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. 2016 Nov 1;6(11):e938.
doi: 10.1038/tp.2016.207.

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

H C Whalley  1 , M J Adams  1 , L S Hall  1 , T-K Clarke  1 , A M Fernandez-Pujals  1 , J Gibson  1 , E Wigmore  1 , J Hafferty  1 , S P Hagenaars  1 , G Davies  2   3 , A Campbell  4 , C Hayward  5 , S M Lawrie  1 , D J Porteous  4 , I J Deary  2   3 , A M McIntosh  1   2
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Dissection of major depressive disorder using polygenic risk scores for schizophrenia in two independent cohorts

H C Whalley et al. Transl Psychiatry. .

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.

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Conflict of interest statement

AMM has previously received grant support from Pfizer, Lilly and Janssen. These studies are not connected to the current investigation. SML has previously received research grant support from Pfizer, Roche, Abbvie and Sunovion, as well as personal fees from Roche, Sunovion and Janssen, outside the present work. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a and b) Scatterplot of SCZ PRS and neuroticism according to MDD status in GS:SFHS, and UK Biobank (UKB), respectively. The size of circles represents the degree of overlapping data points. For clarity, histograms of the distribution of neuroticism scores in cases and controls for both cohorts are presented in the Supplementary Figures 1a and b. GS:SFHS, Generation Scotland: Scottish Family Health Study; MDD, major depressive disorder; PRS, polygenic risk score (PGRS in the figure); SCZ, schizophrenia.
Figure 2
Figure 2
Bar chart of percentage variance explained for distress and neuroticism in GS:SFHS and UK Biobank (UKB). GS:SFHS, Generation Scotland: Scottish Family Health Study; MDD, major depressive disorder; PGRS, polygenic risk score; SCZ, schizophrenia.
See this image and copyright information in PMC

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References

    1. Kessler RC, Berglund P, Demler O, Jin R, Koretz D, Merikangas KR et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003; 289: 3095–3105. - PubMed
    1. Kennedy SH. Core symptoms of major depressive disorder: relevance to diagnosis and treatment. Dialogues Clin Neurosci 2008; 10: 271–277. - PMC - PubMed
    1. Austin MP, Mitchell P, Goodwin GM. Cognitive deficits in depression: possible implications for functional neuropathology. Br J Psychiatry 2001; 178: 200–206. - PubMed
    1. Navrady LB, Ritchie SJ, Chan SWY, Kerr DM, Adams MJ, Hawkins E et al. Intelligence and neuroticism in relation to depression and psychological distress: evidence of interaction using data from Generation Scotland: Scottish Family Health Study and UK Biobank. bioRxiv 2016; http://biorxiv.org/content/early/2016/02/12/039545. - PubMed
    1. Glahn DC, Curran JE, Winkler AM, Carless MA, Kent JWJr, Charlesworth JC et al. High dimensional endophenotype ranking in the search for major depression risk genes. Biol Psychiatry 2012; 71: 6–14. - PMC - PubMed

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