Genome-wide study of DNA methylation shows alterations in metabolic, inflammatory, and cholesterol pathways in ALS
Paul Hop
,
Ramona Zwamborn
(1)
,
Eilis Hannon
,
Gemma Shireby
,
Marta Nabais
,
Emma Walker
,
Wouter van Rheenen
,
Joke van Vugt
(2)
,
Annelot Dekker
,
Henk-Jan Westeneng
,
Gijs Tazelaar
,
Kristel van Eijk
(1)
,
Matthieu Moisse
,
Denis Baird
,
Ahmad Al Khleifat
,
Alfredo Iacoangeli
(3, 4, 5)
,
Nicola Ticozzi
(6, 7)
,
Antonia Ratti
,
Jonathan Cooper-Knock
,
Karen Morrison
,
Pamela Shaw
(8)
,
a Nazli Basak
(9)
,
Adriano Chiò
(10)
,
Adriano Chio
(10, 11)
,
Andrea Calvo
,
Cristina Moglia
,
Antonio Canosa
,
Maura Brunetti
,
Maurizio Grassano
,
Marc Gotkine
,
Yossef Lerner
,
Michal Zabari
,
Patrick Vourc'H
(12, 13)
,
Philippe Corcia
(13)
,
Philippe Couratier
,
Jesus Mora Pardina
,
Teresa Salas
,
Patrick Dion
,
Jay Ross
,
Robert Henderson
,
Susan Mathers
,
Pamela Mccombe
,
Merrilee Needham
,
Garth Nicholson
,
Dominic Rowe
,
Roger Pamphlett
,
Karen Mather
,
Perminder Sachdev
,
Sarah Furlong
,
Fleur Garton
,
Anjali Henders
,
Tian Lin
,
Shyuan Ngo
,
Frederik Steyn
,
Leanne Wallace
,
Kelly Williams
,
Miguel Mitne Neto
,
Ruben Cauchi
,
Ian Blair
,
Matthew Kiernan
,
Vivian Drory
,
Monica Povedano
,
Mamede de Carvalho
,
Susana Pinto
,
Markus Weber
,
Guy Rouleau
,
Vincenzo Silani
,
John Landers
,
Christopher Shaw
,
Peter Andersen
,
Allan Mcrae
,
Michael van Es
,
R Jeroen Pasterkamp
,
Naomi Wray
,
Naomi Wray
,
Russell Mclaughlin
,
Orla Hardiman
,
Orla Hardiman
,
Kevin Kenna
,
Ellen Tsai
,
Heiko Runz
,
Ammar Al-Chalabi
,
Ammar Al-Chalabi
,
Leonard van den Berg
,
Leonard van den Berg
,
Philip van Damme
,
Jonathan Mill
,
Jonathan Mill
,
Jan Veldink
,
Jan Veldink
,
Jan Veldink
,
Ramona A.J. Zwamborn
,
Joke J.F.A. van Vugt
,
Gijs H.P. Tazelaar
,
A. Nazli Basak
,
Patrick Vourc’h
,
R. Jeroen Pasterkamp
,
Bastiaan Heijmans
,
Peter A.C. T Hoen
,
Joyce van Meurs
,
Rick Jansen
,
Lude Franke
,
Dorret Boomsma
,
Rene Pool
,
Jenny van Dongen
,
Joukje Hottenga
,
Marleen M.J. van Greevenbroek
,
Coen D.A. Stehouwer
,
Carla J.H. van der Kallen
,
Casper Schalkwijk
,
Cisca Wijmenga
,
Lude Franke
,
Sasha Zhernakova
,
Ettje Tigchelaar
,
P. Eline Slagboom
,
Marian Beekman
,
Joris Deelen
,
Diana van Heemst
,
Cornelia van Duijn
,
Bert Hofman
,
Aaron Isaacs
,
Andre Uitterlinden
,
Joyce van Meurs
,
P. Mila Jhamai
,
Michael Verbiest
,
H. Eka D. Suchiman
,
Marijn Verkerk
,
Ruud van der Breggen
,
Jeroen van Rooij
,
Nico Lakenberg
,
Hailiang Mei
,
Maarten van Iterson
,
Michiel van Galen
,
Jan Bot
,
Dasha Zhernakova
,
Rick Jansen
,
Patrick Deelen
,
Irene Nooren
,
Peter A.C. T Hoen
,
Bastiaan Heijmans
,
Matthijs Moed
,
Lude Franke
,
Martijn Vermaat
,
Dasha Zhernakova
,
Rene Luijk
,
Marc Jan Bonder
,
Maarten van Iterson
,
Patrick Deelen
,
Freerk van Dijk
,
Michiel van Galen
,
Wibowo Arindrarto
,
Szymon Kielbasa
,
Morris Swertz
,
Erik van Zwet
,
Rick Jansen
,
Peter A.C. T Hoen
,
Bastiaan Heijmans
,
Gilbert Bensimon
,
George Davey Smith
1
Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht
2 University Medical Center [Utrecht]
3 Maurice Wohl Clinical Neuroscience Institut
4 Institute of Psychiatry, Psychology & Neuroscience, King's College London
5 NIHR Biomedical Research Centre [London]
6 IAI - Istituto Auxologico Italiano IRCCS Ospedale San Luca [Milan, Italy]
7 Centro Dino Ferrari [Milano]
8 The Institute of Neuroscience [Sheffield]
9 Koç University
10 UNITO - Università degli studi di Torino = University of Turin
11 A.O.U - Città della Salute e della Scienza di Torino
12 Laboratoire de Biochimie [CHRU Tours]
13 iBraiN - Imaging, Brain & Neuropsychiatry
2 University Medical Center [Utrecht]
3 Maurice Wohl Clinical Neuroscience Institut
4 Institute of Psychiatry, Psychology & Neuroscience, King's College London
5 NIHR Biomedical Research Centre [London]
6 IAI - Istituto Auxologico Italiano IRCCS Ospedale San Luca [Milan, Italy]
7 Centro Dino Ferrari [Milano]
8 The Institute of Neuroscience [Sheffield]
9 Koç University
10 UNITO - Università degli studi di Torino = University of Turin
11 A.O.U - Città della Salute e della Scienza di Torino
12 Laboratoire de Biochimie [CHRU Tours]
