Comprehensive methylation profile of CSF cfDNA revealed pathogenesis and diagnostic markers for early-onset PD

Lay abstract Early-onset Parkinson's disease (EOPD), a progressive disease of the nervous system marked by tremor, muscular rigidity and slow and imprecise movement, is generally found in people under the age of 40 years. In this study, we performed methylation test on cerebrospinal fluid (CSF). The test showed that specific CSF methylation profiles could be used to help EOPD diagnosis. A subset of differentially methylated genes were also identified, which could also be used as markers for EOPD diagnosis. In future, we will validate the methylation test in blood and try to find blood-based diagnostic markers to facilitate the diagnosis of EOPD by a single blood draw. Background: Early-onset Parkinson's disease (EOPD) is one uncommon Parkinson's disease subtype with characteristic clinicopathological features. The full epigenomic profile of EOPD is largely unknown. Methods: We performed the first study to investigate the EOPD full methylation profile of cerebrospinal fluid (CSF) cell-free DNA (cfDNA) from 26 EOPD patients and 10 control patients. Results: 2220 differentially methylated genes were identified in EOPD. Hypermethylation far outweighed hypomethylation in gene numbers. Clustering and enrichment analyses identified aberrant neuronal function and immune response. Weighted correlation network analysis demonstrated significant correlation between methylation signatures and clock drawing test (CDT), mini-mental state examination (MMSE), education, working status, alcohol drinking history and Hamilton anxiety scale (HAMA). Several key networking genes in EOPD aberrant methylation were also identified. Conclusions: The methylation profile and signatures of CSF cfDNA were revealed for the first time in EOPD. Aberrant methylation signatures were correlated with education, working status, alcohol drinking history, CDT, MMSE and HAMA.