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

Paul J. Hop; Ramona A.J. Zwamborn; Eilis Hannon; Gemma L. Shireby; Marta F. Nabais; Emma M. Walker; Wouter van Rheenen; Joke J.F.A. van Vugt; Annelot M. Dekker; Henk Jan Westeneng; Gijs H.P. Tazelaar; Kristel R. van Eijk; Matthieu Moisse; Denis Baird; Ahmad Al Khleifat; Alfredo Iacoangeli; Nicola Ticozzi; Antonia Ratti; Jonathan Cooper-Knock; Karen E. Morrison; Pamela J. Shaw; A. Nazli Basak; Adriano Chiò; Andrea Calvo; Cristina Moglia; Antonio Canosa; Maura Brunetti; Maurizio Grassano; Marc Gotkine; Yossef Lerner; Michal Zabari; Patrick Vourc'H; Philippe Corcia; Philippe Couratier; Jesus S. Mora Pardina; Teresa Salas; Patrick Dion; Jay P. Ross; Robert D. Henderson; Susan Mathers; Pamela A. McCombe; Merrilee Needham; Garth Nicholson; Dominic B. Rowe; Roger Pamphlett; Karen A. Mather; Marleen M.J. van Greevenbroek; Coen D.A. Stehouwer; Carla J.H. van der Kallen; Casper G. Schalkwijk; Jan H. Veldink; BIOS Consortium; Brain MEND Consortium

doi:10.1126/scitranslmed.abj0264

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

Paul J. Hop, Ramona A.J. Zwamborn, Eilis Hannon, Gemma L. Shireby, Marta F. Nabais, Emma M. Walker, Wouter van Rheenen, Joke J.F.A. van Vugt, Annelot M. Dekker, Henk Jan Westeneng, Gijs H.P. Tazelaar, Kristel R. van Eijk, Matthieu Moisse, Denis Baird, Ahmad Al Khleifat, Alfredo Iacoangeli, Nicola Ticozzi, Antonia Ratti, Jonathan Cooper-Knock, Karen E. MorrisonPamela J. Shaw, A. Nazli Basak, Adriano Chiò, Andrea Calvo, Cristina Moglia, Antonio Canosa, Maura Brunetti, Maurizio Grassano, Marc Gotkine, Yossef Lerner, Michal Zabari, Patrick Vourc'H, Philippe Corcia, Philippe Couratier, Jesus S. Mora Pardina, Teresa Salas, Patrick Dion, Jay P. Ross, Robert D. Henderson, Susan Mathers, Pamela A. McCombe, Merrilee Needham, Garth Nicholson, Dominic B. Rowe, Roger Pamphlett, Karen A. Mather, Marleen M.J. van Greevenbroek, Coen D.A. Stehouwer, Carla J.H. van der Kallen, Casper G. Schalkwijk, Jan H. Veldink^*, BIOS Consortium, Brain MEND Consortium

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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Abstract

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.

Original language	English
Article number	eabj0264
Number of pages	15
Journal	Science Translational Medicine
Volume	14
Issue number	633
DOIs	https://doi.org/10.1126/scitranslmed.abj0264
Publication status	Published - 23 Feb 2022

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10.1126/scitranslmed.abj0264

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Hop, P. J., Zwamborn, R. A. J., Hannon, E., Shireby, G. L., Nabais, M. F., Walker, E. M., van Rheenen, W., van Vugt, J. J. F. A., Dekker, A. M., Westeneng, H. J., Tazelaar, G. H. P., van Eijk, K. R., Moisse, M., Baird, D., Al Khleifat, A., Iacoangeli, A., Ticozzi, N., Ratti, A., Cooper-Knock, J., ... Brain MEND Consortium (2022). Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS. Science Translational Medicine, 14(633), Article eabj0264. https://doi.org/10.1126/scitranslmed.abj0264