13 iBraiN - Imaging, Brain & Neuropsychiatry
Paul Hop
- Function : Author
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Eilis Hannon
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Gemma Shireby
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Marta Nabais
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Emma Walker
- Function : Author
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Wouter van Rheenen
- Function : Author
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Annelot Dekker
- Function : Author
Henk-Jan Westeneng
- Function : Author
Gijs Tazelaar
- Function : Author
Matthieu Moisse
- Function : Author
- PersonId : 1215636
- ORCID : 0000-0001-8880-9311
Denis Baird
- Function : Author
Ahmad Al Khleifat
- Function : Author
Nicola Ticozzi
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Antonia Ratti
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Jonathan Cooper-Knock
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Karen Morrison
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Pamela Shaw
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Adriano Chiò
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Andrea Calvo
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Cristina Moglia
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Antonio Canosa
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Maura Brunetti
- Function : Author
Maurizio Grassano
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Marc Gotkine
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Yossef Lerner
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Michal Zabari
- Function : Author
Patrick Vourc'H
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Philippe Couratier
- Function : Author
Jesus Mora Pardina
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Teresa Salas
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Patrick Dion
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Jay Ross
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Robert Henderson
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Susan Mathers
- Function : Author
Pamela Mccombe
- Function : Author
Merrilee Needham
- Function : Author
Garth Nicholson
- Function : Author
Dominic Rowe
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Roger Pamphlett
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Karen Mather
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Perminder Sachdev
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- PersonId : 778032
- ORCID : 0000-0002-9595-3220
- IdRef : 076727041
Sarah Furlong
- Function : Author
Fleur Garton
- Function : Author
Anjali Henders
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- PersonId : 1215645
- ORCID : 0000-0003-3672-1451
Tian Lin
- Function : Author
Shyuan Ngo
- Function : Author
Frederik Steyn
- Function : Author
Leanne Wallace
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- ORCID : 0000-0003-4310-7572
Kelly Williams
- Function : Author
- PersonId : 1215615
- ORCID : 0000-0001-6319-9473
Miguel Mitne Neto
- Function : Author
Ruben Cauchi
- Function : Author
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- ORCID : 0000-0001-6150-1608
Ian Blair
- Function : Author
Matthew Kiernan
- Function : Author
- PersonId : 1215647
- ORCID : 0000-0001-9054-026X
Vivian Drory
- Function : Author
Monica Povedano
- Function : Author
Mamede de Carvalho
- Function : Author
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- ORCID : 0000-0001-7556-0158
Susana Pinto
- Function : Author
- PersonId : 1215648
- ORCID : 0000-0002-0727-5897
Markus Weber
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Guy Rouleau
- Function : Author
Vincenzo Silani
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John Landers
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Christopher Shaw
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Peter Andersen
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Allan Mcrae
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Michael van Es
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R Jeroen Pasterkamp
