The devastating and fatal neurodegenerative disease amyotrophic lateral sclerosis (ALS) has an estimated heritability rate of around 50%, suggesting that a considerable portion of disease risk derives from environmental and lifestyle risk factors that can leave their mark on the epigenome. Can DNA methylation analysis provide new insight into the missing heritability of ALS?
In the hope of uncovering novel ALS-associated functional alterations and identifying potentially druggable targets, researchers led by Jonathan Mill (University of Exeter, UK) and Jan H. Veldink (University Medical Center Utrecht, Netherlands) report on a large-scale meta-analysis of DNA methylation data from 9706 blood samples (6763 patients, 2943 controls) from fourteen countries that possessed extensive clinical and whole-genome sequencing data.
Let’s hear from Hop, Zwamborn, and colleagues about what insight their large-scale DNA methylation analysis provided:
- Thorough quality-control and extensive sensitivity analyses uncovered 45 differentially-methylated positions that robustly associate with ALS
- The 45 sites annotate to 42 genes associated with metabolism, immunity, and cholesterol biosynthesis
- DNA methylation at 18 sites significantly associates with the expression of at least one nearby gene, including the ABCG1, DHCR24, and MSMO1 cholesterol biosynthesis/lipid transport-associated genes
- Specific differentially-methylated positions overlap with trait-associated positions reported in publicly available epigenome-wide association study databases
- These results link ALS with high-density lipoprotein and total cholesterol, triglyceride concentrations, and body-mass index-related traits such as diabetes and hepatic fat content
- An evaluation of DNA methylation-based proxies of ALS risk factors reveals an independent association of ALS with alcohol intake, body mass index, immune cell proportions, and high-density lipoprotein cholesterol
- Integration of this data with the genome-wide association study data reveals a potential causal relation between cholesterol biosynthesis and ALS
- DNA methylation at five differentially-methylated positions and the proportion of specific immune cell types (granulocytes and natural killer cells) in blood also associate with patient survival rates
Overall, the authors demonstrate how DNA methylation studies can help reveal the underlying disease processes (such as alterations to cholesterol biosynthesis or immune function in ALS) that are potentially amenable to various types of therapeutic interventions to block or delay disease progression.
For more on the missing heritability of ALS, head over to Science Translational Medicine, February 2022.