Common X-chromosome variants are associated with Parkinson’s disease risk

Guen, Yann Le; Napolioni, Valerio; Belloy, Michaël E.; Yu, Eric; Krohn, Lynne; Ruskey, Jennifer A.; Gan‐Or, Ziv; Kennedy, Gabriel; Eger, Sarah J.; Greicius, Michael D.

doi:10.1101/2020.12.18.20248459

Cited by 4 publications

(2 citation statements)

References 55 publications

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“…Nevertheless, it should also be noted that EMMAX is known to produce conservative P -values ( Zhou and Stephens 2012 ). In addition to PRNP , an investigation of nominally significant SNPs ( P -value ≤ 5E-05) revealed positional candidate genes previously implicated in aspects of prion disease ( TPH2 ; PDE4DIP ), including scrapie ( ACSL4 ), regulation of the central nervous system ( ADGRB3 ), neuroprotection ( EN1 ), Alzheimer’s ( ASCL1 , AMOTL2 , RYK ), and Parkinson’s disease ( EN1 , ASCL1 , RTL9 ) ( Ide et al 2005 ; Roffé et al 2010 ; Filali et al 2014 ; Nishizawa et al 2014 ; Alleaume-Butaux et al 2015 ; Rekaik et al 2015 ; Dunn et al 2019 ; Meyer et al 2019 ; Scuderi et al 2019 ; Feng et al 2020 ; Gallart-Palau et al 2020 ; Le Guen et al 2020 ). Additional missense variants encoded by PRNP codons 37, 95, and 226 did not meet the nominal significance level ( P -value ≤ 5E-05) for polygenic traits ( Wellcome Trust Case Control Consortium 2007 ; Neibergs et al 2014 ; Seabury et al 2017 , 2020 ).…”

Section: Resultsmentioning

confidence: 99%

Genotype by environment interactions for chronic wasting disease in farmed US white-tailed deer

Seabury

Lockwood

Nichols³

2022

G3 Genes|Genomes|Genetics

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Despite implementation of enhanced management practices, chronic wasting disease (CWD) in U.S. white-tailed deer (Odocoileus virginianus; hereafter WTD) continues to expand geographically. Herein, we perform the largest genome-wide association analysis (GWAA) to date for CWD (n = 412 CWD-positive; n = 758 CWD-non-detect) using a custom Affymetrix Axiom® single nucleotide polymorphism (SNP) array (n = 121,010 SNPs), and confirm that differential susceptibility to CWD is a highly heritable (h2 = 0.611 ± 0.056) polygenic trait in farmed U.S. WTD, but with greater trait complexity than previously appreciated. We also confirm PRNP codon 96 (G96S) as having the largest-effects on risk (P ≤ 3.19E-08; Phenotypic Variance Explained ≥ 0.025) across three U.S. regions (Northeast, Midwest, South). However, 20 CWD-positive WTD possessing codon 96SS genotypes were also observed, including one that was lymph node and obex positive. Beyond PRNP, we also detected 23 significant SNPs (P-value ≤ 5E-05) implicating ≥ 24 positional candidate genes; many of which have been directly implicated in Parkinson’s, Alzheimer’s and prion diseases. Genotype-by-environment (GxE) interaction GWAA revealed a SNP in the lysosomal enzyme gene ARSB as having the most significant regional heterogeneity of effects on CWD (P ≤ 3.20E-06); with increasing copy number of the minor allele increasing susceptibility to CWD in the Northeast and Midwest; but with opposite effects in the South. In addition to ARSB, 38 significant GxE SNPs (P-value ≤ 5E-05) were also detected, thereby implicating ≥ 36 positional candidate genes; the majority of which have also been associated with aspects of Parkinson’s, Alzheimer’s and prion diseases.

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Section: Resultsmentioning

confidence: 99%

Genotype by environment interactions for chronic wasting disease in farmed US white-tailed deer

Seabury

Lockwood

Nichols³

2022

G3 Genes|Genomes|Genetics

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“…Recent GWAS studies have explored the causation behind gender differences in European cohorts. However, they have been unable to find any conclusive argument from the analyses of the autosomal and sex chromosomes [88][89][90]. A comprehensive meta-analysis of several diverse cohorts also did not offer any leads on gender differences [91].…”

Section: Challenges Of Understanding Genome-wide Association At a Mol...mentioning

confidence: 93%

Common genetic risk for Parkinson's disease and dysfunction of the endo-lysosomal system

Bhore,

Bogacki,

O'Callaghan

et al. 2024

Phil. Trans. R. Soc. B

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Parkinson's disease is a progressive neurological disorder, characterized by prominent movement dysfunction. The past two decades have seen a rapid expansion of our understanding of the genetic basis of Parkinson's, initially through the identification of monogenic forms and, more recently, through genome-wide association studies identifying common risk variants. Intriguingly, a number of cellular pathways have emerged from these analysis as playing central roles in the aetiopathogenesis of Parkinson's. In this review, the impact of data deriving from genome-wide analyses for Parkinson's upon our functional understanding of the disease will be examined, with a particular focus on examples of endo-lysosomal and mitochondrial dysfunction. The challenges of moving from a genetic to a functional understanding of common risk variants for Parkinson's will be discussed, with a final consideration of the current state of the genetic architecture of the disorder. This article is part of a discussion meeting issue ‘Understanding the endo-lysosomal network in neurodegeneration’.

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Investigation of Autosomal Genetic Sex Differences in Parkinson’s disease

Blauwendraat

Iwaki

Makarious

et al. 2021

Preprint

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Parkinsons disease (PD) is a complex neurodegenerative disorder. Males are on average ~1.5 times more likely to develop PD compared to females. Over the years genome-wide association studies (GWAS) have identified numerous genetic risk factors for PD, however it is unclear whether genetics contribute to disease etiology in a sex-specific manner. In an effort to study sex-specific genetic factors associated with PD, we explored two large genetic datasets from the International Parkinsons Disease Genomics Consortium and the UK Biobank consisting of 13,020 male PD cases, 7,936 paternal proxy cases, 89,660 male controls, 7,947 female PD cases, 5,473 maternal proxy cases and 90,662 female controls. We performed GWAS meta-analyses to identify distinct patterns of genetic risk contributing to disease in male versus female PD cases. In total 19 genome-wide significant regions were identified and no sex-specific effects were observed. A high genetic correlation between the male and female PD GWASes was identified (rg=0.877) and heritability estimates were identical between male and female PD cases (~20%). We did not detect any significant genetic differences between male or female PD cases. Our study does not support the notion that common genetic variation on the autosomes could explain the difference in prevalence of PD between males and females at least when considering the current sample size under study. Further studies are warranted to investigate the genetic architecture of PD explained by X and Y chromosomes and further evaluate environmental effects that could potentially contribute to PD etiology in male versus females.

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Common X-chromosome variants are associated with Parkinson’s disease risk

Cited by 4 publications

References 55 publications

Genotype by environment interactions for chronic wasting disease in farmed US white-tailed deer

Genotype by environment interactions for chronic wasting disease in farmed US white-tailed deer

Common genetic risk for Parkinson's disease and dysfunction of the endo-lysosomal system

Investigation of Autosomal Genetic Sex Differences in Parkinson’s disease

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