Journal Article

DZNE-2022-01082

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Polygenic resilience modulates the penetrance of Parkinson's disease genetic risk factors.

Liu, H. (First author)DZNE* ; Dehestani, M.DZNE* ; Blauwendraat, C.Extern* ; Makarious, M. B. ; Leonard, H. L.Extern* ; Kim, J. J. ; Schulte, C.DZNE* ; Noyce, A. ; Jacobs, B. M. ; Foote, I. ; Sharma, M.DZNE* ; Consortium, I. P. D. G. (Collaboration Author) ; Genetics, C. U. R. f. A. f. ; Disease, E. i. P. (Collaboration Author) ; Nalls, M. ; Singleton, A. ; Gasser, T.DZNE* ; Bandres-Ciga, S.

2022
Wiley-Blackwell Hoboken, NJ

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Please use a persistent id in citations: doi:10.1002/ana.26416

Abstract: The aim of the current study is to understand why some individuals avoid developing Parkinson's disease (PD) in spite of being at relatively high genetic risk, using the largest datasets of individual-level genetic data available.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 (IPDGC, 7,204 PD cases and 9,412 controls) and validation cohorts (COURAGE-PD, 8,968 cases and 7,598 controls; UKBB, 2,639 PD cases and 14,301 controls; AMP-PD, 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, performed MAGMA gene-based analyses and functional enrichment analyses.A higher polygenic resilience score was associated with a lower risk for PD (Beta= -0.054, 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 potential pathway harboring resilience alleles that could mitigate the effects of PD risk loci.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. This article is protected by copyright. All rights reserved.

Keyword(s): Parkinson's disease ; genetics ; polygenic risk ; resilience

Note: CC BY-NC-ND

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Contributing Institute(s):

1. Parkinson Genetics (AG Gasser)
2. Tübingen common (Tübingen common)
3. Ext Hertie-Institut für klinische Hirnforschung (Ext HIH)

Research Program(s):

1. 353 - Clinical and Health Care Research (POF4-353) (POF4-353)

Appears in the scientific report 2022

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Database coverage:
; ; ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; DEAL Wiley ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 10 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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