Comparing personalized brain-based and genetic risk scores for major depressive disorder in large population samples of adults and adolescents.

Abstract

Major depressive disorder (MDD) is a polygenic disorder associated with brain alterations but until recently, there have been no brain-based metrics to quantify individual-level variation in brain morphology. Here, we evaluated and compared the performance of a new brain-based 'Regional Vulnerability Index' (RVI) with polygenic risk scores (PRS), in the context of MDD. We assessed associations with syndromal MDD in an adult sample (N=702, age=59±10) and with subclinical depressive symptoms in a longitudinal adolescent sample (baseline N=3,825, age=10±1; 2-year follow-up N=2,081, age=12±1). MDD-RVIs quantify the correlation of the individual's corresponding brain metric with the expected pattern for MDD derived in an independent sample. Using the same methodology across samples, subject-specific MDD-PRS and six MDD-RVIs based on different brain modalities (subcortical volume, cortical thickness, cortical surface area, mean diffusivity, fractional anisotropy, and multimodal) were computed. In adults, MDD-RVIs (based on white matter and multimodal measures) were more strongly associated with MDD (β=0.099-0.281, PFDR=0.001-0.043) than MDD-PRS (β=0.056-0.152, PFDR=0.140-0.140). In adolescents, depressive symptoms were associated with MDD-PRS at baseline and follow-up (β=0.084-0.086, p=1.38×10-4-4.77×10-4) but not with any MDD-RVIs (β<0.05, p>0.05). Our results potentially indicate the ability of brain-based risk scores to capture a broader range of risk exposures than genetic risk scores in adults and are also useful in helping us to understand the temporal origins of depression-related brain features. Longitudinal data, specific to the developmental period and on white matter measures, will be useful in informing risk for subsequent psychiatric illness.