Whalley H C, Adams M J, Hall L S, Clarke T-K, Fernandez-Pujals A M, Gibson J, Wigmore E, Hafferty J, Hagenaars S P, Davies G, Campbell A, Hayward C, Lawrie S M, Porteous D J, Deary I J, McIntosh A M
Division of Psychiatry, Royal Edinburgh Hospital, University of Edinburgh, Edinburgh, UK.
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, UK.
Transl Psychiatry. 2016 Nov 1;6(11):e938. doi: 10.1038/tp.2016.207.
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 (β=-0.04, P=0.014 and β=-0.09, P⩽0.001 for GS:SFHS and UKB, respectively) and neuroticism (β=-0.04, P=0.002 and β=-0.06, P=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.
重度抑郁症（MDD）以其显著的临床异质性和可能的病因异质性而闻名。其特征包括情绪低落、精神运动迟缓以及人格特质神经质水平升高；这些因素也与精神分裂症（SCZ）相关。部分MDD病例可能具有较高的SCZ遗传负荷。MDD状态与SCZ多基因风险在认知、人格和情绪测量上的相互作用，将表明存在类似SCZ的MDD亚组。在此，我们假设，较高的SCZ多基因风险将导致MDD病例与对照在认知能力上的差异更大，而在痛苦和神经质方面的差异更小。我们在一个基于人群的大型队列（苏格兰一代：苏格兰家庭健康研究，GS:SFHS）中估计了SCZ的多基因风险评分（PRSs）及其与认知变量、神经质、情绪和心理痛苦的关联。将个体分为患有和未患有抑郁症的两组（分别为n = 2587和n = 16764），以测试MDD状态与精神分裂症风险之间的相互作用。并在英国生物银行（UKB；分别有n = 6049例病例和n = 27476例对照）中进行重复验证。在两个队列中，我们发现SCZ-PRS与MDD状态在心理痛苦测量上存在显著相互作用（GS:SFHS和UKB中β分别为 -0.04，P = 0.014和β = -0.09，P≤0.001）以及在神经质测量上存在显著相互作用（β分别为 -0.04，P = 0.002和β = -0.06，P = 0.023）。在两个队列中，在SCZ遗传风险较高的背景下，病例与对照之间的差异均有所减小。这些发现表明，在SCZ高遗传风险背景下的抑郁症，可能与痛苦和神经质的关联减弱。这可能代表了一种与SCZ更密切相关的、病因上不同的MDD形式。
