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

Abstract

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.

Effects of complement gene‐set polygenic risk score on brain volume and cortical measures in patients with psychotic disorders and healthy controls

“…This study sought to determine the effect of a “complement” PRS, which omitted the already associated C4 structural variant, on measures of memory, hippocampal volume, cortical thickness and total brain volume. Given the previous findings suggesting higher C4A expression levels impact on memory scores (Donohoe et al, 2018), and findings suggesting higher complement PRS related to IQ affects general cognitive function using the same sample (Holland et al, 2019) we hypothesized that higher complement PRS associated with SZ would be associated with lower scores on measures of memory, and that either higher C4 expression or higher “complement” PRS would be associated with lower hippocampal volume, cortical thickness, surface area, and total brain volume.…”

“…Both papers compiled a gene‐set related to “complement” in schizophrenia by collating information from neuroimmunology and general immunology literature, cross‐referenced with multiple gene expression and biology databases (e.g., GO, KEGG, IMPORT, IPA, and IMMUNOME, Molecular Signatures Database, the Human Biological Pathway Unification Database and the HUGO Gene Nomenclature Committee (https://pathcards.genecards.org, (http://software.broadinstitute.org/gsea/msigdb/index.jsp, https://www.genenames.org) to assemble a list of complement‐related genes (Dunkelberger & Song, 2010; Orsini, De Blasio, Zangari, Zanier, & De Simoni, 2014; Ricklin, Hajishengallis, Yang, & Lambris, 2010; Sarma & Ward, 2011; Veerhuis, Nielsen, & Tenner, 2011). After removing the duplicated genes and genes directly encoding for C4 (C4A, C4B, C4BPA, C4BPB, C4_B), and taking into account our previous paper on a complement gene‐set (Holland et al, 2019), 90 genes were brought forward for analysis, which have been shown to relate to cognition in our previous work (Holland et al, 2019).…”

“…Furthermore, a SZ risk variant within CSMD1, encoding a regulator of complement, was also associated with poorer episodic memory performance (Donohoe et al, 2013), and in large independent samples of patients and controls ( n = 1783), expression of complement factor H in the hippocampus was found to be associated with both increased SZ risk and poorer memory function (Zhang et al, 2017). At a gene‐set level, we have recently shown that a complement polygenic score calculated using summary data from a GWAS of IQ (Savage et al, 2018) was associated with variation in general cognitive function (Holland et al, 2019). Furthermore, in a proteomic analysis of the complement signaling pathway using longitudinal population‐based data, individuals who went on to experience psychotic‐like experience and psychotic disorders were found to have upregulation of multiple complement proteins in childhood (English et al, 2018; Föcking et al, 2019).…”

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

“…In the work by Holland and colleagues, they expand on previous research demonstrating a link between complement and pathogenesis of schizophrenia (1). A recent seminal paper in the fields showed SNPs contributing to altered C4 protein expression resulting in an increased risk of schizophrenia.…”

“…Our interest was piqued by the recent study presented in Genes, Brain and Behavior by Holland et al (1). They outline an important investigation highlighting the link between complement gene expression and IQ, in both schizophrenic patients and healthy controls.…”