Penetrance of Parkinson’s disease in <i>LRRK2</i> p.G2019S carriers is modified by a polygenic risk score

Iwaki, Hirotaka; Blauwendraat, Cornelis; Makarious, Mary B; Bandrés‐Ciga, Sara; Leonard, Hampton; Gibbs, J. Raphael; Hernandez, Dena G.; Scholz, Sonja W.; Faghri, Faraz; Nalls, Mike A.; Singleton, Andrew B.

doi:10.1101/738260

Cited by 25 publications

(32 citation statements)

References 23 publications

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“…there are many genetic variants each with a small effect that collectively have a significant effect on the risk of PD in LRRK2 mutation carriers. This result is in line with the recent analysis of Iwaki et al 57 In that study, a PRS was derived using 89 genome-wide significant variants (some of which were also included in our PRS) identified in a PD GWAS of Nalls et al 4 . Iwaki et al found that the PRS was significantly associated with the penetrance of the LRRK2 G2019S mutation.…”

Section: Discussionsupporting

confidence: 88%

Genome-wide association studies of LRRK2 modifiers of Parkinson's disease

Lai

Alipanahi

Fontanillas

et al. 2020

Preprint

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Objective: The aim of this study was to search for genes/variants that modify the effect of LRRK2 mutations in terms of penetrance and age-at-onset of Parkinson's disease. Methods: We performed the first genome-wide association study of penetrance and age-at-onset of Parkinson's disease in LRRK2 mutation carriers (776 cases and 1,103 non-cases at their last evaluation). Cox proportional hazard models and linear mixed models were used to identify modifiers of penetrance and age-at-onset of LRRK2 mutations, respectively. We also investigated whether a polygenic risk score derived from a published genome-wide association study of Parkinson's disease was able to explain variability in penetrance and age-at-onset in LRRK2 mutation carriers. Results: A variant located in the intronic region of CORO1C on chromosome 12 (rs77395454; P-value=2.5E-08, beta=1.27, SE=0.23, risk allele: C) met genome-wide significance for the penetrance model. A region on chromosome 3, within a previously reported linkage peak for Parkinson's disease susceptibility, showed suggestive associations in both models (penetrance top variant: P-value=1.1E-07; age-at-onset top variant: P-value=9.3E-07). A polygenic risk score derived from publicly available Parkinson's disease summary statistics was a significant predictor of penetrance, but not of age-at-onset. Interpretation: This study suggests that variants within or near CORO1C may modify the penetrance of LRRK2 mutations. In addition, common Parkinson's disease associated variants collectively increase the penetrance of LRRK2 mutations.

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Section: Discussionsupporting

confidence: 88%

Genome-wide association studies of LRRK2 modifiers of Parkinson's disease

Lai

Alipanahi

Fontanillas

et al. 2020

Preprint

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“…Because AAO genetic modifiers have been nominated for LRRK2 + /PD + , effect sizes have been small and ethnicity/populations seem to play a role. 11,[15][16][17][18] This study establishes a connection between environmental and lifestyle factors that adds to the complexity in LRRK2 + /PD + .…”

Section: Discussionmentioning

confidence: 59%

Age at Onset ofLRRK2p.Gly2019SerIs Related to Environmental and Lifestyle Factors

et al. 2020

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The effect of environmental and lifestyle factors on patients with LRRK2 (leucine-rich repeat kinase 2) p.Gly2019Ser (LRRK2 + / PD +) compared to idiopathic PD (iPD) has yet to be thoroughly investigated. Methods: In a homogeneous Tunisian Arab Berber population, we recruited 200 idiopathic PD and 199 LRRK2 p.Gly2019Ser mutation carriers, of whom 142 had PD (LRRK2 + /PD +) and 57 were unaffected (LRRK2 + /PD −). Case report form (CRF) questionnaires (motor and non-motor symptoms) including the Geoparkinson Questionnaire were used to assess environmental and lifestyle factors. Results: In LRRK2 + /PD + , tobacco use was significantly associated with a later median age at onset (AAO). The median AAO was 60 years (interquartile range = 52-67.25) for tobacco users, compared to 52 years (interquartile range = 45.25-61) for non-users (P = 0.0042 at adjusted α = 0.025). Additionally, we observed an independent but additive effect of black tea consumption and tobacco use. Conclusions: Our data suggest that tobacco and black tea have a protective effect on age at onset in LRRK2 + /PD + .

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“…All GWAS loci and summary statistics were gathered from our recent PD GWAS studies. [2][3][4][5]14,15 We selected all genes 1 megabase (Mb) up and downstream of each significant variant from the hg19 reference genome. 16 Genes in this 2-Mb range were included in locus zoom plots created for each variant.…”

Section: Gwas Loci and Gene Selectionmentioning

confidence: 99%

The Parkinson's Disease Genome‐Wide Association Study Locus Browser

et al. 2020

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Background Parkinson's disease (PD) is a neurodegenerative disease with an often complex component identifiable by genome‐wide association studies. The most recent large‐scale PD genome‐wide association studies have identified more than 90 independent risk variants for PD risk and progression across more than 80 genomic regions. One major challenge in current genomics is the identification of the causal gene(s) and variant(s) at each genome‐wide association study locus. The objective of the current study was to create a tool that would display data for relevant PD risk loci and provide guidance with the prioritization of causal genes and potential mechanisms at each locus. Methods We included all significant genome‐wide signals from multiple recent PD genome‐wide association studies including themost recent PD risk genome‐wide association study, age‐at‐onset genome‐wide association study, progression genome‐wide association study, and Asian population PD risk genome‐wide association study. We gathered data for all genes 1 Mb up and downstream of each variant to allow users to assess which gene(s) are most associated with the variant of interest based on a set of self‐ranked criteria. Multiple databases were queried for each gene to collect additional causal data. Results We created a PD genome‐wide association study browser tool ( https://pdgenetics.shinyapps.io/GWASBrowser/ ) to assist the PD research community with the prioritization of genes for follow‐up functional studies to identify potential therapeutic targets. Conclusions Our PD genome‐wide association study browser tool provides users with a useful method of identifying potential causal genes at all known PD risk loci from large‐scale PD genome‐wide association studies. We plan to update this tool with new relevant data as sample sizes increase and new PD risk loci are discovered. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. This article has been contributed to by US Government employees and their work is in the public domain in the USA.

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Penetrance of Parkinson’s disease in LRRK2 p.G2019S carriers is modified by a polygenic risk score

Cited by 25 publications

References 23 publications

Genome-wide association studies of LRRK2 modifiers of Parkinson's disease

Genome-wide association studies of LRRK2 modifiers of Parkinson's disease

Age at Onset ofLRRK2p.Gly2019SerIs Related to Environmental and Lifestyle Factors

The Parkinson's Disease Genome‐Wide Association Study Locus Browser

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