Accurate DNA methylation predictor for C9orf72 repeat expansion alleles in the pathogenic range

TL;DR

Researchers developed a highly accurate DNA methylation predictor to identify individuals with a genetic mutation linked to frontotemporal dementia and amyotrophic lateral sclerosis.

Contribution

A novel DNA methylation-based LASSO model was developed and validated for detecting C9orf72 repeat expansion carriers.

Findings

Eight CpG sites at the C9orf72 locus were significantly hypermethylated in carriers.

The LASSO model achieved 98.6% accuracy in predicting repeat expansion status.

Validation in a 2,500-subject cohort identified four carriers confirmed by PCR.

Abstract

The hexanucleotide (G4C2) repeat expansion in the promoter region of C9orf72 is the most frequent genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). In this study, we conducted a genome-wide DNA methylation (DNAm) analysis using EPIC version 2 (EPICv2) arrays on an FTD cohort comprising 27 carriers and 250 non-carriers of the pathogenic C9orf72 repeat expansion from the Amsterdam Dementia Cohort. We identified differentially methylated CpGs probes associated with the pathogenic C9orf72 expansion and used these findings to create a DNAm least absolute shrinkage and selection operator (LASSO) predictor to identify repeat expansion carriers. Eight CpG sites at the C9orf72 locus were significantly differentially hypermethylated in repeat expansion carriers compared to non-carriers. The LASSO model predicted repeat expansion status with an average accuracy of 98.6%. The LASSO predictor was further validated in a separate, independent validation cohort containing 1,589 subjects with bipolar disorder, 580 first-degree relatives, and 289 independent control subjects with available EPICv2 data, identifying four C9orf72 repeat expansion carriers, subsequently confirmed by repeat-primed PCR. This result highlights the accuracy and generalizability of the DNAm predictor of C9orf72 repeat expansion carriers. The identification of a highly accurate DNAm biomarker for a repeat expansion locus associated with neurodegenerative disorders may provide great value for studying this locus. The approach holds significant promise for investigating this and other repeat expansion loci, particularly given the growing interest in epigenetic epidemiological studies involving large cohorts with available DNAm data.

Ramesh et al. developed a robust DNA methylation (DNAm)-based predictor to identify C9orf72 repeat expansion carriers, a major cause of amyotrophic lateral sclerosis and frontotemporal dementia. The array-based DNAm predictor was independently validated in a large cohort of almost 2,500 subjects, in which they observed a prevalence of 0.18% of repeat expansion carriers.

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