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

P.J. Hop; R.A.J. Zwamborn; E. Hannon; G.L. Shireby; M.F. Nabais; E.M. Walker; W. van Rheenen; J.J.F.A. van Vugt; A.M. Dekker; H-J Westeneng; G.H.P. Tazelaar; K.R. van Eijk; M. Moisse; D. Baird; A. Al Khleifat; A. Iacoangeli; N. Ticozzi; A. Ratti; J. Cooper-Knock; K.E. Morrison; P.J. Shaw; A.N. Basak; A. Chiò; A. Calvo; C. Moglia; A. Canosa; M. Brunetti; M. Grassano; M. Gotkine; Y. Lerner; M. Zabari; P. Vourc’h; P. Corcia; P. Couratier; J.S. Mora Pardina; T. Salas; P. Dion; J.P. Ross; R.D. Henderson; S. Mathers; P.A. McCombe; M. Needham; G. Nicholson; D.B. Rowe; R. Pamphlett; K.A. Mather; P.S. Sachdev; S. Furlong; F.C. Garton; A.K. Henders; T. Lin; S.T. Ngo; F.J. Steyn; L. Wallace; K.L. Williams; M.M. Neto; R.J. Cauchi; I.P. Blair; M.C. Kiernan; V. Drory; M. Povedano; M. de Carvalho; S. Pinto; M. Weber; G.A. Rouleau; V. Silani; J.E. Landers; C.E. Shaw; P.M. Andersen; A.F. McRae; M.A. van Es; R.J. Pasterkamp; N.R. Wray; R.L. McLaughlin; O. Hardiman; K.P. Kenna; E. Tsai; H. Runz; A. Al-Chalabi; L.H. van den Berg; P. Van Damme; J. Mill; J.H. Veldink; B.T. Heijmans; P.A.C. t Hoen; J. van Meurs; R. Jansen; L. Franke; D.I. Boomsma; R. Pool; J. van Dongen; J.J. Hottenga; M.M.J. van Greevenbroek; C.D.A. Stehouwer; C.J.H. van der Kallen; C.G. Schalkwijk; C. Wijmenga; S. Zhernakova; E.F. Tigchelaar; P.E. Slagboom; M. Beekman; J. Deelen; D. Van Heemst; C.M. van Duijn; B.A. Hofman; A. Isaacs; A.G. Uitterlinden; J.B.C. van Meurs; P.M. Jhamai; M. Verbiest; H.E.D. Suchiman; M. Verkerk; R. van der Breggen; J. van Rooij; N. Lakenberg; H. Mei; M. van Iterson; M. van Galen; J. Bot; D.V. Zhernakova; P. van ‘t Hof; P. Deelen; I. Nooren; M. Moed; M. Vermaat; R. Luijk; M. Jan Bonder; F. van Dijk; W. Arindrarto; S.M. Kielbasa; M.A. Swertz; E.W. van Zwet; P.A.C. Hoen; G. Bensimon; A. Chio; G.D. Smith

doi:10.1126/scitranslmed.abj0264

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

Journal article

Peer reviewed

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

P.J. Hop, R.A.J. Zwamborn, E. Hannon, G.L. Shireby, M.F. Nabais, E.M. Walker, W. van Rheenen, J.J.F.A. van Vugt, A.M. Dekker, H-J Westeneng, …

Science Translational Medicine, Vol.14(633), Art. abj0264

2022

DOI: https://doi.org/10.1126/scitranslmed.abj0264

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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.

