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

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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.

Originele taal-2	Engels
Pagina's (van-tot)	4932
Tijdschrift	Nature Communications
Volume	13
Nummer van het tijdschrift	1
DOI's	https://doi.org/10.1038/s41467-022-32619-z
Status	Gepubliceerd - 22 aug. 2022

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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), 4932. https://doi.org/10.1038/s41467-022-32619-z

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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 = "{\textcopyright} 2022. The Author(s).",

year = "2022",

month = aug,

day = "22",

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

language = "English",

volume = "13",

pages = "4932",

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, nr. 1, blz. 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

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

C2 - 35995800

SN - 2041-1723

VL - 13

SP - 4932

JO - Nature Communications

JF - Nature Communications

IS - 1

ER -

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

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