In this ASHG workshop presentation, Stuart Scott of the Icahn School of Medicine at Mount Sinai, presented on using the PacBio system for amplicon sequencing in pharmacogenomics and clinical genomics…
DNA Methylation at the Schizophrenia and Intelligence GWAS-Implicated MIR137HG Locus May Be Associated with Disease and Cognitive Functions
The largest genome-wide association studies have identified schizophrenia and intelligence associated variants in the MIR137HG locus containing genes encoding microRNA-137 and microRNA-2682. In the present study, we investigated DNA methylation in the MIR137HG intragenic CpG island (CGI) in the peripheral blood of 44 patients with schizophrenia and 50 healthy controls. The CGI included the entire MIR137 gene and the region adjacent to the 5′-end of MIR2682. The aim of the study was to examine the relationship of the CGI methylation with schizophrenia and cognitive functioning. The methylation level of 91 CpG located in the selected region was established for each participant by means of single-molecule real-time bisulfite sequencing. All subjects completed the battery of neuropsychological tests. We found that the CGI was hypomethylated in both groups, except for one site—CpG (chr1: 98?511?049), with significant interindividual variability in methylation. A higher level of methylation of this CpG was seen in male patients and was associated with a decrease in the cognitive index in the combined sample of patients and controls. Our data suggest that further investigation of mechanisms that regulate the MIR137 and MIR2682 genes expression might help to understand the molecular basis of cognitive deficits in schizophrenia.
Methylation of the reelin gene promoter in peripheral blood and its relationship with the cognitive function of schizophrenia patients.
There is a decrease in the expression of the reelin gene (RELN) in the brain of schizophrenia patients, which can underlie observed cognitive abnormalities. It is suggested that this decrease is caused by the hypermethylation of the RELN promoter. The aim of the study was to investigate methylation of the RELN promoter in the peripheral blood of schizophrenia patients and its association with their cognitive deficits. A modified SMRT-BS (single-molecule real-time bisulfite sequencing) was used. We determined the methylation rate of 170 CpG sites within a 1465 bp DNA region containing the entire CpG island in the RELN promoter in 51 schizophrenia patients and 52 healthy controls. All subjects completed a battery of neuropsychological tests. There were no DNA methylation changes associated with schizophrenia. Most CpGs sites were unmethylated in both groups. At the same time, there was a variability in the methylation level of different regions within the promoter. The methylation level in the area from -258 to -151 bp relative to RELN transcription start site was a significant predictor of the index of patients’ cognitive functioning if sex, age, smoking, education, and polymorphism rsl858815 had been considered. The positive correlation between the methylation rate in this region and cognitive index suggests that the hypomethylation of the RELN promoter could contribute to the development of cognitive deficits in schizophrenia.
Relationship between Alzheimer’s disease-associated SNPs within the CLU gene, local DNA methylation and episodic verbal memory in healthy and schizophrenia subjects.
Genetic variation may impact on local DNA methylation patterns. Therefore, information about allele-specific DNA methylation (ASM) within disease-related loci has been proposed to be useful for the interpretation of GWAS results. To explore mechanisms that may underlie associations between Alzheimer’s disease (AD) and schizophrenia risk CLU gene and verbal memory, one of the most affected cognitive domains in both conditions, we studied DNA methylation in a region between AD-associated SNPs rs9331888 and rs9331896 in 72 healthy individuals and 73 schizophrenia patients. Using single-molecule real-time bisulfite sequencing we assessed the haplotype-dependent ASM in this region. We then investigated whether its methylation could influence episodic verbal memory measured with the Rey Auditory Verbal Learning Test in these two cohorts. The region showed a complex methylation pattern, which was similar in healthy and schizophrenia individuals and unrelated to haplotypes. The pattern predicted memory scores in controls. The results suggest that epigenetic modifications within the CLU locus may play a role in memory variation, independent of ASM. Copyright © 2018 Elsevier B.V. All rights reserved.