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Probability of Alzheimer’s disease based on common and rare genetic variants

Escott-Price, Valentina ORCID: and Schmidt, Karl Michael ORCID: 2021. Probability of Alzheimer’s disease based on common and rare genetic variants. Alzheimer's Research & Therapy 13 , 140. 10.1186/s13195-021-00884-7

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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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher: BioMed Central
ISSN: 1758-9193
Funders: MRC
Date of First Compliant Deposit: 10 August 2021
Date of Acceptance: 5 August 2021
Last Modified: 23 May 2023 16:49

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