Abstract
Major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BD) have both shared and discrete genetic risk factors, and are associated with peripheral abnormalities. The relationships between such genetic architectures and blood-based markers are, however, unclear.We investigated relationships between polygenic risk scores (PRS) for these disorders and peripheral markers in the UK Biobank cohort. We calculated polygenic risk scores for n = 367,329 (MDD PRS), n = 366,465 (SCZ PRS), and n = 366,383 (BD PRS) UK Biobank cohort subjects. We then examined associations between disorder PRS and 58 inflammatory/immune, hematological, bone, cardiovascular, hormone, liver, renal and diabetes-associated blood markers using two generalized linear regression models: ‘minimally adjusted’ controlling for variables such as age and sex, and ‘fully adjusted’ including additional lifestyle covariates: BMI, alcohol and smoking status, and medication intake.There were 38/58 MDD PRS, 32/58 SCZ PRS, and 20/58 BD PRS-blood marker associations detected for our minimally adjusted model. Of these, 13/38 (MDD PRS), 14/32 (SCZ PRS), and 10/20 (BD PRS) associations remained significant after controlling for lifestyle factors. Many were disorder-specific, with 8/13 unique MDD PRS associations identified. Several disorder-specific associations for MDD and SCZ were immune-related, with mostly positive and negative associations identified for MDD and SCZ PRS respectively.This study suggests that MDD, SCZ and BD have both shared and distinct peripheral markers associated with disorder-specific genetic risk. The results also implicate inflammatory dysfunction in MDD and SCZ, albeit with differences in patterns between the two conditions, and enrich our understanding of potential underlying pathophysiological mechanisms in major psychiatric disorders.
Highlights
Major depressive disorder (MDD), schizophrenia (SCZ) and bipolar disorder (BD) are potentially debilitating psychiatric disorders with significant morbidity and economic impact worldwide (Vigo et al, 2016)
This study suggests that MDD, SCZ and BD have both shared and distinct peripheral markers associated with disorder-specific genetic risk
The same measures were not implemented for MDD polygenic risk scores (PRS) analysis, as we were able to directly identify UK Biobank (UKB) subjects who had participated in MDD Psy chiatric Genomics Consortium (PGC) studies in order for them to be removed in the current analysis (See Genotyping and PRS Generation in Methods)
Summary
Major depressive disorder (MDD), schizophrenia (SCZ) and bipolar disorder (BD) are potentially debilitating psychiatric disorders with significant morbidity and economic impact worldwide (Vigo et al, 2016). Similarities and dif ferences in the nature of these, such as elevated inflammatory markers, have been observed in patients across the three disorders (Goldsmith et al, 2016; Horsdal et al, 2017; Lu et al, 2019; Yuan et al, 2019) These peripheral perturbations, including in immune system measures, have differentiated cases from healthy controls (Gold smith et al, 2016; Modabbernia et al, 2013; Osimo et al, 2020), their potential role in disorder pathophysiology has not yet been ascertained, and currently there are no markers available that can predict the risk of these disorders (Peedicayil, 2019). Conflicting data concerning associ ations in case-control studies, such as those investigating the relation ship between inflammatory marker C-reactive protein (CRP) and schizophrenia (Fond et al, 2018), may be attributable to limitations such as selection bias, small sample sizes, and illness-related con founding factors such as medication
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