@article{96382ab3898a46bfb1eae0da5f697d60,

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

abstract = "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.",

author = "Hop, {Paul J.} and Zwamborn, {Ramona A.J.} and Eilis Hannon and Shireby, {Gemma L.} and Nabais, {Marta F.} and Walker, {Emma M.} and {van Rheenen}, Wouter and {van Vugt}, {Joke J.F.A.} and Dekker, {Annelot M.} and Westeneng, {Henk Jan} and Tazelaar, {Gijs H.P.} and {van Eijk}, {Kristel R.} and Matthieu Moisse and Denis Baird and {Al Khleifat}, Ahmad and Alfredo Iacoangeli and Nicola Ticozzi and Antonia Ratti and Jonathan Cooper-Knock and Morrison, {Karen E.} and Shaw, {Pamela J.} and Basak, {A. Nazli} and Adriano Chi{\`o} and Andrea Calvo and Cristina Moglia and Antonio Canosa and Maura Brunetti and Maurizio Grassano and Marc Gotkine and Yossef Lerner and Michal Zabari and Patrick Vourc'H and Philippe Corcia and Philippe Couratier and {Mora Pardina}, {Jesus S.} and Teresa Salas and Patrick Dion and Ross, {Jay P.} and Henderson, {Robert D.} and Susan Mathers and McCombe, {Pamela A.} and Merrilee Needham and Garth Nicholson and Rowe, {Dominic B.} and Roger Pamphlett and Mather, {Karen A.} and {van Greevenbroek}, {Marleen M.J.} and Stehouwer, {Coen D.A.} and {van der Kallen}, {Carla J.H.} and Schalkwijk, {Casper G.} and Veldink, {Jan H.} and {BIOS Consortium} and {Brain MEND Consortium}",

note = "Funding Information: The research reported in this publication was supported by grants from The Dutch Research Council (NWO) (VENI scheme grant 09150161810018 to W.v.R.) and Prinses Beatrix Spierfond (neuromuscular fellowship grant W.F19-03 to W.v.R.), The Prinses Beatrix Spierfonds (W.OR20-08 to J.J.F.A.v.V. and J.H.V.), The Canadian Institutes of Health Research (FRN 159279 to J.P.R.), The Dutch Research Council (NWO) (VIDI grant 91719350 to K.P.K.), The European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 772376-EScORIAL to J.H.V.), the Swedish Brain Foundation (grant nos. 2012-0262, 2012-0305, 2013-0279, 2016-0303, 2018-0310, and 2020-0353 to P.M.A.), the Swedish Research Council (grant nos. 2012-3167 and 2017-03100 to P.M.A.), the Knut and Alice Wallenberg Foundation (grant nos. 2012.0091, 2014.0305, and 2020.0232 to P.M.A.), the Ulla-Carin Lindquist Foundation and the V{\"a}sterbotten County Council (grant no. 56103-7002829 to P.M.A.), and King Gustaf V's and Queen Victoria's Freemason's Foundation. This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND (www.jpnd.eu) [United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)] and through the Motor Neurone Disease Association (MNDA). This study represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. A.A.-C. is supported by an NIHR Senior Investigator Award. Samples used in this research were entirely/in part obtained from the U.K. National DNA Bank for MND Research, funded by the MND Association and the Wellcome Trust. We would like to thank people with MND and their families for their participation in this project. We acknowledge sample management undertaken by Biobanking Solutions funded by the Medical Research Council at the Centre for Integrated Genomic Medical Research, University of Manchester. R.J.P. is funded through the Gravitation program of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (BRAINSCAPES). G.L.S. was supported by a PhD studentship from the Alzheimer's Society. S.T.N. acknowledges support through a FightMND Mid-Career Fellowship. V.S. is supported by the Italian Ministry of