Details

Title: Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
Authors/Creators: P.J. Hop (Author/Creator) - University Medical Center Utrecht
R.A.J. Zwamborn (Author/Creator) - University Medical Center Utrecht
E. Hannon (Author/Creator) - University of Exeter
G.L. Shireby (Author/Creator) - University of Exeter
M.F. Nabais (Author/Creator) - The University of Queensland
E.M. Walker (Author/Creator) - University of Exeter
W. van Rheenen (Author/Creator) - University Medical Center Utrecht
J.J.F.A. van Vugt (Author/Creator) - University Medical Center Utrecht
A.M. Dekker (Author/Creator) - University Medical Center Utrecht
H-J Westeneng (Author/Creator) - University Medical Center Utrecht
G.H.P. Tazelaar (Author/Creator) - University Medical Center Utrecht
K.R. van Eijk (Author/Creator) - University Medical Center Utrecht
M. Moisse (Author/Creator) - KU Leuven
D. Baird (Author/Creator) - University of Bristol
A. Al Khleifat (Author/Creator) - King's College London
A. Iacoangeli (Author/Creator) - King's College London
N. Ticozzi (Author/Creator) - IRCCS Istituto Auxologico Italiano
A. Ratti (Author/Creator) - University of Milan
J. Cooper-Knock (Author/Creator) - University of Sheffield
K.E. Morrison (Author/Creator) - Queen's University Belfast
P.J. Shaw (Author/Creator) - University of Sheffield
A.N. Basak (Author/Creator) - Koç University
A. Chiò (Author/Creator) - Azienda Ospedaliera Citta' della Salute e della Scienza di Torino
A. Calvo (Author/Creator) - Azienda Ospedaliera Citta' della Salute e della Scienza di Torino
C. Moglia (Author/Creator) - Azienda Ospedaliera Citta' della Salute e della Scienza di Torino
A. Canosa (Author/Creator) - Azienda Ospedaliera Citta' della Salute e della Scienza di Torino
M. Brunetti (Author/Creator) - University of Turin
M. Grassano (Author/Creator) - University of Turin
M. Gotkine (Author/Creator) - Hadassah Medical Center
Y. Lerner (Author/Creator) - Hadassah Medical Center
M. Zabari (Author/Creator) - Hadassah Medical Center
P. Vourc’h (Author/Creator)
P. Corcia (Author/Creator) - Université de Tours
P. Couratier (Author/Creator) - Université de Limoges
J.S. Mora Pardina (Author/Creator)
T. Salas (Author/Creator) - Carlos III Hospital
P. Dion (Author/Creator) - Montreal Neurological Institute and Hospital
J.P. Ross (Author/Creator) - McGill University
R.D. Henderson (Author/Creator) - Royal Brisbane and Women's Hospital
S. Mathers (Author/Creator) - Calvary Health Care Bethlehem
P.A. McCombe (Author/Creator) - The University of Queensland
M. Needham (Author/Creator) - Fiona Stanley Hospital
G. Nicholson (Author/Creator) - Concord Repatriation General Hospital
D.B. Rowe (Author/Creator) - Macquarie University
R. Pamphlett (Author/Creator) - The University of Sydney
K.A. Mather (Author/Creator) - UNSW Sydney
P.S. Sachdev (Author/Creator) - UNSW Sydney
S. Furlong (Author/Creator) - Macquarie University
F.C. Garton (Author/Creator) - The University of Queensland
A.K. Henders (Author/Creator) - The University of Queensland
T. Lin (Author/Creator) - The University of Queensland
S.T. Ngo (Author/Creator) - The University of Queensland
F.J. Steyn (Author/Creator) - The University of Queensland
L. Wallace (Author/Creator) - The University of Queensland
K.L. Williams (Author/Creator) - Macquarie University
M.M. Neto (Author/Creator) - Universidade de São Paulo
R.J. Cauchi (Author/Creator) - University of Malta
I.P. Blair (Author/Creator) - Macquarie University
M.C. Kiernan (Author/Creator) - The University of Sydney
V. Drory (Author/Creator) - Tel Aviv Sourasky Medical Center
M. Povedano (Author/Creator) - Bellvitge University Hospital
M. de Carvalho (Author/Creator) - Medicina
S. Pinto (Author/Creator) - Medicina
M. Weber (Author/Creator) - Kantonsspital St. Gallen
G.A. Rouleau (Author/Creator) - Montreal Neurological Institute and Hospital
V. Silani (Author/Creator) - IRCCS Istituto Auxologico Italiano
J.E. Landers (Author/Creator) - University of Massachusetts Chan Medical School
