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Summary-Based Methylome-Wide Association Analyses Suggest Potential Genetically Driven Epigenetic Heterogeneity of Alzheimer’s Disease

Biodemography of Aging Research Unit, Social Science Research Institute, Duke University, Durham, NC 27705, USA
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J. Clin. Med. 2020, 9(5), 1489; https://doi.org/10.3390/jcm9051489
Received: 14 February 2020 / Revised: 30 April 2020 / Accepted: 13 May 2020 / Published: 15 May 2020
(This article belongs to the Section Psychiatry)
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder with no curative treatment available. Exploring the genetic and non-genetic contributors to AD pathogenesis is essential to better understand its underlying biological mechanisms, and to develop novel preventive and therapeutic strategies. We investigated potential genetically driven epigenetic heterogeneity of AD through summary data-based Mendelian randomization (SMR), which combined results from our previous genome-wide association analyses with those from two publicly available methylation quantitative trait loci studies of blood and brain tissue samples. We found that 152 probes corresponding to 113 genes were epigenetically associated with AD at a Bonferroni-adjusted significance level of 5.49E-07. Of these, 10 genes had significant probes in both brain-specific and blood-based analyses. Comparing males vs. females and hypertensive vs. non-hypertensive subjects, we found that 22 and 79 probes had group-specific associations with AD, respectively, suggesting a potential role for such epigenetic modifications in the heterogeneous nature of AD. Our analyses provided stronger evidence for possible roles of four genes (i.e., AIM2, C16orf80, DGUOK, and ST14) in AD pathogenesis as they were also transcriptionally associated with AD. The identified associations suggest a list of prioritized genes for follow-up functional studies and advance our understanding of AD pathogenesis. View Full-Text
Keywords: neurodegenerative diseases; dementia; aging; GWAS; mQTLs; eQTLs; Alzheimer’s disease; Alzheimer’s disease pathogenesis; methylome-wide association analyses; summary data-based mendelian randomization neurodegenerative diseases; dementia; aging; GWAS; mQTLs; eQTLs; Alzheimer’s disease; Alzheimer’s disease pathogenesis; methylome-wide association analyses; summary data-based mendelian randomization
MDPI and ACS Style

Nazarian, A.; Yashin, A.I.; Kulminski, A.M. Summary-Based Methylome-Wide Association Analyses Suggest Potential Genetically Driven Epigenetic Heterogeneity of Alzheimer’s Disease. J. Clin. Med. 2020, 9, 1489. https://doi.org/10.3390/jcm9051489

AMA Style

Nazarian A, Yashin AI, Kulminski AM. Summary-Based Methylome-Wide Association Analyses Suggest Potential Genetically Driven Epigenetic Heterogeneity of Alzheimer’s Disease. Journal of Clinical Medicine. 2020; 9(5):1489. https://doi.org/10.3390/jcm9051489

Chicago/Turabian Style

Nazarian, Alireza; Yashin, Anatoliy I.; Kulminski, Alexander M. 2020. "Summary-Based Methylome-Wide Association Analyses Suggest Potential Genetically Driven Epigenetic Heterogeneity of Alzheimer’s Disease" J. Clin. Med. 9, no. 5: 1489. https://doi.org/10.3390/jcm9051489

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