Blood methylome offers clues to schizophrenia

By Eleanor McDermid, Senior medwireNews Reporter

Researchers show that a methylome-wide association study (MWAS) of the blood can provide a glimpse of past environmental insults that may contribute to the development of schizophrenia.

For example, many of the significant findings linked to genes involving hypoxia. “Although we can only speculate about the cause, we note that a substantial amount of literature exists showing that hypoxia during fetal development increases the risk of schizophrenia,” say study author Edwin van den Oord (Virginia Commonwealth University, Richmond, USA) and colleagues.

A total of 139 methylated sites were significantly different in whole blood DNA from 759 patients with schizophrenia and 738 controls. The researchers conducted a cost-effective version of a full MWAS, which involved extracting and sequencing only methylated DNA, although they note that this may miss some methylated fragments.

Of the methylated sites associated with schizophrenia, 112 overlapped with genes. Hypoxia was the “dominant theme” regardless of whether the researchers looked at protein–protein interactions, pathway databases, or micro RNA networks. For example, methylated sites overlapped with four genes involved in the hypoxia-inducible factor 1 alpha (HIF1α) transcription factor network, two products of which form hypoxia-inducible factor, which regulates hypoxia-inducible genes.

This demonstrates how methylation studies, by revealing potential contributors to a disease, can guide further research into disease mechanisms, says the team.

After targeted replication of the most significant findings in a further 178 patients and 182 controls, the top finding overall was methylation of three sites associated with the gene RELN.

This gene was part of four micro RNA networks, three of which were linked to neuronal differentiation and dopaminergic gene expression. The team notes that RELN can also be linked to hypoxia, as it is regulated by HIF1/2α.

A broader implication is that methylation of RELN has previously been associated with schizophrenia in research using postmortem brain samples, say the researchers, suggesting that methylation in the blood, which is easily accessible, may mirror that in brain tissue.

Other findings in the first set of patients and controls showed associations with immune system genes. After replication, however, these results were statistically much weaker than those for hypoxia-associated genes.

“Our results demonstrate how methylation studies in whole blood can advance schizophrenia research,” write van den Oord et al in JAMA Psychiatry.

They suggest that methylation markers might help to identify schizophrenia subtypes, and that being able to identify these with “cost-effective assays, using DNA from blood that is stable and easy to collect, would be of great clinical importance.”

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