Polygenic Risk Score of Sporadic late Onset Alzheimer Disease Reveals a Shared Architecture with the Familial and Early Onset Forms

Aguila, Jorge L Del; Saef, Benjamin; Black, Kathleen; Fernandez, Maria-Victoria; Budde, John John; Ibáñez, Laura; Kapoor, Manav; Tosto, Giuseppe; Mayeux, Richard; Holtzman, David M.; Morris, John C.; Bateman, Randall J.; Goate, Alison; Cruchaga, Carlos; Harari, Oscar

doi:10.1101/165209

2017

DOI: 10.1101/165209

|View full text |Cite

Preprint

Polygenic Risk Score of Sporadic late Onset Alzheimer Disease Reveals a Shared Architecture with the Familial and Early Onset Forms

Jorge L Del Aguila¹,

Benjamin Saef²,

Kathleen Black³

et al.

Abstract: Objective: To determine whether the genetic architecture of sporadic late--onset Alzheimer's Disease (sLOAD) has an effect on familial late--onset AD (fLOAD), sporadic early--onset (sEOAD) and autosomal dominant early--onset (eADAD).Methods: Polygenic risk scores (PRS) were constructed using previously identified 21 genome--wide significant loci for LOAD risk.Results: We found that there is an overlap in the genetic architecture among sEOAD, fLOAD, and sLOAD. sEOAD showed the highest odds for the PRS (OR=2.27;… Show more

Help me understand this report

View published versions

Search citation statements

Order By: Relevance

Paper Sections

Select...

Citation Types

Supporting

Mentioning

Contrasting

Year Published

2017

2023

Publication Types

Select...

Article2

Relationship

Self Cite1

Independent1

Authors

Journals

Cited by 2 publications

References 48 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Early‐onset Alzheimer's disease explained by polygenic risk of late‐onset disease?

Mantyh,

Cochran,

Taylor

et al. 2023

Alz & Dem Diag Ass & Dis Mo

View full text Add to dashboard Cite

Early‐onset Alzheimer's disease (AD) is highly heritable, yet only 10% of cases are associated with known pathogenic mutations. For early‐onset AD patients without an identified autosomal dominant cause, we hypothesized that their early‐onset disease reflects further enrichment of the common risk‐conferring single nucleotide polymorphisms associated with late‐onset AD.We applied a previously validated polygenic hazard score for late‐onset AD to 193 consecutive patients diagnosed at our tertiary dementia referral center with symptomatic early‐onset AD. For comparison, we included 179 participants with late‐onset AD and 70 healthy controls. Polygenic hazard scores were similar in early‐ versus late‐onset AD. The polygenic hazard score was not associated with age‐of‐onset or disease biomarkers within early‐onset AD. Early‐onset AD does not represent an extreme enrichment of the common single nucleotide polymorphisms associated with late‐onset AD. Further exploration of novel genetic risk factors of this highly heritable disease is warranted.Highlights There is a unique genetic architecture of early‐ versus late‐onset Alzheimer's disease (AD). Late‐onset AD polygenic risk is not an explanation for early‐onset AD. Polygenic risk of late‐onset AD does not predict early‐onset AD biology. Unique genetic architecture of early‐ versus late‐onset AD parallels AD heterogeneity.

show abstract

Early‐onset Alzheimer's disease explained by polygenic risk of late‐onset disease?

Mantyh,

Cochran,

Taylor

et al. 2023

Alz & Dem Diag Ass & Dis Mo

View full text Add to dashboard Cite

show abstract

Parkinson disease polygenic risk score is associated with Parkinson disease status and age at onset but not with alpha-synuclein cerebrospinal fluid levels

et al. 2017

Self Cite

View full text Add to dashboard Cite

BackgroundThe genetic architecture of Parkinson’s Disease (PD) is complex and not completely understood. Multiple genetic studies to date have identified multiple causal genes and risk loci. Nevertheless, most of the expected genetic heritability remains unexplained. Polygenic risk scores (PRS) may provide greater statistical power and inform about the genetic architecture of multiple phenotypes. The aim of this study was to test the association between PRS and PD risk, age at onset and cerebrospinal fluid (CSF) biomarkers (α-synuclein, Aβ1–42, t-tau and p-tau).MethodsThe weighted PRS was created using the genome-wide loci from Nalls et al., 2014 PD GWAs meta-analysis. The PRS was tested for association with PD status, age at onset and CSF biomarker levels in 829 cases and 432 controls of European ancestry.ResultsThe PRS was associated with PD status (p = 5.83×10−08) and age at onset (p = 5.70×10−07). The CSF t-tau levels showed a nominal association with the PRS (p = 0.02). However, CSF α-synuclein, amyloid beta and phosphorylated tau were not found to be associated with the PRS.ConclusionOur study suggests that there is an overlap in the genetic architecture of PD risk and onset, although the different loci present different weights for those phenotypes. In our dataset we found a marginal association of the PRS with CSF t-tau but not with α-synuclein CSF levels, suggesting that the genetic architecture for the CSF biomarker levels is different from that of PD risk.Electronic supplementary materialThe online version of this article (10.1186/s12883-017-0978-z) contains supplementary material, which is available to authorized users.

show abstract

scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.

Contact Info

hi@scite.ai

10624 S. Eastern Ave., Ste. A-614

Henderson, NV 89052, USA

Blog Terms and Conditions API Terms Privacy Policy Contact Cookie Preferences Do Not Sell or Share My Personal Information

Made with 💙 for researchers

Part of the Research Solutions Family.

Polygenic Risk Score of Sporadic late Onset Alzheimer Disease Reveals a Shared Architecture with the Familial and Early Onset Forms

Cited by 2 publications

References 48 publications

Early‐onset Alzheimer's disease explained by polygenic risk of late‐onset disease?

Early‐onset Alzheimer's disease explained by polygenic risk of late‐onset disease?

Parkinson disease polygenic risk score is associated with Parkinson disease status and age at onset but not with alpha-synuclein cerebrospinal fluid levels

Contact Info

Product

Resources

About