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 - 2022/12
Y1 - 2022/12
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.
UR - http://www.scopus.com/inward/record.url?scp=85136238080&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-022-32619-z
DO - https://doi.org/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
M1 - 4932
ER -