Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS.

Publication

Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS.

Journal Paper/Review - Feb 23, 2022

Hop Paul J, Zwamborn Ramona A J, Hannon Eilis, Shireby Gemma, Nabais Marta F, Walker Emma M, van Rheenen Wouter, Van Vugt Joke J F A, Dekker Annelot M, Westeneng Henk-Jan, Tazelaar Gijs H P, van Eijk Kristel R, Moisse Matthieu, Baird Denis, Al Khleifat Ahmad, Iacoangeli Alfredo, Ticozzi Nicola, Ratti Antonia, Cooper-Knock Jonathan, Morrison Karen E, Shaw Pamela J, Basak A Nazli, Chio Adriano, Calvo Andrea, Moglia Cristina, Canosa Antonio, Brunetti Maura, Grassano Maurizio, Gotkine Marc, Lerner Yossef, Zabari Michal, Vourc'h Patrick, Corcia Philippe, Couratier Philippe, Mora Pardina Jesus S, Salas Teresa, Dion Patrick A, Ross Jay P, Henderson Robert D, Mathers Susan, McCombe Pamela A, Needham Merrilee, Nicholson Garth A, Rowe Dominic B, Pamphlett Roger, Mather Karen A, Sachdev Perminder S, Furlong Sarah, Garton Fleur C, Henders Anjali K, Lin Tian, Ngo Shyuan T, Steyn Frederik J, Wallace Leanne, Williams Kelly L, ĀăąĆĉČĎ Ā ā Ă ă Ą ą Ć ć Ĉ ĉ Ċ ċ Č č Ď ď Đ đ Ē ē Ĕ ĕ Ė ė Ę ę Ě ě Ĝ ĝ Ğ ğ Ġ ġ Ģ ģ Ĥ ĥ Ħ ħ Ĩ ĩ Ī ī Ĭ ĭ Į į İ ı Ĳ ĳ Ĵ ĵ Ķ ķ ĸ Ĺ ĺ Ļ ļ Ľ ľ Ŀ ŀ Ł ł Ń ń Ņ ņ Ň ň ŉ Ŋ ŋ Ō ō Ŏ ŏ Ő ő Œ œ Ŕ ŕ Ŗ ŗ Ř ř Ś ś Ŝ ŝ Ş ş Š š Ţ ţ Ť ť Ŧ ŧ Ũ ũ Ū ū Ŭ ŭ Ů ů Ű ű Ų ų Ŵ ŵ Ŷ ŷ Ÿ Ź ź Ż ż Ž ž ſ, Neto Miguel Mitne, Cauchi Ruben J, Blair Ian P, Kiernan Matthew C, Drory Vivian, Povedano Monica, de Carvalho Mamede, Pinto Susana, Weber Markus, Rouleau Guy A, Silani Vincenzo, Landers John E, Shaw Christopher E, Andersen Peter M, McRae Allan F, van Es Michael A, Pasterkamp R Jeroen, Wray Naomi R, McLaughlin Russell L, Hardiman Orla, Kenna Kevin P, Tsai Ellen, Runz Heiko, Al-Chalabi Ammar, van den Berg Leonard H, Van Damme Philip, Mill Jonathan, Veldink Jan H

Citation

Hop P, Zwamborn R, Hannon E, Shireby G, Nabais M, Walker E, van Rheenen W, Van Vugt J, Dekker A, Westeneng H, Tazelaar G, van Eijk K, Moisse M, Baird D, Al Khleifat A, Iacoangeli A, Ticozzi N, Ratti A, Cooper-Knock J, Morrison K, Shaw P, Basak A, Chio 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 J, Salas T, Dion P, Ross J, Henderson R, Mathers S, McCombe P, Needham M, Nicholson G, Rowe D, Pamphlett R, Mather K, Sachdev P, Furlong S, Garton F, Henders A, Lin T, Ngo S, Steyn F, Wallace L, Williams K, ĀăąĆĉČĎ Ā, Neto M, Cauchi R, Blair I, Kiernan M, Drory V, Povedano M, de Carvalho M, Pinto S, Weber M, Rouleau G, Silani V, Landers J, Shaw C, Andersen P, McRae A, van Es M, Pasterkamp R, Wray N, McLaughlin R, Hardiman O, Kenna K, Tsai E, Runz H, Al-Chalabi A, van den Berg L, Van Damme P, Mill J, Veldink J. Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS. Sci Transl Med 2022; 14:eabj0264.

Type

Journal Paper/Review (English)

Journal

Sci Transl Med 2022; 14

Publication Date

Feb 23, 2022

Issn Electronic

1946-6242

Pages

eabj0264

Brief description/objective

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.