Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS.
Hop PJ., Zwamborn RAJ., Hannon E., Shireby GL., Nabais MF., Walker EM., van Rheenen W., van Vugt JJFA., Dekker AM., Westeneng H-J., Tazelaar GHP., van Eijk KR., Moisse M., Baird D., Al Khleifat A., Iacoangeli A., Ticozzi N., Ratti A., Cooper-Knock J., Morrison KE., Shaw PJ., Basak AN., Chiò A., Calvo A., Moglia C., Canosa A., Brunetti M., Grassano M., Gotkine M., Lerner Y., Zabari M., Vourc'h P., Corcia P., Couratier P., Mora Pardina JS., Salas T., Dion P., Ross JP., Henderson RD., Mathers S., McCombe PA., Needham M., Nicholson G., Rowe DB., Pamphlett R., Mather KA., Sachdev PS., Furlong S., Garton FC., Henders AK., Lin T., Ngo ST., Steyn FJ., Wallace L., Williams KL., BIOS Consortium None., Brain MEND Consortium None., Neto MM., Cauchi RJ., Blair IP., Kiernan MC., Drory V., Povedano M., de Carvalho M., Pinto S., Weber M., Rouleau GA., Silani V., Landers JE., Shaw CE., Andersen PM., McRae AF., van Es MA., Pasterkamp RJ., Wray NR., McLaughlin RL., Hardiman O., Kenna KP., Tsai E., Runz H., Al-Chalabi A., van den Berg LH., Van Damme P., Mill J., Veldink JH.
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with an estimated heritability between 40 and 50%. DNA methylation patterns can serve as proxies of (past) exposures and disease progression, as well as providing a potential mechanism that mediates genetic or environmental risk. Here, we present a blood-based epigenome-wide association study meta-analysis in 9706 samples passing stringent quality control (6763 patients, 2943 controls). We identified a total of 45 differentially methylated positions (DMPs) annotated to 42 genes, which are enriched for pathways and traits related to metabolism, cholesterol biosynthesis, and immunity. We then tested 39 DNA methylation-based proxies of putative ALS risk factors and found that high-density lipoprotein cholesterol, body mass index, white blood cell proportions, and alcohol intake were independently associated with ALS. Integration of these results with our latest genome-wide association study showed that cholesterol biosynthesis was potentially causally related to ALS. Last, DNA methylation at several DMPs and blood cell proportion estimates derived from DNA methylation data were associated with survival rate in patients, suggesting that they might represent indicators of underlying disease processes potentially amenable to therapeutic interventions.