biological endophenotype for suicide risk and mood disorder. No group differences were observed in MOOD+SA or MOOD vs. HV, suggesting the effects are associated with familial risk for, but not previous, suicide attempt and mood disorder. Our findings suggest familial suicide risk may be mediated in part by smaller CA1 and CA3 volumes. The structures may serve as therapeutic targets for suicide prevention strategies in high risk families