Abstract
Background: Mounting evidence from diffusion tensor imaging (DTI) and epigenetic studies, respectively, confirmed the abnormal alterations of brain white matter integrity and DNA methylation (DNAm) in schizophrenia. However, few studies have been carried out in the same sample to simultaneously explore the WM pathology relating to clinical behaviors, as well as the DNA methylation basis underlying the WM deficits.Methods: We performed DTI scans in 42 treatment-naïve first-episode schizophrenia patients and 38 healthy controls. Voxel-based method of fractional anisotropy (FA) derived from DTI was used to assess WM integrity. Participants' peripheral blood genomic DNAm status, quantified by using Infinium® Human Methylation 450K BeadChip, was examined in parallel with DTI scanning. Participants completed Digit Span test and Trail Making test, as well as Positive and Negative Syndrome Scale measurement. We acquired genes that are differentially expressed in the brain regions with abnormal FA values according to the Allen anatomically comprehensive atlas, obtained DNAm levels of the corresponding genes, and then performed Z-test to compare the differential epigenetic-imaging associations (DEIAs) between the two groups.Results: Significant decreases of FA values in the patient group were in the right middle temporal lobe WM, right cuneus WM, right anterior cingulate WM, and right inferior parietal lobe WM, while the significant increases were in the bilateral middle cingulate WM (Ps < 0.01, GRF correction). Abnormal FA values were correlated with patients' clinical symptoms and cognitive impairments. In the DEIAs, patients showed abnormal couple patterns between altered FA and DNAm components, for which the enriched biological processes and pathways could be largely grouped into three biological procedures: the neurocognition, immune, and nervous system.Conclusion: Schizophrenia may not cause widespread neuropathological changes, but subtle alterations affecting local cingulum WM, which may play a critical role in positive symptoms and cognitive impairments. This imaging-epigenetics study revealed for the first time that DNAm of genes enriched in neuronal, immunologic, and cognitive processes may serve as the basis in the effect of WM deficits on clinical behaviors in schizophrenia.
Highlights
Schizophrenia is a severe mental disorder defined by a disruption in emotion and cognition along with positive and negative symptoms [1]
Significant decreases in the Fractional anisotropy (FA) values were detected to be located in the right middle temporal lobe (R_MTL) White matter (WM) (P < 0.01 with GRF correction, Cohen’s d = 1.238), R_cuneus WM (P < 0.01 with GRF correction, Cohen’s d = 0.956), right anterior cingulate (R_AC) WM (P < 0.01 with GRF correction, Cohen’s d = 0.988), and right inferior parietal lobe (R_IPL) WM (P < 0.01 with GRF correction, Cohen’s d = 0.871) in first-episode schizophrenia patients, while a significant increase in the left middle cingulate (L_MCG) WM (P < 0.01 with GRF correction, Cohen’s d = 0.780) and right middle cingulate (R_MCG) WM (P < 0.01 with GRF correction, Cohen’s d = 0.978)
By computing the differential epigenetic-imaging associations (DEIAs) between the two groups, we found that the associations between the R_AC_FA and the 2nd DNA methylation (DNAm) component (Z = −3.61, P = 0.0049 corrected by FDR, [95% confidence interval (95% CI) −2.759 ∼ −0.4.224], Figure 4A), R_AC_FA and the 6th DNAm component (Z = −3.73, P = 0.00451 corrected by FDR, [95% CI −2.441 ∼ −0.4.429], Figure 4B), R_AC_FA and the 13th DNAm component (Z = −4.32, P = 0.000741 corrected by FDR, [95% CI −3.137 ∼ −0.4.717], Figure 4C), as well as R_Cuneus_FA and the 3rd DNAm component (Z = 3.17, P = 0.0186 corrected by FDR, [95% CI 2.270 ∼ 3.738], Figure 4D), showed significant differences between patient and healthy control groups
Summary
Schizophrenia is a severe mental disorder defined by a disruption in emotion and cognition along with positive and negative symptoms [1]. Mounting evidence, such as neuropathological connectivity alterations from magnetic resonance imaging (MRI) studies, supports the neurodevelopmental model of schizophrenia, in which prenatal viral infection is proposed to result in activation of DNA methylation process, maternal immune response, as well as altered expression of genes involved in multiple signaling systems, and subsequent genesis of schizophrenia [2, 3]. Mounting evidence from diffusion tensor imaging (DTI) and epigenetic studies, respectively, confirmed the abnormal alterations of brain white matter integrity and DNA methylation (DNAm) in schizophrenia. Few studies have been carried out in the same sample to simultaneously explore the WM pathology relating to clinical behaviors, as well as the DNA methylation basis underlying the WM deficits
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