C.E. Shaw (Author/Creator) - King's College London
P.M. Andersen (Author/Creator) - Umeå University
A.F. McRae (Author/Creator) - The University of Queensland
M.A. van Es (Author/Creator) - University Medical Center Utrecht
R.J. Pasterkamp (Author/Creator) - University Medical Center Utrecht
N.R. Wray (Author/Creator) - The University of Queensland
R.L. McLaughlin (Author/Creator) - Trinity College Dublin
O. Hardiman (Author/Creator) - Trinity College Dublin
K.P. Kenna (Author/Creator) - University Medical Center Utrecht
E. Tsai (Author/Creator) - Biogen (United States)
H. Runz (Author/Creator) - Biogen (United States)
A. Al-Chalabi (Author/Creator) - King's College Hospital
L.H. van den Berg (Author/Creator) - University Medical Center Utrecht
P. Van Damme (Author/Creator) - KU Leuven
J. Mill (Author/Creator) - University of Exeter
J.H. Veldink (Author/Creator) - University Medical Center Utrecht
B.T. Heijmans (Author/Creator)
P.A.C. t Hoen (Author/Creator)
J. van Meurs (Author/Creator)
R. Jansen (Author/Creator)
L. Franke (Author/Creator)
D.I. Boomsma (Author/Creator)
R. Pool (Author/Creator)
J. van Dongen (Author/Creator)
J.J. Hottenga (Author/Creator)
M.M.J. van Greevenbroek (Author/Creator)
C.D.A. Stehouwer (Author/Creator)
C.J.H. van der Kallen (Author/Creator)
C.G. Schalkwijk (Author/Creator)
C. Wijmenga (Author/Creator)
L. Franke (Author/Creator)
S. Zhernakova (Author/Creator)
E.F. Tigchelaar (Author/Creator)
P.E. Slagboom (Author/Creator)
M. Beekman (Author/Creator)
J. Deelen (Author/Creator)
D. Van Heemst (Author/Creator)
J.H. Veldink (Author/Creator) - University Medical Center Utrecht
L.H. van den Berg (Author/Creator) - University Medical Center Utrecht
C.M. van Duijn (Author/Creator)
B.A. Hofman (Author/Creator)
A. Isaacs (Author/Creator)
A.G. Uitterlinden (Author/Creator)
J.B.C. van Meurs (Author/Creator)
P.M. Jhamai (Author/Creator)
M. Verbiest (Author/Creator)
H.E.D. Suchiman (Author/Creator)
M. Verkerk (Author/Creator)
R. van der Breggen (Author/Creator)
J. van Rooij (Author/Creator)
N. Lakenberg (Author/Creator)
H. Mei (Author/Creator)
M. van Iterson (Author/Creator)
M. van Galen (Author/Creator)
J. Bot (Author/Creator)
D.V. Zhernakova (Author/Creator)
R. Jansen (Author/Creator)
P. van ‘t Hof (Author/Creator)
P. Deelen (Author/Creator)
I. Nooren (Author/Creator)
P.A.C. t Hoen (Author/Creator)
B.T. Heijmans (Author/Creator)
M. Moed (Author/Creator)
L. Franke (Author/Creator)
M. Vermaat (Author/Creator)
D.V. Zhernakova (Author/Creator)
R. Luijk (Author/Creator)
M. Jan Bonder (Author/Creator)
M. van Iterson (Author/Creator)
P. Deelen (Author/Creator)
F. van Dijk (Author/Creator)
M. van Galen (Author/Creator)
W. Arindrarto (Author/Creator)
S.M. Kielbasa (Author/Creator)
M.A. Swertz (Author/Creator)
E.W. van Zwet (Author/Creator)
R. Jansen (Author/Creator)
P.A.C. Hoen (Author/Creator)
B.T. Heijmans (Author/Creator)
A. Al-Chalabi (Author/Creator) - King's College Hospital
N.R. Wray (Author/Creator) - The University of Queensland
G. Bensimon (Author/Creator)
O. Hardiman (Author/Creator) - Trinity College Dublin
A. Chio (Author/Creator) - Azienda Ospedaliera Citta' della Salute e della Scienza di Torino
J.H. Veldink (Author/Creator) - University Medical Center Utrecht
G.D. Smith (Author/Creator)
J. Mill (Author/Creator) - University of Exeter
Publication Details: Science Translational Medicine, Vol.14(633), Art. abj0264
Publisher: AAAS
Identifiers: 991005543189607891
Copyright: © 2022 American Association for the Advancement of Science.
Murdoch Affiliation: Institute for Immunology and Infectious Diseases
Language: English
Resource Type: Journal article

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Collaboration types: Industry collaboration; Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.52 Neurodegenerative Diseases; 1.52.765 ALS Mechanisms
Web Of Science research areas: Cell Biology; Medicine, Research & Experimental
ESI research areas: Biology & Biochemistry