Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology

Lasse Pihlstrøm; Gemma Shireby; Hanneke Geut; Sandra Pilar Henriksen; Annemieke J M Rozemuller; Jon-Anders Tunold; Eilis Hannon; Paul Francis; Alan J Thomas; Seth Love; Jonathan Mill; Wilma D J van de Berg; Mathias Toft

doi:10.1038/s41467-022-32619-z

Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology

Lasse Pihlstrøm^*
, Gemma Shireby
, Hanneke Geut
, Sandra Pilar Henriksen
, Annemieke J M Rozemuller
, Jon-Anders Tunold
, Eilis Hannon
, Paul Francis
, Alan J Thomas
, Seth Love
, Jonathan Mill
, Wilma D J van de Berg
, Mathias Toft

^*Corresponding author for this work

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

28 Citations (Scopus)

53 Downloads (Pure)

Abstract

Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2, SFMBT2, AKAP6 and PHYHIP. Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.

Original language	English
Article number	4932
Number of pages	10
Journal	Nature Communications
Volume	13
Issue number	1
DOIs	https://doi.org/10.1038/s41467-022-32619-z
Publication status	Published - 22 Aug 2022

Bibliographical note

Funding Information:
The study was funded by the Norwegian Health Association (grant 4799, L.P.) and the Research Council of Norway (grant 250597, M.T.). L.P. and M.T. also received additional funding from the South-Eastern Regional Health Authority, Norway, the Norwegian Parkinson Research Fund and Reberg’s Legacy. W.D.J.v.d.B. received funding from the Dutch Parkinson association, Health Holland, and Rotary Club Aalsmeer-Uithoorn. The authors are grateful to the Netherlands Brain Bank and its funders for providing the samples that made the study possible. The Brains for Dementia Research cohort, including the generation of DNA methylation data, is jointly funded by the UK Alzheimer’s Society and Alzheimer’s Research UK.

Funding Information:
The study was funded by the Norwegian Health Association (grant 4799, L.P.) and the Research Council of Norway (grant 250597, M.T.). L.P. and M.T. also received additional funding from the South-Eastern Regional Health Authority, Norway, the Norwegian Parkinson Research Fund and Reberg’s Legacy. W.D.J.v.d.B. received funding from the Dutch Parkinson association, Health Holland, and Rotary Club Aalsmeer-Uithoorn. The authors are grateful to the Netherlands Brain Bank and its funders for providing the samples that made the study possible. The Brains for Dementia Research cohort, including the generation of DNA methylation data, is jointly funded by the UK Alzheimer’s Society and Alzheimer’s Research UK.

Publisher Copyright:
© 2022, The Author(s).

Research Groups and Themes

Cerebrovascular and Dementia Research Group

Keywords

Epigenome
Frontal Lobe/pathology
Humans
Lewy Bodies/metabolism
Lewy Body Disease/genetics
Methylation
Parkinson Disease/genetics
alpha-Synuclein/genetics

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Pihlstrøm, L., Shireby, G., Geut, H., Henriksen, S. P., Rozemuller, A. J. M., Tunold, J.-A., Hannon, E., Francis, P., Thomas, A. J., Love, S., Mill, J., van de Berg, W. D. J., & Toft, M. (2022). Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology. Nature Communications, 13(1), Article 4932. https://doi.org/10.1038/s41467-022-32619-z

@article{28329172588d4cd5aebd5c51e7305cc4,

title = "Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology",

abstract = "Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2, SFMBT2, AKAP6 and PHYHIP. Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.",

keywords = "Epigenome, Frontal Lobe/pathology, Humans, Lewy Bodies/metabolism, Lewy Body Disease/genetics, Methylation, Parkinson Disease/genetics, alpha-Synuclein/genetics",

author = "Lasse Pihlstr{\o}m and Gemma Shireby and Hanneke Geut and Henriksen, \{Sandra Pilar\} and Rozemuller, \{Annemieke J M\} and Jon-Anders Tunold and Eilis Hannon and Paul Francis and Thomas, \{Alan J\} and Seth Love and Jonathan Mill and \{van de Berg\}, \{Wilma D J\} and Mathias Toft",

