Stratifying major depressive disorder by polygenic risk for schizophrenia in relation to structural brain measures

Matthew A. Harris, Xueyi Shen, Simon R. Cox, Jude Gibson, Mark James Adams, Toni-Kim Clarke, Ian J. Deary, Stephen M. Lawrie, Andrew M. McIntosh, Heather C. Whalley

Research output: Contribution to journalArticlepeer-review


Substantial clinical heterogeneity of major depressive disorder (MDD) suggests it may group together individuals with diverse aetiologies. Identifying distinct subtypes should lead to more effective diagnosis and treatment, while providing more useful targets for further research. Genetic and clinical overlap between MDD and schizophrenia (SCZ) suggests an MDD subtype may share underlying mechanisms with SCZ.

MethodsThe present study investigated whether a neurobiologically distinct subtype of MDD could be identified by SCZ polygenic risk score (PRS). We explored interactive effects between SCZ PRS and MDD case/control status on a range of cortical, subcortical and white matter metrics among 2,370 male and 2,574 female UK Biobank participants.

ResultsThere was a significant SCZ PRS by MDD interaction for rostral anterior cingulate cortex (RACC) thickness (β=.191, q=.043). This was driven by a positive association between SCZ PRS and RACC thickness among MDD cases (β=.098, p=.026), compared to a negative association among controls (β=–.087, p=.002). MDD cases with low SCZ PRS showed thinner RACC, although the opposite difference for high-SCZ-PRS cases was not significant. There were nominal interactions for other brain metrics, but none remained significant after correcting for multiple comparisons.

Our significant results indicate that MDD case-control differences in RACC thickness vary as a function of SCZ PRS. Although this was not the case for most other brain measures assessed, our specific findings still provide some further evidence that MDD in the presence of high genetic risk for SCZ is subtly neurobiologically distinct from MDD in general.
Original languageEnglish
Pages (from-to)1653-1662
JournalPsychological Medicine
Issue number10
Early online date18 Jul 2019
Publication statusE-pub ahead of print - 18 Jul 2019


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