Health, AriSLA, and E-Rare Joint Transnational Call. A.A.K. is funded by the MNDA and NIHR Maudsley Biomedical Research Centre. D.B., E.T., and H.R. are employees of Biogen. L.H.v.d.B. reports grants from the Netherlands ALS Foundation, grants from The Netherlands Organization for Health Research and Development (Vici scheme), grants from The European Community's Health Seventh Framework Programme [grant agreement no. 259867 (EuroMOTOR) to L.H.v.d.B.], and grants from The Netherlands Organization for Health Research and Development (the STRENGTH project, funded through the EU Joint Programme-Neurodegenerative Disease Research, JPND), during the conduct of the study. Project MinE Belgium was supported by a grant from IWT (no. 140935), the ALS Liga Belgi{\"e}, the National Lottery of Belgium, and the KU Leuven Opening the Future Fund. P.V.D. holds a senior clinical investigatorship of FWO-Vlaanderen and is supported by the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga Belgi{\"e}, and the KU Leuven funds “Een Hart voor ALS”, “Laeversfonds voor ALS Onderzoek”, and the “Val{\'e}ry Perrier Race against ALS Fund”. This work was supported by the Italian Ministry of Health (Ministero della Salute, Ricerca Sanitaria Finalizzata, grant RF-2016-02362405 to A. Chi{\`o}), the Progetti di Rilevante Interesse Nazionale program of the Ministry of Education, University and Research (grant 2017SNW5MB to A. Chi{\`o}); the European Commission's Health Seventh Framework Programme (FP7/2007-2013 under grant agreement 259867 to A. Chi{\`o}), and the Joint Programme-Neurodegenerative Disease Research (Strength, ALS-Care and Brain-Mend projects), granted by Italian Ministry of Education, University, and Research. This study was performed under the Department of Excellence grant of the Italian Ministry of Education, University and Research to the “Rita Levi Montalcini” Department of Neuroscience, University of Torino, Italy. We acknowledge funding from the Australian National Health and Medical Research (NHMRC) Council: 1151854, 1083187, 1173790, 1078901, 1113400, 1095215, and 1176913 Enabling Grant #402703 to N.R.W. Additional funding was provided by the Motor Neurone Disease Research Institute of Australia Ice Bucket Challenge grant for the SALSA-SGC consortium. The OATS (used for controls) was facilitated through Twins Research Australia, a national resource in part supported by a Centre for Research Excellence from the Australian NHMRC Council (NHMRC 1079102 to N.R.W.). Funding for this study was awarded by the (NHMRC)/Australian Research Council Strategic Award (grant 401162 to N.R.W.) and NHMRC grants (1405325, 1024224, 1025243, 1045325, 1085606, 568969, and 1093083 to N.R.W.). The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. This study was supported by the ALS Foundation Netherlands. This work was sponsored by NWO Domain Science for the use of the national computer facilities. A.N.B. is grateful to the Suna and Inan Kirac Foundation and Koc University for the excellent research environment created and for financial support. G.A.R. is supported by the Canadian Institutes of Health. Several authors of this publication are members of the Netherlands Neuromuscular Center (NL-NMD) and the European Reference Network for rare neuromuscular diseases EURO-NMD. French ALS patients of the Piti{\'e}-Salp{\^e}tri{\`e}re hospital (Paris) have been collected with ARSla funding support. Publisher Copyright: Copyright {\textcopyright} 2022 The Authors, some rights reserved",

