Table 1.
(A) Topmost implicated plasma proteins of the coagulation and complement pathways implicated in longitudinal studies observing conversion to psychotic disorder, or psychotic experiences, and clinical high-risk (CHR) transition to psychotic disorder, as well as case-control comparison for schizophrenia and psychosis spectrum disorders. (B) Overview of topmost implicated plasma proteins of the coagulation and complement pathways identified in two or more studies.
| (A) | |||||||
|---|---|---|---|---|---|---|---|
| Reference | No. of samples | Sample | Disease | Age range | Method | Complement | Coagulation |
| Transition studies—psychosis | |||||||
| English et al. [59]* | 37 PD, 38 no PD and 40 PE, 66 no PE | Age 12, blood. 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. [56]* | 10 SZ, 10 HC and 47 SZ, 53 HC | Blood, case-control | SZ | 24–58.8 | LC–MS/MS | C4BPB (↓), C8B (↑), IGHM (↑) | F7 (↓), PROS (↓), SERPINA5 (↑) |
| Jaros et al. [26]* | 20 SZ, 20 HC | Blood, case-control | SZ | 22–41.4 | Immobilized metal ion affinity chromatography (IMAC) combined with LC–MS/MS | C4BPA (↑), C6 (↑), CFB (↑), FCN3 (↑) | |
| Levin et al. [25]* | 22 SZ, 33 HC | Blood, case-control | SZ | 18–44 | LC–MS/MS | IGHM(↓) | F13B (↓) |
| Cooper et al. [144] | 60 SZ, 77 HC, 892 blood spot samples | Blood, neonatal blood spots | SZ | 23.7–43.7 | Multiple reaction monitoring mass spectrometry | C4A (↑), C4BPA (↓), C9 (↑), CLUS (↑) | |
| Walss-Bass et al. [145] | 60 SZ, 20 HC | Blood | SZ | 41.1–43.7 | X-aptamer technology | C4A (↑) | |
| Ramsey et al. [146] | 133 SZ, 133 HC | Blood, female vs male | SZ | 16.5–49.6 | Multianalyte profiling, immunoassay | C3 (↑) | F7 (↓), SERPINA1 (↑) |
| Moriyana et al. [147]* | 6 SZ, 6 HC | Umbilical arterial serum | SZ | 22.8–38.3 | LC–MS/MS | C1QB (↑), C1QC (↑), C1R (↑), C1S (↑), C2 (↑), C3 (↑), C4A (↑), C4B (↑), C5 (↑), C7 (↓), C9 (↑), CFB (↑), CFI (↑), C6 (↑), CLU (↑), VTN (↑), IGHM (↑) | F2 (↑), F10 (↑), F12 (↑), F13B (↑), KLKB1 (↑), SERPINA5 (↑), SERPINC1 (↑), SERPIND1 (↑), HC2 (↑), SERPINF2 (↑), SERPING1 (↑), |
| Jiang et al. [148]* | 20 SZ, 10 HC plus 40 SZ, 40 HC | Leukocyte profiling | First-episode SZ | 17.3–33.3 | Proteomic signatures | C1QBP (↑), C1QC (↑), C1R (↑), C4B (↑), C4BPA (↑), C6 (↑), C8B (↓), CD59 (↑), CFB (↑), CFD (↑), CFI (↑), CFH (↑), CR1 (↑) | |
| Gupta et al. [149] | 2 SZ, 2 HC | Cerebrospinal fluid | SZ | 23–28 (SZ) and 53–60 (HC) | Proteomics, iTRAQ | A2M (↓) | |
| Velasquez et al. [150] | 12 SZ, 8 HC | Case-control, brain samples of mitochondria (MIT), crude nuclear fraction (NUC), and cytoplasm (CYT) | SZ | Not stated | Quantitative proteomics, using iTRAQ labeling and SRM | C3 (↑) | |
| Case–control studies—psychosis spectrum | |||||||
| Domenici et al. [55] | 245 MDD, 229 SZ, 254 HC | Blood, case-control | Major depressive Disorder (MDD) and SZ | 27.1–67.5 | Multianalyte profiling, immunoassay | C3 (↑) | A2M (↑), F7 (↑), SERPINA1 (↑) |
| Yang et al. [151] | 24 MDD, 12 HC and 98 MDD, 49 HC | Blood, case-control | Major depressive Disorder (MDD), suicide attempters and nonattempters | 16–46.5 | 2-DE-MALDI-TOF/TOF MS and iTRAQ-LC-MS/MS, western blots and ELISAQ | CFB(↑) | F7 (↑), F10 (↓), SERPINA1 (↑) |
| Turck et al. [152] | 39 MDD, 24 responders, 15 nonresponders | Antidepressant treatment | MDD | 27.4–64.6 | C7 (↓), CFHR1 (↑), CFHR2 (↑), CFHR5 (↑) | F5 (↑), F10 (↓), FGA (↑), FGB (↑), SERPING1 (↓) | |
