TY - JOUR
T1 - Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
AU - Hop, Paul J.
AU - Zwamborn, Ramona A.J.
AU - Hannon, Eilis
AU - Shireby, Gemma L.
AU - Nabais, Marta F.
AU - Walker, Emma M.
AU - van Rheenen, Wouter
AU - van Vugt, Joke J.F.A.
AU - Dekker, Annelot M.
AU - Westeneng, Henk Jan
AU - Tazelaar, Gijs H.P.
AU - van Eijk, Kristel R.
AU - Moisse, Matthieu
AU - Baird, Denis
AU - Al Khleifat, Ahmad
AU - Iacoangeli, Alfredo
AU - Ticozzi, Nicola
AU - Ratti, Antonia
AU - Cooper-Knock, Jonathan
AU - Morrison, Karen E.
AU - Shaw, Pamela J.
AU - Basak, A. Nazli
AU - Chiò, Adriano
AU - Calvo, Andrea
AU - Moglia, Cristina
AU - Canosa, Antonio
AU - Brunetti, Maura
AU - Grassano, Maurizio
AU - Gotkine, Marc
AU - Lerner, Yossef
AU - Zabari, Michal
AU - Vourc'H, Patrick
AU - Corcia, Philippe
AU - Couratier, Philippe
AU - Mora Pardina, Jesus S.
AU - Salas, Teresa
AU - Dion, Patrick
AU - Ross, Jay P.
AU - Henderson, Robert D.
AU - Mathers, Susan
AU - McCombe, Pamela A.
AU - Needham, Merrilee
AU - Nicholson, Garth
AU - Rowe, Dominic B.
AU - Pamphlett, Roger
AU - Mather, Karen A.
AU - Sachdev, Perminder S.
AU - Furlong, Sarah
AU - Garton, Fleur C.
AU - Henders, Anjali K.
AU - Lin, Tian
AU - Ngo, Shyuan T.
AU - Steyn, Frederik J.
AU - Wallace, Leanne
AU - Williams, Kelly L.
AU - Neto, Miguel Mitne
AU - Cauchi, Ruben J.
AU - Blair, Ian P.
AU - Kiernan, Matthew C.
AU - Drory, Vivian
AU - Povedano, Monica
AU - de Carvalho, Mamede
AU - Pinto, Susana
AU - Weber, Markus
AU - Rouleau, Guy A.
AU - Silani, Vincenzo
AU - Landers, John E.
AU - Shaw, Christopher E.
AU - Andersen, Peter M.
AU - McRae, Allan F.
AU - van Es, Michael A.
AU - Pasterkamp, R. Jeroen
AU - Wray, Naomi R.
AU - McLaughlin, Russell L.
AU - Hardiman, Orla
AU - Kenna, Kevin P.
AU - Tsai, Ellen
AU - Runz, Heiko
AU - Al-Chalabi, Ammar
AU - van den Berg, Leonard H.
AU - Van Damme, Philip
AU - Mill, Jonathan
AU - Veldink, Jan H.
AU - Heijmans, Bastiaan T.
AU - t Hoen, Peter A.C.
AU - van Meurs, Joyce
AU - Jansen, Rick
AU - Franke, Lude
AU - Boomsma, Dorret I.
AU - Pool, René
AU - van Dongen, Jenny
AU - Hottenga, Joukje J.
AU - van Greevenbroek, Marleen M.J.
AU - Stehouwer, Coen D.A.
AU - van der Kallen, Carla J.H.
AU - Schalkwijk, Casper G.
AU - Wijmenga, Cisca
AU - Zhernakova, Sasha
AU - Tigchelaar, Ettje F.
AU - Slagboom, P. Eline
AU - Beekman, Marian
AU - Deelen, Joris
AU - van Heemst, Diana
AU - van Duijn, Cornelia M.
AU - Hofman, Bert A.
AU - Isaacs, Aaron
AU - Uitterlinden, André G.
AU - Jhamai, P. Mila
AU - Verbiest, Michael
AU - Suchiman, Eka H.D.
AU - Verkerk, Marijn
AU - van der Breggen, Ruud
AU - van Rooij, Jeroen
AU - Lakenberg, Nico
AU - Mei, Hailiang
AU - van Iterson, Maarten
AU - van Galen, Michiel
AU - Bot, Jan
AU - van 'T Hof, Peter
AU - Nooren, Irene
AU - Moed, Matthijs
AU - Vermaat, Martijn
AU - Luijk, René
AU - Bonder, Marc Jan
AU - van Dijk, Freerk
AU - Arindrarto, Wibowo
AU - Kielbasa, Szymon M.
AU - Swertz, Morris A.
AU - van Zwet, Erik W.
AU - Bensimon, Gilbert
AU - Smith, George Davey
AU - BIOS consortium
PY - 2022/2
Y1 - 2022/2
N2 - 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.
AB - 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.
UR - https://www.mendeley.com/catalogue/afb5876b-b16a-3f30-a823-b4fea858593b/
UR - https://www.scopus.com/pages/publications/85128472001
UR - https://www.scopus.com/pages/publications/85128472001#tab=citedBy
U2 - 10.1126/scitranslmed.abj0264
DO - 10.1126/scitranslmed.abj0264
M3 - Article
SN - 1946-6234
VL - 14
SP - 1
EP - 15
JO - Science translational medicine
JF - Science translational medicine
IS - 633
M1 - eabj0264
ER -