Integrated Lipidomics and Proteomics Point to Early Blood-Based Changes in Childhood Preceding Later Development of Psychotic Experiences: Evidence From the Avon Longitudinal Study of Parents and Children

Abstract

BACKGROUND: The identification of early biomarkers of psychotic experiences (PEs) is of interest because early diagnosis and treatment of those at risk of future disorder is associated with improved outcomes. The current study investigated early lipidomic and coagulation pathway protein signatures of later PEs in subjects from the Avon Longitudinal Study of Parents and Children cohort. METHODS: Plasma of 115 children (12 years of age) who were first identified as experiencing PEs at 18 years of age (48 cases and 67 controls) were assessed through integrated and targeted lipidomics and semitargeted proteomics approaches. We assessed the lipids, lysophosphatidylcholines (n = 11) and phosphatidylcholines (n = 61), and the protein members of the coagulation pathway (n = 22) and integrated these data with complement pathway protein data already available on these subjects. RESULTS: Twelve phosphatidylcholines, four lysophosphatidylcholines, and the coagulation protein plasminogen were altered between the control and PEs groups after correction for multiple comparisons. Lipidomic and proteomic datasets were integrated into a multivariate network displaying a strong relationship between most lipids that were significantly associated with PEs and plasminogen. Finally, an unsupervised clustering approach identified four different clusters, with one of the clusters presenting the highest case-control ratio (p , .01) and associated with a higher concentration of smaller low-density lipoprotein cholesterol particles. CONCLUSIONS: Our findings indicate that the lipidome and proteome of subjects who report PEs at 18 years of age are already altered at 12 years of age, indicating that metabolic dysregulation may contribute to an early vulnerability to PEs and suggesting crosstalk between these lysophosphatidylcholines, phosphatidylcholines, and coagulation and complement proteins.

Dysregulation of complement and coagulation pathways: emerging mechanisms in the development of psychosis

“…Comparison of age 18 PD vs non-PD Psychotic disorder 12 LC–MS/MS C1R (↑), C1S (↓), CFD (↑), C6 (↑), C7 (↑), C4BP (↓), CFH (↑), CFI (↑), CLU (↑), VTN (↑), IGHM (↓) FXII (↑), FXI (↑), FIX (↑), FII (↑), FV (↑), FXIII (↑), PLG (↑), SERPINF2 (↑), A2M (↓) Föcking et al [ 60 ]* 64 PE, 67 no PE Age 12, blood. Comparison of age 18 PE vs non-PE Psychotic experiences 12 LC–MS/MS C1RL (↑), C5 (↑), C8 (↑), C4BP (↓), CFH (↑), VTN (↑), IGHM (↓), IGG (↓) PLG (↑), A2M (↓) Madrid-Gambin et al [ 61 ] 48 PE, 67 no PE Comparison of blood at age 12 against PE at age 18 Psychotic experiences 12 Targeted proteomics (DIA) VTN (↑) F11 (↑), HC2 (↑), PLG (↑), SERPINF2 (↑) Perkins et al [ 40 ] 32 CHR psychosis, 35 HC, 40 CHR no psychosis Transition vs nontransition Clinical high risk for psychosis 12–35 Multianalyte profiling, immunoassay VTN (↑) FVII (↑), vWF (↑), A2M (↑) Mongan et al [ 10 ]* 49 transition to psychosis and 84 no transition, 61 PE, 61 HC Blood, Transition vs nontransition Schizophrenia (SZ) 18–27 and 12 LC–MS/MS C1QA (↑), C1QB (↑), C1R (↑), C1S (↑), C1RL (↑), C2 (↑), C3 (↑), C4A (↑), C4B (↑), C5 (↓), C6 (↑), C7 (↑), C8A (↑), C8B (↓), C9 (↓), CFB (↑), CFHR1 (↑), CFHR2 (↑), CFHR5 (↑), CLUS (↑), CFI (↑), CFH (↑), C4BPA (↓), FCN3 (↓), VTN (↓), IGHM (↓) A2M (↓), F2 (↑), F9 (↑), F10 (↑), F11 (↑), F12 (↑), F13A (↓), F13B (↑), PLG (↑), SERPING1 (↓), SERPINA1 (↓), SERPINA5 (↓), SERPINA10 (↓), PROZ (↓), HC2 (↓), PROC (↓), PROS (↓), SERPINC1 (↑), SERPIND1 (↑) Case–control studies—psychosis Chan et al [ 58 ] 127 first onset SZ, 204 HC Control vs FEP SZ 18–49 Multianalyte profiling, immunoassay FVII (↑), vWF (↑), A2M (↑) Herberth et al [ 143 ] 17 SZ, 17 HC Control vs FEP SZ 22–39 Multianalyte profiling, immunoassay A2M (↓) Li et al [ ...…”

“…This consistency may be attributed to the fact that three out of five studies were conducted in the ALSPAC cohort, a longitudinal study of the general population. In this study, mostly well children were observed, some of whom went on to have psychotic experiences [ 59 – 61 ], and distinct criteria for conversion to psychotic experiences or psychotic disorder were compared. Interestingly, protease inhibitor A2M was consistently downregulated across all conversion and transition studies.…”

Metabolomics in Pediatric Neuropsychiatry

“…Metabolomics is able to anticipate the occurrence of psychosis. Indeed, individuals that experience a psychotic episode at 18 years of age, show metabolic abnormalities already at 12 years of age (Madrid-Gambin et al, 2019).…”

Special Issue: Psychosis from early intervention to treatment resistance

“…In addition to many examples of clinicians researching psychotic illness and health service provision for such disorders in Ireland, several university-affiliated academic research programmes concentrate on aspects of schizophrenia and related psychoses through local clinical research and with international consortia. These employ a host of diverse investigative techniques, including epidemiology, molecular genetics, proteomics, lipidomics, neuroimaging, cognition and psychological interventions (Emsell et al 2013;Kelleher et al 2013;McCarthy et al 2014;O'Donoghue et al 2015;Donohoe et al 2018;English et al 2018;Kincaid et al 2018;Madrid-Gambin et al 2019;Mothersill et al 2018;Föcking et al in press). Given this broad thematic convergence on clinical research into psychosis, academic clinicians and research colleagues throughout the island have recently established the Irish Psychosis Research Network (http:// www.psychosisireland.ie), which seeks to foster collaborative links between disciplines, institutions and the public in order to advance clinical research and service development for psychotic disorders.…”