Epigenomic and clinical analyses of striatal DAT binding in healthy individuals reveal well-known loci of Parkinson's disease
Background: Striatal dopamine transporter (DAT) binding is a sensitive and specific endophenotype for detecting dopaminergic deficits across Parkinson's disease (PD) spectrum. Molecular and clinical signatures of PD in asymptomatic phases help understand the earliest pathophysiological mechanis...
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Elsevier
2024-12-01
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| author | Arash Yaghoobi Homa Seyedmirzaei Marzie Jamaat Moein Ala |
| author_facet | Arash Yaghoobi Homa Seyedmirzaei Marzie Jamaat Moein Ala |
| author_sort | Arash Yaghoobi |
| collection | DOAJ |
| description | Background: Striatal dopamine transporter (DAT) binding is a sensitive and specific endophenotype for detecting dopaminergic deficits across Parkinson's disease (PD) spectrum. Molecular and clinical signatures of PD in asymptomatic phases help understand the earliest pathophysiological mechanisms underlying the disease. We aimed to investigate whether blood epigenetic markers are associated with inter-individual variation of striatal DAT binding among healthy elderly individuals. We also investigated whether this potential inter-individual variation can manifest as dysfunction of particular cognitive domains. Omics studies conducted on endophenotypes of PD among healthy asymptomatic individuals can provide invaluable insights into early detection, disease mechanisms, and potential therapeutic targets for PD. Method: We conducted a blood epigenome-wide association study of striatal DAT binding on 96 healthy individuals using the Illumina EPIC array. For functional annotation of our top results, we employed the enhancer-gene mapping strategy using a midbrain single-nucleus multimodal dataset. Finally, we conducted several investigative regression analyses on several neuropsychological tests across five cognitive domains to assess their association with striatal DAT binding among 250 healthy subjects. Results: We identified seven suggestive (P-value<10−5) CpG probes. Specifically, three probes were colocalized with three risk loci previously identified in PD's largest Genome-Wide Association Study (GWAS). UCN5A and APOE loci were identified as suggestive DMRs associated with striatal DAT binding. Functional analyses prioritized the FDFT1 gene as the potential target gene in the previously reported CTSB GWAS locus. We also showed that delayed recall memory impairment was correlated with reduced striatal DAT binding, irrespective of age. Conclusion: Our study suggested epigenetic and cognitive signatures of striatal DAT binding among healthy individuals, providing valuable insights for future experimental and clinical studies of early PD. |
| format | Article |
| id | doaj-art-6bc217d29b9a44699b6c7bb791c5fde8 |
| institution | OA Journals |
| issn | 2405-8440 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
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| series | Heliyon |
| spelling | doaj-art-6bc217d29b9a44699b6c7bb791c5fde82025-08-20T01:59:38ZengElsevierHeliyon2405-84402024-12-011023e4061810.1016/j.heliyon.2024.e40618Epigenomic and clinical analyses of striatal DAT binding in healthy individuals reveal well-known loci of Parkinson's diseaseArash Yaghoobi0Homa Seyedmirzaei1Marzie Jamaat2Moein Ala3School of Biological Sciences, Institute for Research in Fundamental Sciences (IPM), Tehran, 19395-5746, IranSports Medicine Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, IranIslamic Azad University, Tehran North Branch, Faculty of Biological Sciences, Tehran, IranExperimental Research Center, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Corresponding author. School of Medicine, Tehran University of Medical Sciences (TUMS), Tehran, Iran.Background: Striatal dopamine transporter (DAT) binding is a sensitive and specific endophenotype for detecting dopaminergic deficits across Parkinson's disease (PD) spectrum. Molecular and clinical signatures of PD in asymptomatic phases help understand the earliest pathophysiological mechanisms underlying the disease. We aimed to investigate whether blood epigenetic markers are associated with inter-individual variation of striatal DAT binding among healthy elderly individuals. We also investigated whether this potential inter-individual variation can manifest as dysfunction of particular cognitive domains. Omics studies conducted on endophenotypes of PD among healthy asymptomatic individuals can provide invaluable insights into early detection, disease mechanisms, and potential therapeutic targets for PD. Method: We conducted a blood epigenome-wide association study of striatal DAT binding on 96 healthy individuals using the Illumina EPIC array. For functional annotation of our top results, we employed the enhancer-gene mapping strategy using a midbrain single-nucleus multimodal dataset. Finally, we conducted several investigative regression analyses on several neuropsychological tests across five cognitive domains to assess their association with striatal DAT binding among 250 healthy subjects. Results: We identified seven suggestive (P-value<10−5) CpG probes. Specifically, three probes were colocalized with three risk loci previously identified in PD's largest Genome-Wide Association Study (GWAS). UCN5A and APOE loci were identified as suggestive DMRs associated with striatal DAT binding. Functional analyses prioritized the FDFT1 gene as the potential target gene in the previously reported CTSB GWAS locus. We also showed that delayed recall memory impairment was correlated with reduced striatal DAT binding, irrespective of age. Conclusion: Our study suggested epigenetic and cognitive signatures of striatal DAT binding among healthy individuals, providing valuable insights for future experimental and clinical studies of early PD.http://www.sciencedirect.com/science/article/pii/S2405844024166492DAT scanParkinson's diseaseEpigenome-wide association studyCognitive domainsHealthy individuals |
| spellingShingle | Arash Yaghoobi Homa Seyedmirzaei Marzie Jamaat Moein Ala Epigenomic and clinical analyses of striatal DAT binding in healthy individuals reveal well-known loci of Parkinson's disease Heliyon DAT scan Parkinson's disease Epigenome-wide association study Cognitive domains Healthy individuals |
| title | Epigenomic and clinical analyses of striatal DAT binding in healthy individuals reveal well-known loci of Parkinson's disease |
| title_full | Epigenomic and clinical analyses of striatal DAT binding in healthy individuals reveal well-known loci of Parkinson's disease |
| title_fullStr | Epigenomic and clinical analyses of striatal DAT binding in healthy individuals reveal well-known loci of Parkinson's disease |
| title_full_unstemmed | Epigenomic and clinical analyses of striatal DAT binding in healthy individuals reveal well-known loci of Parkinson's disease |
| title_short | Epigenomic and clinical analyses of striatal DAT binding in healthy individuals reveal well-known loci of Parkinson's disease |
| title_sort | epigenomic and clinical analyses of striatal dat binding in healthy individuals reveal well known loci of parkinson s disease |
| topic | DAT scan Parkinson's disease Epigenome-wide association study Cognitive domains Healthy individuals |
| url | http://www.sciencedirect.com/science/article/pii/S2405844024166492 |
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