Rare damaging variants in DNA repair and cell cycle pathways are associated with hippocampal and cognitive dysfunction: a combined genetic imaging study in first-episode treatment-naive patients with schizophrenia

Abstract

Schizophrenia is a complex neurodevelopmental disorder where changes in both hippocampus and memory-related cognitive functions are central. However, the exact relationship between neurodevelopmental-genetic factors and hippocampal-cognitive dysfunction remains unclear. The general aim of our study is to link the occurrence of rare damaging mutations involved in susceptibility gene pathways to the structure and function of hippocampus in order to define genetically and phenotypically based subgroups in schizophrenia. In the present study, by analyzing the exome sequencing and magnetic resonance imaging data in 94 first-episode treatment-naive schizophrenia patients and 134 normal controls, we identified that a cluster of rare damaging variants (RDVs) enriched in DNA repair and cell cycle pathways was present only in a subgroup including 39 schizophrenic patients. Furthermore, we found that schizophrenic patients with this RDVs show increased resting-state functional connectivity (rsFC) between left hippocampus (especially for left dentate gyrus) and left inferior parietal cortex, as well as decreased rsFC between left hippocampus and cerebellum. Moreover, abnormal rsFC was related to the deficits of spatial working memory (SWM; that is known to recruit the hippocampus) in patients with the RDVs. Taken together, our data demonstrate for the first time, to our knowledge, that damaging rare variants of genes in DNA repair and cell cycle pathways are associated with aberrant hippocampal rsFC, which was further relative to cognitive deficits in first-episode treatment-naive schizophrenia. Therefore, our data provide some evidence for the occurrence of phenotypic alterations in hippocampal and SWM function in a genetically defined subgroup of schizophrenia.

Figure 1

The developmental expression profile of 22 genes in the cell cycle pathway and 20 genes in the DNA repair pathway in hippocampus. Following colors for different Gene Ontology (GO) categories were used: red for DNA repair and blue for cell cycle, and a smooth curve with confidence interval (gray range). The expression profiles show high expression during the stage of brain development before birth, with a sharp decrease in expression after birth.

Figure 2

Aberrant resting-state functional connectivity (rsFC) of the left hippocampus among three groups. (a) Left inferior parietal cortex and right cerebellum posterior lobe showed significantly different rsFC with left hippocampus among three groups. The statistical significance threshold was set at P<0.05 and corrected for multiple comparisons based on Monte Carlo simulations, for main effect for diagnosis of functional connectivity (FC) of left hippocampus. (b) ANCOVA with sex, age, education and the hippocampal volume as covariances. rsFC between left hippocampus and left inferior parietal cortex is increased, whereas rsFC between left hippocampus and cerebellum is decreased only in schizophrenic patients with rare damage variants (RDVs). The statistical significance threshold was set at P<0.05, post hoc test by least significant difference. ANCOVA, analysis of covariance; HIP, hippocampus; IPL, inferior parietal cortex; L, left; PCL, cerebellum posterior lobe; R, right. Notes: s.e. for all figures.

Figure 3

Aberrant resting-state functional connectivity (rsFC) of hippocampal subregions. (a) The brain map of aberrant rsFC with hippocampal subregions among three groups. The statistical significance threshold was set at P<0.05, corrected for multiple comparisons based on Monte Carlo simulations, for main effect for diagnosis of functional connectivity (FC) of the different hippocampal subregions. (b) rsFC between left DG and left IPL increased only in schizophrenic patients with rare damage variants, whereas decreased rsFC of left SC with MFG was only found in schizophrenic patients without rare damage variants. The statistical significance threshold was set at P<0.05, post hoc test by least significant difference. CA, cornuammonis; Cal, calcarine; DG, dentate gyrus; Fus, fusiform; IPL, inferior parietal cortex; L, left; MFG, medial frontal cortex; PCC, posterior cingulate cortex; R, right; RDV, rare damaging variant; SC, subicular complex. Notes: s.e. for all figures.

Figure 4

Relationships between resting-state functional connectivity (rsFC) of hippocampus and spatial working memory. Increased rsFC between left dentate gyrus and left inferior parietal cortex was positively related to number of errors of spatial working memory in schizophrenic patients with rare damaging variants and negatively related to number of errors of spatial working memory in healthy controls, uncorrected P<0.05. The difference in the degree of correlation was statistically significant between schizophrenic patients with RDVs and healthy controls (Z=3.331, P=8.65 × 10⁻⁴) after the Bonferroni correction, and a trend toward significance between patients with RDVs and patients without RDVs (Z=2.171, P=0.030 before Bonferroni correction), but not significant between patients without RDVs and healthy controls (Z=0.884, P=0.377). DG, dentate gyrus; IPL, inferior parietal cortex; NoE, number of error; L, left; RDV, rare damaging variant. Note: partial correlation analysis was used to analyze the relationship between rsFC of hippocampus and spatial working memory with age, sex and educations and structural hippocampal volume as covariates.