Complement Gene Expression Correlates with Superior Frontal Cortical Thickness in Humans

Abstract

Recent work suggests that genes encoding complement proteins that are active in the innate immune system may confer risk for schizophrenia by disrupting typical synaptic pruning in late adolescence. Alterations in the complement pathway may contribute to aberrant cortical thinning in schizophrenia prodromes and reduced prefrontal cortical thickness in chronic schizophrenia patients; however, this theory needs to be translated to humans. We conducted a series of analyses in a sample of adult Swedish twins enriched for schizophrenia (N=129) to assess the plausibility of a relationship between complement gene expression and cortical thickness that could go awry in the etiology of schizophrenia. First, we identified that peripheral mRNA expression levels of two complement genes (C5, SERPING1) made unique contributions to the variance in superior frontal cortical thickness among all participants. Vertex-wise maps of the association between gene expression levels and thickness across the cortex suggested that this relationship was especially strong with SERPING1 in the superior frontal region, consistent with the pattern of disruption in cortical thickness observed in schizophrenia. Additional analyses identified that these genes are expressed in the human superior frontal cortex, that heritable genetic factors influence SERPING1 gene expression levels, and that these associations are observed regardless of case status. These findings provide initial evidence linking the complement system with cortical thinning in humans, a process potentially involved in the pathogenesis of schizophrenia.

Figure 1

Number of resampled subsets (85% of sample) in which each gene was associated with superior frontal thickness below the prescreening threshold (p<0.05), out of 1000 subsets. Dashed line represents number of expected associations due to chance with this threshold.

Figure 2

Statistical brain atlases plotting the association between SERPING1 gene expression levels and cortical thickness across the cortex. Cooler colors represent a negative association between gene expression levels and cortical thickness. Sim., simulation.

Figure 3

Statistical brain atlases plotting the association between C5 gene expression levels and cortical thickness across the cortex. Cooler colors represent a negative association between gene expression levels and cortical thickness. Sim., simulation.