Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS.
Paul J HopRamona A J ZwambornEilis J HannonGemma L ShirebyMarta F NabaisEmma M WalkerWouter Van RheenenJoke J F A van VugtAnnelot M DekkerHenk-Jan WestenengGijs H P TazelaarKristel R van EijkMatthieu MoisseDenis BairdAhmad Al KhleifatAlfredo IacoangeliNicola TicozziAntonia RattiJohnathan Cooper-KnockKaren E MorrisonDame Pamela J ShawAyse Nazli BasakAdriano ChioAndrea CalvoCristina MogliaAntonio CanosaMaura BrunettiMaurizio GrassanoMarc GotkineYossef LernerMichal ZabariPatrick Vourc'hPhilippe CorciaPhilippe CouratierJesus S MoraTeresa SalasPatrick DionJay P RossRobert David HendersonSusan MathersPamela A McCombeMerrilee NeedhamGarth NicholsonDominic B RoweRoger PamphlettKaren A MatherPerminder Singh SachdevSarah FurlongFleur C GartonAnjali K HendersTian LinShyuan T NgoFrederik J SteynLeanne WallaceKelly Louise Williamsnull nullnull nullMiguel Mitne NetoRuben J CauchiIan P BlairMatthew C KiernanVivian DroryMonica PovedanoMamede de CarvalhoSusana PintoMarkus WeberGuy A RouleauVincenzo SilaniJohn E LandersChristopher E ShawPeter Munch AndersenAllan F McRaeMichael A van EsR Jeroen PasterkampNaomi R WrayRussell Lewis McLaughlinOrla HardimanKevin P KennaEllen A TsaiHeiko RunzAmmar Al ChalabiLeonard H van den BergPhilip Van DammeJonathan S MillJan Herman VeldinkPublished in: Science translational medicine (2022)
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.
Keyphrases
- dna methylation
- genome wide
- amyotrophic lateral sclerosis
- gene expression
- end stage renal disease
- body mass index
- systematic review
- newly diagnosed
- copy number
- chronic kidney disease
- risk factors
- ejection fraction
- oxidative stress
- prognostic factors
- quality control
- peritoneal dialysis
- cell therapy
- genome wide association study
- randomized controlled trial
- weight gain
- weight loss
- risk assessment
- low density lipoprotein
- air pollution