year = "2022",

month = feb,

day = "23",

doi = "10.1126/scitranslmed.abj0264",

language = "English",

volume = "14",

journal = "Science Translational Medicine",

issn = "1946-6234",

publisher = "American Association for the Advancement of Science",

number = "633",

}

Hop, PJ, Zwamborn, RAJ, Hannon, E, Shireby, GL, Nabais, MF, Walker, EM, van Rheenen, W, van Vugt, JJFA, Dekker, AM, Westeneng, HJ, 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, van Greevenbroek, MMJ , Stehouwer, CDA , van der Kallen, CJH , Schalkwijk, CG, Veldink, JH, BIOS Consortium & Brain MEND Consortium 2022, 'Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS', Science Translational Medicine, vol. 14, no. 633, eabj0264. https://doi.org/10.1126/scitranslmed.abj0264

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 - van Greevenbroek, Marleen M.J.

AU - Stehouwer, Coen D.A.

AU - van der Kallen, Carla J.H.

AU - Schalkwijk, Casper G.

AU - Veldink, Jan H.

AU - BIOS Consortium

AU - Brain MEND Consortium

N1 - Funding Information: The research reported in this publication was supported by grants from The Dutch Research Council (NWO) (VENI scheme grant 09150161810018 to W.v.R.) and Prinses Beatrix Spierfond (neuromuscular fellowship grant W.F19-03 to W.v.R.), The Prinses Beatrix Spierfonds (W.OR20-08 to J.J.F.A.v.V. and J.H.V.), The Canadian Institutes of Health Research (FRN 159279 to J.P.R.), The Dutch Research Council (NWO) (VIDI grant 91719350 to K.P.K.), The European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 772376-EScORIAL to J.H.V.), the Swedish Brain Foundation (grant nos. 2012-0262, 2012-0305, 2013-0279, 2016-0303, 2018-0310, and 2020-0353 to P.M.A.), the Swedish Research Council (grant nos. 2012-3167 and 2017-03100 to P.M.A.), the Knut and Alice Wallenberg Foundation (grant nos. 2012.0091, 2014.0305, and 2020.0232 to P.M.A.), the Ulla-Carin Lindquist Foundation and the Västerbotten County Council (grant no. 56103-7002829 to P.M.A.), and King Gustaf V's and Queen Victoria's Freemason's Foundation. This is an EU Joint Programme-Neurodegenerative Disease Research (JPND) project. The project is supported through the following funding organizations under the aegis of JPND (www.jpnd.eu) [United Kingdom, Medical Research Council (MR/L501529/1; MR/R024804/1) and Economic and Social Research Council (ES/L008238/1)] and through the Motor Neurone Disease Association (MNDA). This study represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King's College London. A.A.-C. is supported by an NIHR Senior Investigator Award. Samples used in this research were entirely/in part obtained from the U.K. National DNA Bank for MND Research, funded by the MND Association and the Wellcome Trust. We would like to thank people with MND and their families for their participation in this project. We acknowledge sample management undertaken by Biobanking Solutions funded by the Medical Research Council at the Centre for Integrated Genomic Medical Research, University of Manchester. R.J.P. is funded through the Gravitation program of the Dutch Ministry of Education, Culture, and Science and the Netherlands Organization for Scientific Research (BRAINSCAPES). G.L.S. was supported by a PhD studentship from the Alzheimer's Society. S.T.N. acknowledges support through a FightMND Mid-Career Fellowship. V.S. is supported by the Italian Ministry of Health, AriSLA, and E-Rare Joint Transnational Call. A.A.K. is funded by the MNDA and NIHR Maudsley Biomedical Research Centre. D.B., E.T., and H.R. are employees of Biogen. L.H.v.d.B. reports grants from the Netherlands ALS Foundation, grants from The Netherlands Organization for Health Research and Development (Vici scheme), grants from The European Community's Health Seventh Framework Programme [grant agreement no. 259867 (EuroMOTOR) to L.H.v.d.B.], and grants from The Netherlands Organization for Health Research and Development (the STRENGTH project, funded through the EU Joint Programme-Neurodegenerative Disease Research, JPND), during the conduct of the study. Project MinE Belgium was supported by a grant from IWT (no. 140935), the ALS Liga België, the National Lottery of Belgium, and the KU Leuven Opening the Future Fund. P.V.D. holds a senior clinical investigatorship of FWO-Vlaanderen and is supported by the E. von Behring Chair for Neuromuscular and Neurodegenerative Disorders, the ALS Liga België, and the KU Leuven funds “Een Hart voor ALS”, “Laeversfonds voor ALS Onderzoek”, and the “Valéry Perrier Race against ALS Fund”. This work was supported by the Italian Ministry of Health (Ministero della Salute, Ricerca Sanitaria Finalizzata, grant RF-2016-02362405 to A. Chiò), the Progetti di Rilevante Interesse Nazionale program of the Ministry of Education, University and Research (grant 2017SNW5MB to A. Chiò); the European Commission's Health Seventh Framework Programme (FP7/2007-2013 under grant agreement 259867 to A. Chiò), and the Joint Programme-Neurodegenerative Disease Research (Strength, ALS-Care and Brain-Mend projects), granted by Italian Ministry of Education, University, and Research. This study was performed under the Department of Excellence grant of the Italian Ministry of Education, University and Research to the “Rita Levi Montalcini” Department of Neuroscience, University of Torino, Italy. We acknowledge funding from the Australian National Health and Medical Research (NHMRC) Council: 1151854, 1083187, 1173790, 1078901, 1113400, 1095215, and 1176913 Enabling Grant #402703 to N.R.W. Additional funding was provided by the Motor Neurone Disease Research Institute of Australia Ice Bucket Challenge grant for the SALSA-SGC consortium. The OATS (used for controls) was facilitated through Twins Research Australia, a national resource in part supported by a Centre for Research Excellence from the Australian NHMRC Council (NHMRC 1079102 to N.R.W.). Funding for this study was awarded by the (NHMRC)/Australian Research Council Strategic Award (grant 401162 to N.R.W.) and NHMRC grants (1405325, 1024224, 1025243, 1045325, 1085606, 568969, and 1093083 to N.R.W.). The collaboration project is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships. This study was supported by the ALS Foundation Netherlands. This work was sponsored by NWO Domain Science for the use of the national computer facilities. A.N.B. is grateful to the Suna and Inan Kirac Foundation and Koc University for the excellent research environment created and for financial support. G.A.R. is supported by the Canadian Institutes of Health. Several authors of this publication are members of the Netherlands Neuromuscular Center (NL-NMD) and the European Reference Network for rare neuromuscular diseases EURO-NMD. French ALS patients of the Pitié-Salpêtrière hospital (Paris) have been collected with ARSla funding support. Publisher Copyright: Copyright © 2022 The Authors, some rights reserved

PY - 2022/2/23

Y1 - 2022/2/23

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.

U2 - 10.1126/scitranslmed.abj0264

DO - 10.1126/scitranslmed.abj0264

M3 - Article

C2 - 35196023

SN - 1946-6234

VL - 14

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 633

M1 - eabj0264

ER -