title: Dissection of major depressive disorder using polygenic risk scores for schizophrenia in two independent cohorts.
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.
authors: Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
authors: H C
authors: HC
authors: Whalley
authors: Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
authors: M J
authors: MJ
authors: Adams
authors: Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
authors: L S
authors: LS
authors: Hall
authors: Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
authors: T-K
authors: TK
authors: Clarke
authors: Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
authors: A M
authors: AM
authors: Fernandez-Pujals
authors: Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
authors: J
authors: J
authors: Gibson
authors: Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
authors: E
authors: E
authors: Wigmore
authors: Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
authors: J
authors: J
authors: Hafferty
authors: Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
authors: S P
authors: SP
authors: Hagenaars
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors: G
authors: G
authors: Davies
authors: Centre for Genetics and Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, UK.
authors: A
authors: A
authors: Campbell
authors: MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, UK.
authors: C
authors: C
authors: Hayward
authors: Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
authors: S M
authors: SM
authors: Lawrie
authors: Centre for Genetics and Molecular Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, University of Edinburgh, Edinburgh, UK.
authors: D J
authors: DJ
authors: Porteous
authors: Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.|Department of Psychology, University of Edinburgh, Edinburgh, UK.
authors: I J
authors: IJ
authors: Deary
authors: Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.|Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
authors: A M
authors: AM
authors: McIntosh
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D015331:Cohort Studies; D003865:Major Depressive Disorder / Q000235:genetics* / Q000523:psychology*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D020412:Multifactorial Inheritance / Q000235:genetics*; D009483:Neuropsychological Tests; D000075384:Neuroticism; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D018570:Risk Assessment; D012559:Schizophrenia / Q000235:genetics*; D012565:Schizophrenic Psychology; D012606:Scotland; D013223:Statistics as Topic; D013694:Temperament