Machine Learning Identifies Epigenetic Markers of Schizophrenia
Schizophrenia is a severe mental disorder, which has a 1% global lifetime risk. With the exact cause unknown, identifying biomarkers could be the key to unravelling the underlying mechanisms of this disease. Published in JAMA Psychiatry this week, researchers used whole-blood DNA methylation data and machine learning to identify a epigenetic signature for schizophrenia.
We know from twin studies that Schizophrenia carries a 80% heritability risk, but haven’t yet managed to deduce exact genetic risk factors. Epigenetic markers can account for heritability that is not captured by standard genetic association methods, such as polygenic risk scores or twin studies and are being increasingly explored in multifactorial diseases.
Compared to other studies that focussed on a single gene or locus, this study used whole-blood samples to get an overview of the disease. Using machine learning trained on DNA methylation profiles of healthy controls, a polymethylation score (PMS) was generated. This PMS was then applied to 2230 whole-blood samples from 6 global independent cohorts – 36% of which had schizophrenia, and correctly differentiated those with this disorder from control samples.
This DNA methylation signature was then found to be associated with an intermediate phenotype of schizophrenia – those not fully symptomatic – in healthy controls. This linked the epigenetic profile to negative connectivity in the dorsolateral prefrontal cortex hippocampus in relation to working memory. This intermediate phenotype was found in those who are healthy first-degree relatives of schizophrenics, suggesting a potential pre-disposition or risk factor. This could be used to identify those in high-risk groups and go on to explore how this epigenetic mark interacts with other biomarkers of schizophrenia.
By using whole-blood samples and machine learning, this paves the way for PMS to be used in other multifactorial diseases to identify novel targets for drug development or personalised therapeutics.
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