Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress

Föcking, Melanie; Sabherwal, Sophie; Cates, Hannah M.; Scaife, Caitríona; Hryniewiecka, Magdalena; Wynne, Kieran; Rutten, Bart P. F.; Cannon, Mary; Nestler, Eric J.; Heurich, Meike; Cagney, Gerard; Zammit, Stanley; Cotter, David

doi:10.1038/s41380-018-0306-z

Cited by 44 publications

(42 citation statements)

References 82 publications

(128 reference statements)

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“…Some patients in the non-psychiatric group had high plasma levels of C3bc, and we cannot exclude that these children may develop psychiatric disorders later in life. In a longitudinal population-based study, Föcking et al demonstrated that complement pathway changes at age 12 are associated with psychotic experiences at age 18 [43]. Therefore, there is a need for a follow-up longitudinal study to investigate the role of complement activation in psychiatric disorders in childhood and adulthood.…”

Section: Discussionmentioning

confidence: 99%

Complement Activation in 22q11.2 Deletion Syndrome

et al. 2020

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The 22q11.2 deletion syndrome (22q11.2 del), also known as DiGeorge syndrome, is a genetic disorder with an estimated incidence of 1:3000 to 1:6000 births. These patients may suffer from affection of many organ systems with cardiac malformations, immunodeficiency, hypoparathyroidism, autoimmunity, palate anomalies, and psychiatric disorders being the most frequent. The importance of the complement system in 22q11.2 del has not been investigated. The objective of this study was to evaluate the complement system in relation to clinical and immunological parameters in patients. A national cohort of patients (n = 69) with a proven heterozygous deletion of chromosome 22q11.2 and a group of age and sex matched controls (n = 56) were studied. Functional capacity of the classical, lectin, and alternative pathways of the complement system as well as complement activation products C3bc and terminal complement complex (TCC) were accessed and correlated to clinical features. All patients in our study had normal complement activation in both classical and alternative pathways. The frequency of mannose-binding lectin deficiency was comparable to the normal population. The patients had significantly raised plasma levels of C3bc and a slight, but not significant, increase in TCC compared with controls. This increase was associated with the presence of psychiatric disorders in patients. The present study shows no complement deficiencies in 22q11.2 deletion syndrome. On the contrary, there are signs of increased complement activation in these patients. Complement activation is particularly associated with the presence of psychiatric disorders.Journal of Clinical Immunology (2020) 40:515-523Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Section: Discussionmentioning

confidence: 99%

Complement Activation in 22q11.2 Deletion Syndrome

et al. 2020

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“…In addition to these examples, complement gene expression more broadly has been linked to superior frontal cortex thickness in healthy humans, which has been linked to general intelligence in previous studies . Furthermore, in a proteomic analysis of the complement signaling pathway using longitudinal population‐based data, individuals who went on to experience psychotic like experience were found to have upregulation of multiple complement proteins …”

Section: Introductionmentioning

confidence: 91%

“…Examples of other complement function related genes that have been associated with both SZ risk and cognition include Cub and Sushi Multiple Domains-1 (CSMD1), complement factor H (CFH), and complement C3b/C4b receptor 1 (CR1). 3,[13][14][15] In patients with SZ and health participants, we previously reported that a GWAS-identified SZ risk variant within CSMD1, which encodes for a regulator of complement, was associated with poorer general cognitive ability and episodic memory function. 8 Other variants within CSMD1 gene have also been associated with poorer cognitive performance in large samples of healthy participants.…”

Section: Introductionmentioning

confidence: 99%

“…16 Furthermore, in a proteomic analysis of the complement signaling pathway using longitudinal populationbased data, individuals who went on to experience psychotic like experience were found to have upregulation of multiple complement proteins. 14,17 Given these lines of evidence, this study aimed to systematically characterize, for the first time, the association between genetic variation within genes related to complement function and both SZ risk and cognition. To do this, we performed gene-set analysis (GSA) of complement pathway genes, based on prior work in curating complement gene-sets based on publically available data by References 18 and 19.…”

Section: Introductionmentioning

confidence: 99%

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Beyond C4: Analysis of the complement gene pathway shows enrichment for IQ in patients with psychotic disorders and healthy controls

Holland

Cosgrove

Whitton

et al. 2019

Genes Brain and Behavior

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Variation in cognitive performance, which strongly predicts functional outcome in schizophrenia (SZ), has been associated with multiple immune‐relevant genetic loci. These loci include complement component 4 (C4A), structural variation at which was recently associated with SZ risk and synaptic pruning during neurodevelopment and cognitive function. Here, we test whether this genetic association with cognition and SZ risk is specific to C4A, or extends more broadly to genes related to the complement system. Using a gene‐set with an identified role in “complement” function (excluding C4A), we used MAGMA to test if this gene‐set was enriched for genes associated with human intelligence and SZ risk, using genome‐wide association summary statistics (IQ; N = 269 867, SZ; N = 105 318). We followed up this gene‐set analysis with a complement gene‐set polygenic score (PGS) regression analysis in an independent data set of patients with psychotic disorders and healthy participants with cognitive and genomic data (N = 1000). Enrichment analysis suggested that genes within the complement pathway were significantly enriched for genes associated with IQ, but not SZ. In a gene‐based analysis of 90 genes, SERPING1 was the most enriched gene for the phenotype of IQ. In a PGS regression analysis, we found that a complement pathway PGS associated with IQ genome‐wide association studies statistics also predicted variation in IQ in our independent sample. This association (observed across both patients and controls) remained significant after controlling for the relationship between C4A and cognition. These results suggest a robust association between the complement system and cognitive function, extending beyond structural variation at C4A.

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“…The method allows the study of the relationship of two multivariate datasets, for instance, the relationship between specific lipids and proteins within the same individuals (41) . Quantitative data, derived from DIA analysis, on the broad family of complement pathway proteins were also available on these same subjects (42) , and these data were available for integrative analysis. Regularization parameters were estimated by means of a leave-one-out cross-validation.…”

Section: Methodsmentioning

confidence: 99%

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

Madrid-Gambin

Föcking

Sabherwal

et al. 2019

Biological Psychiatry

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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.

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Complement pathway changes at age 12 are associated with psychotic experiences at age 18 in a longitudinal population-based study: evidence for a role of stress

Cited by 44 publications

References 82 publications

Complement Activation in 22q11.2 Deletion Syndrome

Complement Activation in 22q11.2 Deletion Syndrome

Beyond C4: Analysis of the complement gene pathway shows enrichment for IQ in patients with psychotic disorders and healthy controls

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

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