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Naomi Wray
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Naomi Wray
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Russell Mclaughlin
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Orla Hardiman
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Orla Hardiman
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Kevin Kenna
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Ellen Tsai
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Heiko Runz
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Ammar Al-Chalabi
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Ammar Al-Chalabi
- Function : Author
Leonard van den Berg
- Function : Author
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Leonard van den Berg
- Function : Author
Philip van Damme
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Jonathan Mill
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- ORCID : 0000-0003-1115-3224
Jonathan Mill
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Jan Veldink
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- PersonId : 802642
- ORCID : 0000-0001-5572-9657
Jan Veldink
- Function : Author
Jan Veldink
- Function : Author
Ramona A.J. Zwamborn
- Function : Author
- PersonId : 1215654
- ORCID : 0000-0003-3952-5042
Joke J.F.A. van Vugt
- Function : Author
- PersonId : 1215655
- ORCID : 0000-0002-4161-4004
Gijs H.P. Tazelaar
- Function : Author
A. Nazli Basak
- Function : Author
- PersonId : 1215656
- ORCID : 0000-0001-6977-2517
Patrick Vourc’h
- Function : Author
- PersonId : 1215657
- IdHAL : patrick-vourch
- ORCID : 0000-0001-7960-8139
R. Jeroen Pasterkamp
- Function : Author
Bastiaan Heijmans
- Function : Author
Peter A.C. T Hoen
- Function : Author
Joyce van Meurs
- Function : Author
Rick Jansen
- Function : Author
Lude Franke
- Function : Author
Dorret Boomsma
- Function : Author
Rene Pool
- Function : Author
Jenny van Dongen
- Function : Author
Joukje Hottenga
- Function : Author
Marleen M.J. van Greevenbroek
- Function : Author
Coen D.A. Stehouwer
- Function : Author
Carla J.H. van der Kallen
- Function : Author
Casper Schalkwijk
- Function : Author
Cisca Wijmenga
- Function : Author
Lude Franke
- Function : Author
Sasha Zhernakova
- Function : Author
Ettje Tigchelaar
- Function : Author
P. Eline Slagboom
- Function : Author
Marian Beekman
- Function : Author
Joris Deelen
- Function : Author
Diana van Heemst
- Function : Author
Cornelia van Duijn
- Function : Author
Bert Hofman
- Function : Author
Aaron Isaacs
- Function : Author
Andre Uitterlinden
- Function : Author
Joyce van Meurs
- Function : Author
P. Mila Jhamai
- Function : Author
Michael Verbiest
- Function : Author
H. Eka D. Suchiman
- Function : Author
Marijn Verkerk
- Function : Author
Ruud van der Breggen
- Function : Author
Jeroen van Rooij
- Function : Author
Nico Lakenberg
- Function : Author
Hailiang Mei
- Function : Author
Maarten van Iterson
- Function : Author
Michiel van Galen
- Function : Author
Jan Bot
- Function : Author
Dasha Zhernakova
- Function : Author
Rick Jansen
- Function : Author
Patrick Deelen
- Function : Author
Irene Nooren
- Function : Author
Peter A.C. T Hoen
- Function : Author
Bastiaan Heijmans
- Function : Author
Matthijs Moed
- Function : Author
Lude Franke
- Function : Author
Martijn Vermaat
- Function : Author
Dasha Zhernakova
- Function : Author
Rene Luijk
- Function : Author
Marc Jan Bonder
- Function : Author
Maarten van Iterson
- Function : Author
Patrick Deelen
- Function : Author
Freerk van Dijk
- Function : Author
Michiel van Galen
- Function : Author
Wibowo Arindrarto
- Function : Author
Szymon Kielbasa
- Function : Author
Morris Swertz
- Function : Author
Erik van Zwet
- Function : Author
Rick Jansen
- Function : Author
Peter A.C. T Hoen
- Function : Author
Bastiaan Heijmans
- Function : Author
Gilbert Bensimon
- Function : Author
George Davey Smith
- Function : Author
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.
Domains
Life Sciences [q-bio]
Origin : Files produced by the author(s)