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Methylation Differences in Schizophrenia Uncovered in Epigenome-Wide Association Study

NEW YORK (GenomeWeb) – A Johns Hopkins University School of Medicine-led team has uncovered nearly 175 genomic loci that are differentially methylated in people with schizophrenia.

As they reported today in JAMA Psychiatry, Hopkins' Andrew Feinberg and his colleagues performed an epigenome-wide association study that drew upon some 690 cases and 645 controls to uncover 923 CpG sites whose methylation levels varied in people with schizophrenia. Of these, 172 were replicated in a separate set of cases and controls, and these loci included ones near genes associated with neuronal function. As the researchers noted, a number of these spots are in a region that had previously been linked with schizophrenia through a genome-wide association study.

"The overlap with previous genome-wide association study data can provide potential insights into the functional relevance of genetic signals for [schizophrenia]," Feinberg and his colleagues wrote in their paper.

To search for differentially methylated CpG sites, he and his colleagues pulled together 1,334 blood-derived DNA samples from three ongoing studies of genetics and schizophrenia. After filtering, they gauged the DNA methylation of each sample at some 450,000 sites using Illumina's Infinium450 platform. From this, they uncovered 923 CpG sites that were differentially methylated in cases as compared to controls.

The researchers then confirmed 172 of these sites in a separate set of 247 schizophrenia cases and 250 controls.

They also examined the proportions of various cell types found within the samples from cases and controls, as different tissues have varying DNA methylation patterns, which could influence the analysis. They noted that the cases exhibited a decreased proportion of CD8+ T cells and an increased proportion of monocytes and granulocytes, a finding they took into account when searching for differentially methylated sites. They also filtered their results based on smoking, age, and race or ethnicity, as well as for batch effects.

A number of the differentially methylated loci Feinberg and his colleagues uncovered are situated near genes like RPS6KA1, MAD1L1, and PIK3R1 that have previously been linked to schizophrenia, while other loci are near genes like S100A2, FOXO1, and IRS1 that have known roles in neuronal development. Some of these neuronal genes, such as SORL1, CARD10, and IRS1, have also been associated with Alzheimer's disease, the researchers noted. Other genes were involved in T-cell development.

A handful of genes had multiple differentially methylated loci nearby, including DDR1 and IFITM1, both of which have been associated with schizophrenia, as well as RPTOR, which is part of the rapamycin signaling pathway, and NCOR, a key neurogenesis gene, the researchers reported.

Both pathway and gene ontology analyses found that the genes near these differentially methylated loci were often involved in amino acid metabolism, neurological disease, and embryonic development, among other biological processes.

These schizophrenia-related differentially methylated loci overlapped with three genomic regions that the Psychiatric Genomics Consortium analysis reported in 2014. In one region, two schizophrenia-linked SNPs are associated with a schizophrenia-linked differentially methylated locus that falls in an intergenic region between the FURIN and FES genes.

Feinberg and his colleagues examined whether DNA methylation mediates this genetic risk. They found that the risk allele was associated with lower methylation in schizophrenia cases, but that the genotype influences methylation and schizophrenia risk independently.

"Using a robust analysis pipeline, with cell proportion correction and sequential replication in independent datasets, we provided candidate loci that contribute to the knowledge of [schizophrenia] and possibly other psychoses," the researchers wrote. "These findings lay a firm groundwork for the implementation of genome-wide methylation approaches to the understanding of neuropsychiatric disorders."