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Polygenic Resilienc...
Polygenic Resilience Modulates the Penetrance of Parkinson Disease Genetic Risk Factors
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- Liu, Hui (author)
- University of Tübingen
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Dehestani, Mohammad (author)
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- Blauwendraat, Cornelis (author)
- National Institute on Aging, United States
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- Makarious, Mary B (author)
- National Institute on Aging, United States
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- Leonard, Hampton (author)
- Data Tecnica International
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- Kim, Jonggeol J (author)
- National Institute on Aging, United States
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Schulte, Claudia (author)
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- Noyce, Alastair (author)
- Queen Mary University
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- Jacobs, Benjamin M (author)
- Queen Mary University
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- Foote, Isabelle (author)
- Queen Mary University
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Sharma, Manu (author)
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- Nalls, Mike (author)
- National Health Research Institutes Taiwan (NHRI)
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- Singleton, Andrew (author)
- National Institute on Aging, United States
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Gasser, Thomas (author)
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- Bandres-Ciga, Sara (author)
- National Institute on Aging, United States
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- Puschmann, Andreas (creator_code:cre_t)
- Lund University,Lunds universitet,Neurologi, Lund,Sektion IV,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Klinisk neurogenetik,Forskargrupper vid Lunds universitet,Neurology, Lund,Section IV,Department of Clinical Sciences, Lund,Faculty of Medicine,Clinical Neurogenetics,Lund University Research Groups
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(creator_code:org_t)
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- 2022-06-24
- 2022
- English.
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In: Annals of Neurology. - : Wiley. - 1531-8249 .- 0364-5134. ; 92:2, s. 270-278
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Abstract
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- OBJECTIVE: The aim of the current study is to understand why some individuals avoid developing Parkinson disease (PD) despite being at relatively high genetic risk, using the largest datasets of individual-level genetic data available.METHODS: We calculated polygenic risk score to identify controls and matched PD cases with the highest burden of genetic risk for PD in the discovery cohort (International Parkinson's Disease Genomics Consortium, 7,204 PD cases and 9,412 controls) and validation cohorts (Comprehensive Unbiased Risk Factor Assessment for Genetics and Environment in Parkinson's Disease, 8,968 cases and 7,598 controls; UK Biobank, 2,639 PD cases and 14,301 controls; Accelerating Medicines Partnership-Parkinson's Disease Initiative, 2,248 cases and 2,817 controls). A genome-wide association study meta-analysis was performed on these individuals to understand genetic variation associated with resistance to disease. We further constructed a polygenic resilience score, and performed multimarker analysis of genomic annotation (MAGMA) gene-based analyses and functional enrichment analyses.RESULTS: A higher polygenic resilience score was associated with a lower risk for PD (β = -0.054, standard error [SE] = 0.022, p = 0.013). Although no single locus reached genome-wide significance, MAGMA gene-based analyses nominated TBCA as a putative gene. Furthermore, we estimated the narrow-sense heritability associated with resilience to PD (h2 = 0.081, SE = 0.035, p = 0.0003). Subsequent functional enrichment analysis highlighted histone methylation as a potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci.INTERPRETATION: The present study represents a novel and comprehensive assessment of heritable genetic variation contributing to PD resistance. We show that a genetic resilience score can modify the penetrance of PD genetic risk factors and therefore protect individuals carrying a high-risk genetic burden from developing PD. ANN NEUROL 2022;92:270-278.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Neurosciences (hsv//eng)
Keyword
- Genetic Predisposition to Disease/genetics
- Genome-Wide Association Study
- Humans
- Parkinson Disease/genetics
- Penetrance
- Polymorphism, Single Nucleotide
- Risk Factors
Publication and Content Type
- art (subject category)
- ref (subject category)
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- By the author/editor
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Liu, Hui
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Dehestani, Moham ...
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Blauwendraat, Co ...
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Makarious, Mary ...
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Leonard, Hampton
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Kim, Jonggeol J
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Schulte, Claudia
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Noyce, Alastair
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Jacobs, Benjamin ...
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Foote, Isabelle
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Sharma, Manu
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Nalls, Mike
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Singleton, Andre ...
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Gasser, Thomas
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Bandres-Ciga, Sa ...
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Puschmann, Andre ...
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- About the subject
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- MEDICAL AND HEALTH SCIENCES
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MEDICAL AND HEAL ...
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and Basic Medicine
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and Neurosciences
- Articles in the publication
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Annals of Neurol ...
- By the university
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Lund University
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Karolinska Institutet