note = "Funding Information: The study was funded by the Norwegian Health Association (grant 4799, L.P.) and the Research Council of Norway (grant 250597, M.T.). L.P. and M.T. also received additional funding from the South-Eastern Regional Health Authority, Norway, the Norwegian Parkinson Research Fund and Reberg{\textquoteright}s Legacy. W.D.J.v.d.B. received funding from the Dutch Parkinson association, Health Holland, and Rotary Club Aalsmeer-Uithoorn. The authors are grateful to the Netherlands Brain Bank and its funders for providing the samples that made the study possible. The Brains for Dementia Research cohort, including the generation of DNA methylation data, is jointly funded by the UK Alzheimer{\textquoteright}s Society and Alzheimer{\textquoteright}s Research UK. Funding Information: The study was funded by the Norwegian Health Association (grant 4799, L.P.) and the Research Council of Norway (grant 250597, M.T.). L.P. and M.T. also received additional funding from the South-Eastern Regional Health Authority, Norway, the Norwegian Parkinson Research Fund and Reberg{\textquoteright}s Legacy. W.D.J.v.d.B. received funding from the Dutch Parkinson association, Health Holland, and Rotary Club Aalsmeer-Uithoorn. The authors are grateful to the Netherlands Brain Bank and its funders for providing the samples that made the study possible. The Brains for Dementia Research cohort, including the generation of DNA methylation data, is jointly funded by the UK Alzheimer{\textquoteright}s Society and Alzheimer{\textquoteright}s Research UK. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = aug,

day = "22",

doi = "10.1038/s41467-022-32619-z",

language = "English",

volume = "13",

journal = "Nature Communications",

issn = "2041-1723",

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Pihlstrøm, L, Shireby, G, Geut, H, Henriksen, SP, Rozemuller, AJM, Tunold, J-A, Hannon, E, Francis, P, Thomas, AJ, Love, S, Mill, J, van de Berg, WDJ & Toft, M 2022, 'Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology', Nature Communications, vol. 13, no. 1, 4932. https://doi.org/10.1038/s41467-022-32619-z

TY - JOUR

T1 - Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology

AU - Pihlstrøm, Lasse

AU - Shireby, Gemma

AU - Geut, Hanneke

AU - Henriksen, Sandra Pilar

AU - Rozemuller, Annemieke J M

AU - Tunold, Jon-Anders

AU - Hannon, Eilis

AU - Francis, Paul

AU - Thomas, Alan J

AU - Love, Seth

AU - Mill, Jonathan

AU - van de Berg, Wilma D J

AU - Toft, Mathias

N1 - Funding Information: The study was funded by the Norwegian Health Association (grant 4799, L.P.) and the Research Council of Norway (grant 250597, M.T.). L.P. and M.T. also received additional funding from the South-Eastern Regional Health Authority, Norway, the Norwegian Parkinson Research Fund and Reberg’s Legacy. W.D.J.v.d.B. received funding from the Dutch Parkinson association, Health Holland, and Rotary Club Aalsmeer-Uithoorn. The authors are grateful to the Netherlands Brain Bank and its funders for providing the samples that made the study possible. The Brains for Dementia Research cohort, including the generation of DNA methylation data, is jointly funded by the UK Alzheimer’s Society and Alzheimer’s Research UK. Funding Information: The study was funded by the Norwegian Health Association (grant 4799, L.P.) and the Research Council of Norway (grant 250597, M.T.). L.P. and M.T. also received additional funding from the South-Eastern Regional Health Authority, Norway, the Norwegian Parkinson Research Fund and Reberg’s Legacy. W.D.J.v.d.B. received funding from the Dutch Parkinson association, Health Holland, and Rotary Club Aalsmeer-Uithoorn. The authors are grateful to the Netherlands Brain Bank and its funders for providing the samples that made the study possible. The Brains for Dementia Research cohort, including the generation of DNA methylation data, is jointly funded by the UK Alzheimer’s Society and Alzheimer’s Research UK. Publisher Copyright: © 2022, The Author(s).

PY - 2022/8/22

Y1 - 2022/8/22

N2 - Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2, SFMBT2, AKAP6 and PHYHIP. Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.

AB - Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are closely related progressive disorders with no available disease-modifying therapy, neuropathologically characterized by intraneuronal aggregates of misfolded α-synuclein. To explore the role of DNA methylation changes in PD and DLB pathogenesis, we performed an epigenome-wide association study (EWAS) of 322 postmortem frontal cortex samples and replicated results in an independent set of 200 donors. We report novel differentially methylated replicating loci associated with Braak Lewy body stage near TMCC2, SFMBT2, AKAP6 and PHYHIP. Differentially methylated probes were independent of known PD genetic risk alleles. Meta-analysis provided suggestive evidence for a differentially methylated locus within the chromosomal region affected by the PD-associated 22q11.2 deletion. Our findings elucidate novel disease pathways in PD and DLB and generate hypotheses for future molecular studies of Lewy body pathology.

KW - Epigenome

KW - Frontal Lobe/pathology

KW - Humans

KW - Lewy Bodies/metabolism

KW - Lewy Body Disease/genetics

KW - Methylation

KW - Parkinson Disease/genetics

KW - alpha-Synuclein/genetics

U2 - 10.1038/s41467-022-32619-z

DO - 10.1038/s41467-022-32619-z

M3 - Article (Academic Journal)

C2 - 35995800

SN - 2041-1723

VL - 13

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4932

ER -

Epigenome-wide association study of human frontal cortex identifies differential methylation in Lewy body pathology

Abstract

Bibliographical note

Research Groups and Themes

Keywords

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