Probability of Alzheimer's disease based on common and rare genetic variants.
APOE
Alzheimer’s disease
Disease risk
Polygenic risk score
Rare variants
Journal
Alzheimer's research & therapy
ISSN: 1758-9193
Titre abrégé: Alzheimers Res Ther
Pays: England
ID NLM: 101511643
Informations de publication
Date de publication:
17 08 2021
17 08 2021
Historique:
received:
23
04
2021
accepted:
05
08
2021
entrez:
18
8
2021
pubmed:
19
8
2021
medline:
14
9
2021
Statut:
epublish
Résumé
Alzheimer's disease, among other neurodegenerative disorders, spans decades in individuals' life and exhibits complex progression, symptoms and pathophysiology. Early diagnosis is essential for disease prevention and therapeutic intervention. Genetics may help identify individuals at high risk. As thousands of genetic variants may contribute to the genetic risk of Alzheimer's disease, the polygenic risk score (PRS) approach has been shown to be useful for disease risk prediction. The APOE-ε4 allele is a known common variant associated with high risk to AD, but also associated with earlier onset. Rare variants usually have higher effect sizes than common ones; their impact may not be well captured by the PRS. Instead of standardised PRS, we propose to calculate the disease probability as a measure of disease risk that allows comparison between individuals. We estimate AD risk as a probability based on PRS and separately accounting for APOE, AD rare variants and the disease prevalence in age groups. The mathematical framework makes use of genetic variants effect sizes from summary statistics and AD disease prevalence in age groups. The AD probability varies with respect to age, APOE status and presence of rare variants. In age group 65+, the probability of AD grows from 0.03 to 0.18 (without APOE) and 0.07 to 0.7 (APOE e4e4 carriers) as PRS increases. In 85+, these values are 0.08-0.6 and 0.3-0.85. Presence of rare mutations, e.g. in TREM2, may increase the probability (in 65+) from 0.02 at the negative tail of the PRS to 0.3. Our approach accounts for the varying disease prevalence in different genotype and age groups when modelling the APOE and rare genetic variants risk in addition to PRS. This approach has potential for use in a clinical setting and can easily be updated for novel rare variants and for other populations or confounding factors when appropriate genome-wide association data become available.
Sections du résumé
BACKGROUND
Alzheimer's disease, among other neurodegenerative disorders, spans decades in individuals' life and exhibits complex progression, symptoms and pathophysiology. Early diagnosis is essential for disease prevention and therapeutic intervention. Genetics may help identify individuals at high risk. As thousands of genetic variants may contribute to the genetic risk of Alzheimer's disease, the polygenic risk score (PRS) approach has been shown to be useful for disease risk prediction. The APOE-ε4 allele is a known common variant associated with high risk to AD, but also associated with earlier onset. Rare variants usually have higher effect sizes than common ones; their impact may not be well captured by the PRS. Instead of standardised PRS, we propose to calculate the disease probability as a measure of disease risk that allows comparison between individuals.
METHODS
We estimate AD risk as a probability based on PRS and separately accounting for APOE, AD rare variants and the disease prevalence in age groups. The mathematical framework makes use of genetic variants effect sizes from summary statistics and AD disease prevalence in age groups.
RESULTS
The AD probability varies with respect to age, APOE status and presence of rare variants. In age group 65+, the probability of AD grows from 0.03 to 0.18 (without APOE) and 0.07 to 0.7 (APOE e4e4 carriers) as PRS increases. In 85+, these values are 0.08-0.6 and 0.3-0.85. Presence of rare mutations, e.g. in TREM2, may increase the probability (in 65+) from 0.02 at the negative tail of the PRS to 0.3.
CONCLUSIONS
Our approach accounts for the varying disease prevalence in different genotype and age groups when modelling the APOE and rare genetic variants risk in addition to PRS. This approach has potential for use in a clinical setting and can easily be updated for novel rare variants and for other populations or confounding factors when appropriate genome-wide association data become available.
Identifiants
pubmed: 34404470
doi: 10.1186/s13195-021-00884-7
pii: 10.1186/s13195-021-00884-7
pmc: PMC8369699
doi:
Substances chimiques
Apolipoproteins E
0
Membrane Glycoproteins
0
Receptors, Immunologic
0
TREM2 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
140Subventions
Organisme : Medical Research Council
ID : MR/T033371/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0801418
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/T04604X/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P005748/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : UKDRI-3003
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L010305/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/L023784/2
Pays : United Kingdom
Commentaires et corrections
Type : ErratumIn
Informations de copyright
© 2021. The Author(s).
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