Polygenic risk scores for major depression can be calculated using results from recent genome-wide association studies [4, 55]. Wray et al. identified 44 SNPs at genome-wide significance and showed that a PRS built from SNPs with a p value < 0.05 had the highest predictive ability. Individuals in the upper PRS decile had approximately 2.5-fold increased risk of disease compared to those in the lowest decile, which translates into a substantial change in absolute risk, given an approximate 15% lifetime risk of major depression. However, this score has an AUC of 0.57 and captures only 2% of variance in disease risk (R2 on the liability scale), whilst the remaining 98% is uncaptured by the PRS. An individual’s risk of depression therefore comprises 2% of measurable genetic risk score and 98% unaccounted variation from unmodelled genetic and environmental factors. Even for an individual at very high genetic risk, the PRS signal would be overpowered by the unmodelled component. Depression PRS is therefore not yet useful, and any future utility would be based on substantially increasing the variance explained by the PRS
