Do regional brain volumes and major depressive disorder share genetic architecture? A study of Generation Scotland (n=19,762), UK Biobank (n=24,048) and the English Longitudinal Study of Ageing (n=5,766)

Major depressive disorder (MDD) is a highly debilitating and heritable disorder. It is commonly associated with subcortical volumetric abnormalities, the most replicated of these being reduced hippocampal volume. Using the most recent published data from ENIGMA consortium’s genome-wide association study (GWAS) of regional brain volume, we sought to test whether there is shared genetic architecture between subcortical brain volumes and MDD. Using LD score regression utilising summary statistics from ENIGMA and the Psychiatric Genomics Consortium, we demonstrated that hippocampal volume was genetically correlated with MDD (rG=0.46, P=0.02), although this did not survive multiple comparison testing. None of other six regions were genetically correlated and amygdala volume heritability was too low for analysis. We also generated polygenic risk scores (PRS) to assess potential pleiotropy on regional brain volumes and MDD in three cohorts (Generation Scotland; Scottish Family Health Study (n=19,762), UK Biobank (n=24,048) and the English Longitudinal Study of Ageing (n=5,766)). We used logistic regression to examine volumetric PRS and MDD and performed a meta-analysis across the three cohorts. No regional volumetric PRS demonstrated any significant association with lifetime MDD or recurrent MDD. In this study we provide evidence that hippocampal volume and MDD have a shared genetic architecture providing further evidence of the potential mechanistic importance of the hippocampus in depression. We found no evidence to support a shared genetic architecture for MDD with any other subcortical region.