LAUSR

Background Bipolar Disorder (BP) is a highly heritable mood disorder as demonstrated by a 5 to 10 fold increased risk amongst first degree relatives of BP probands. Structural imaging differences and clinical symptoms have also been observed amongst those with familial risk (At-Risk or AR) prior to any diagnosis of BP. Alternatively, a Polygenic Risk Score (PRS) based on known risk alleles for BD can be used as an index for increased genetic risk, facilitating an examination of the biological mechanism of BP pathogenesis. Methods Within a group of 50 young first-degree relatives of BP probands (mean age 22.6 years, SD 4.2) and 50 gender and age matched controls (22.5 years, SD 4.3) we explored the main and interactive effects of familial and polygenic risk for BP on brain structure. A PRS was derived for each subject from 32 replicated BP associated risk alleles from the first Psychiatric Genomics Consortium genome-wide association study. Using familial risk, PRS, age, and gender as independent factors, a series of general linear models were applied to both vertex-wise cortical thickness data and subcortical regions of interest segmentations extracted from T1-weighted magnetic resonance images. Results While familial risk was associated with greater cortical thickness in the right inferior frontal gyrus, greater PRS was associated with a thicker cortex in AR, and thinner cortex in controls. Age-dependent effects of PRS were also observed in AR individuals, with the youngest subjects demonstrating the thickest cortex. For all subcortical regions of interest examined, no main or interaction effects were observed for familial or polygenic risk. Discussion These findings of differential PRS effects in AR and controls subjects point to the modulating role of other genetic and familial risk factors in the effects of PRS on brain structure. The age dependence of PRS effects in those with familial risk indicates the possibility of a complex developmental trajectory and highlights the need for longitudinal studies.