Genetically predicted complement component 4A expression: effects on memory function and middle temporal lobe activation

Abstract

These data suggest that the effects of C4 on cognition were observable at both a cortical and behavioural level, and may represent one mechanism by which illness risk is mediated. As such, deficits in learning and memory may represent a therapeutic target for new molecular developments aimed at altering C4's developmental role.

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

“…To determine whether the association between complement PGS and IQ remained significant once variations in the reported C4A structural haplotype were accounted for, we re‐ran the analysis by including predicted C4A RNA expression scores as a covariate (score previously used by group, seen to impact on cognition). After the effects of C4A had been accounted for in this way, complement PGS continued to significantly predict variation in premorbid IQ ( F change = 6.057; Std beta = 0.088, df = 3771; P = .014) and verbal IQ ( F change = 4.016, Std beta = 0.067, df = 3902; P = .045).…”

“…Collectively, these findings suggest that, whereas individual genetic components of the complement pathway (including C4A as analysed in Reference and closely related gene CSMD1) maybe associated with SZ risk, the complement pathway as a whole is associated with neurodevelopmental processes related to cognition. This is evident in the effects of PGS on IQ in the healthy control population for full scale IQ, and in the whole group irrespective of diagnosis.…”

“…In total, 808 cases and 192 healthy participants completed a full neuropsychological assessment battery and had full genome‐wide data available. Cases consisted of n = 585 clinically stable patients with a diagnosis of SZ and schizoaffective disorder (SZA), and an additional n = 223 patients diagnosed with bipolar disorder with psychotic features, major depressive disorder with psychotic features, delusional disorder, or psychosis not otherwise specified, as described elsewhere . Participants were recruited from five sites across Ireland, and ethics approval was obtained from local ethics committees.…”

“…As in our previous study of C4, an unrotated principle components analysis based on the four available episodic memory tests was carried out to reduce multiple testing burden. This memory factor explained 72% of variance in memory scores, as described previously . Spatial working memory was assessed in the samples using the WMS‐III letter‐number sequencing task and the spatial working memory task from the Cambridge Automated Neuropsychological Test Battery (CANTAB SWM) …”

“…This study found that structural variation at C4 was associated with (a) variation in RNA expression levels in postmortem brain samples, (b) increased risk for SZ, and (c) that increased RNA expression predicted by C4 structural variation influenced development of the neural system via a pattern of altered synaptic pruning. Following up these findings, we recently showed that higher predicted C4 RNA expression was associated with poorer performance on measures of memory function in both patients with SZ and healthy participants, and with reduced cortical activation during visual task performance in healthy participants . This, along with evidence that other risk‐related genes and proteins within the complement system are also associated with variation in both cognition and brain structure in both patients and healthy individuals, led us to consider whether variation within genes that encode the complement system could, as a whole, influence cognition.…”