| Stelzhammer et al. [153] | 40 MDD, 63 HC | Depression, case-control, drugnaive | MDD | 26.4–53.8 | LC–MS/MS | C4B (↑) | |
| Gui et al. [154] | 20 MDD, 20 HC | Blood | MDD | 18–60 | iTRAQ-based quantitative proteomics (and metabolomics) | CFH (↓) | |
| de Jesus et al. [155] | 14 BPD, 12 HC, 23 SZ, other PD:4 | Serum | Bipolar Disorder (BPD), SZ, other Psychotic Disorders | 23–55 | 2D-DiGE | C4A (↑) | |
| Haenisch et al. [156] | 17 BPD, 46 HC | Blood, case-control | BPD | 21–47 | Multianalyte profiling, immunoassay | C3 (↑) | |
| (B) | |||||||
|---|---|---|---|---|---|---|---|
| Pathway | Nested population-based studies (ALSPAC) | Clinical high risk (CHR) – transition (T) vs non-transition (NT) studies | FEP and schizophrenia case-control studies | Other psychosis spectrum case-control studies | |||
| Complement (↑) | CFH, VTN | CFH, VTN C1Q, C1R, CFI, C5, C7, C8 | C4-B, CFB, C6 C1Q, C1R, C3, CFI, C9, CLU | C3 | |||
| Complement (↓) | C4BP, IGM | C4BP, IGM | |||||
| Coagulation (↑) | FXI, PLG SERPINF2 | FXI, PLG FXII, FIX, FII | FXI, PLG FXII, FIX, FII, SERPINF2 | FVII, SERPINA1 | |||
| Coagulation (↓) | A2M | FXI, PLG FXII, FIX, FII | FX | ||||
In (A), topmost proteins are selected by significance (p < 0.05) of expression level fold changes. Studies that conducted comprehensive pathway analyses are labeled with asterisk (*). Upregulation (↑) and downregulation (↓) are indicated for each protein—shown with corresponding gene name.
In (B), overview of protein markers is depicted for longitudinal conversion to psychotic disorder and clinical high risk (CHR)—transition (T) vs nontransition (NT) studies, first-episode psychosis (FEP) and schizophrenia case–control studies, and other psychosis spectrum disorder case–control studies. Longitudinal studies of a general population observing conversion to psychotic experiences and psychotic disorder in the ALSPAC cohort are shown in a separate column. Fold change direction shown for upregulation (↑) and downregulation (↓) is indicated for each protein- shown with corresponding gene name. Only studies that showed consistent fold change direction were included. Proteins marked in bold were found to be altered in >2 studies.
A2M alpha-2-macroglobulin, ADAMTS13 a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 also known as von Willebrand factor-cleaving protease (VWFCP), C1Q complement component 1q, C1R complement component 1r, C1RL complement component 1r Like, C1S complement component 1s, C4BP complement 4 binding protein, C5 complement C5, C6 complement C6, C7 complement C7, C8 complement C8, C8A complement C8A, CFB complement factor B, CFD complement factor D, CFH complement factor H, CFI complement factor I, CLU clusterin, FIC3 ficolin 3, FII prothrombin, FIX factor IX, FVII factor VII, FXI factor XI, FXII factor XII, FXIII factor XIII, IGG immunglobulin G, IGHM immunoglobulin heavy constant Mu, IL10 interleukin 10, IL13 interleukin 13, IL15 interleukin 15, IL8 interleukin 8, PLG plasminogen, PROS vitamin K-dependent protein S, PROZ vitamin K-dependent protein Z, SERPINA7 serpin peptidase inhibitor, clade A member 7, SERPIND1 serpin family D member 1, SERPINF2 serpin family F member 2, SERPING1 plasma protease C1 inhibitor, VTN vitronectin, vWF van Willebrand factor.