Dissection of major depressive disorder using polygenic risk scores for schizophrenia in two independent cohorts.

H C Whalley,D J Porteous,T-K Clarke,J Gibson,A Campbell,E Wigmore,A M Fernandez-Pujals,L S Hall,S M Lawrie,A M Mcintosh,I J Deary,M J Adams,C Hayward,J Hafferty,G Davies,S P Hagenaars

doi:10.1038/tp.2016.207

Abstract

Major depressive disorder (MDD) is known for its substantial clinical and suspected causal heterogeneity. It is characterized by low mood, psychomotor slowing and increased levels of the personality trait neuroticism; factors also associated with schizophrenia (SCZ). It is possible that some cases of MDD may have a substantial genetic loading for SCZ. The presence of SCZ-like MDD subgroups would be indicated by an interaction between MDD status and polygenic risk of SCZ on cognitive, personality and mood measures. Here, we hypothesized that higher SCZ polygenic risk would define larger MDD case–control differences in cognitive ability, and smaller differences in distress and neuroticism. Polygenic risk scores (PRSs) for SCZ and their association with cognitive variables, neuroticism, mood and psychological distress were estimated in a large population-based cohort (Generation Scotland: Scottish Family Health Study, GS:SFHS). The individuals were divided into those with, and without, depression (n=2587 and n=16 764, respectively) to test for the interactions between MDD status and schizophrenia risk. Replication was sought in UK Biobank (UKB; n=6049 and n=27 476 cases and controls, respectively). In both the cohorts, we found significant interactions between SCZ-PRS and MDD status for measures of psychological distress (βGS=−0.04, PGS=0.014 and βUKB=−0.09, PUKB⩽0.001 for GS:SFHS and UKB, respectively) and neuroticism (βGS=−0.04, PGS=0.002 and βUKB=−0.06, PUKB=0.023). In both the cohorts, there was a reduction of case–control differences on a background of higher genetic risk of SCZ. These findings suggest that depression on a background of high genetic risk for SCZ may show attenuated associations with distress and neuroticism. This may represent a causally distinct form of MDD more closely related to SCZ.

Highlights

Major depressive disorder (MDD) has a lifetime prevalence of approximately 16% and is a heritable and severely disabling psychiatric condition.[1]
For both distress and neuroticism, the SCZ-polygenic risk score (PRS) × MDD status interactions remained significant after modelling if the individuals were experiencing a current depressive episode at the time of assessment according to the Statistical Manual of Mental Disorders (SCID), and remained significant when modelling if individuals were taking antidepressant medication at the time of assessment according to self-report; full details in cohorts (Po0.05)
We demonstrate that the greatest variance explained for neuroticism and distress was higher in controls than in the MDD cases, in ASReml-R using the same methods as above

Summary

INTRODUCTION

Major depressive disorder (MDD) has a lifetime prevalence of approximately 16% and is a heritable and severely disabling psychiatric condition.[1] It is highly clinically heterogeneous, relying on diagnostic criteria that are fulfilled through the presence of an arbitrary threshold of symptoms that lack empirical validation. Individuals passing this threshold can have a very different combination of symptoms. We sought to test these predictions in a population-based cohort study, the Generation Scotland cohort: The Scottish Family Health Study sample (GS:SFHS).[29,30] Replication of any significant findings was sought in UK Biobank (UKB)

MATERIALS AND METHODS

RESULTS

Limitations