Frequency of variants in Mendelian Alzheimer's disease genes within the Alzheimer's Disease Sequencing Project

BackgroundPrior studies examined variants within presenilin-2 ( ), presenilin-1 ( ), and amyloid precursor protein ( ) genes. However, previously-reported clinically-relevant variants and other predicted damaging missense (DM) variants have not been characterized in a newer release of the Alzheimer&...

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Published in:Journal of Alzheimer's disease Vol. 104; no. 3; p. 841
Main Authors: Wang, Dongyu, Scalici, Alexandra, Wang, Yanbing, Lin, Honghuang, Pitsillides, Achilleas, Heard-Costa, Nancy, Cruchaga, Carlos, Ziegemeier, Ellen, Bis, Joshua C, Fornage, Myriam, Boerwinkle, Eric, De Jager, Philip L, Wijsman, Ellen, Dupuis, Josée, Renton, Alan E, Seshadri, Sudha, Goate, Alison M, DeStefano, Anita L, Peloso, Gina M
Format: Journal Article
Language:English
Published: United States 01.04.2025
Subjects:
Aged
Alzheimer Disease - genetics
Amyloid beta-Protein Precursor - genetics
Exome Sequencing
Female
Gene Frequency
Genetic Predisposition to Disease
Genetic Variation - genetics
Humans
Male
Presenilin-1 - genetics
Presenilin-2 - genetics
Whole Genome Sequencing
genetic databases
whole genome sequencing
genetic profile
Alzheimer's disease
whole exome sequencing
ISSN:1875-8908, 1875-8908
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Summary:BackgroundPrior studies examined variants within presenilin-2 ( ), presenilin-1 ( ), and amyloid precursor protein ( ) genes. However, previously-reported clinically-relevant variants and other predicted damaging missense (DM) variants have not been characterized in a newer release of the Alzheimer's Disease Sequencing Project (ADSP).ObjectiveTo characterize previously-reported clinically-relevant variants and DM variants in within the participants from the ADSP.MethodsWe identified rare variants (MAF < 1%) in , and in 14,641 individuals with whole genome sequencing and 16,849 individuals with whole exome sequencing available (N = 31,490). We additionally curated variants from ClinVar, OMIM, and Alzforum and report carriers of variants in clinical databases as well as predicted DM variants in these genes.ResultsWe detected 31 previously-reported clinically-relevant variants with alternate alleles observed within the ADSP: 4 variants in , 25 in , and 2 in . The overall variant carrier rate for the 31 clinically-relevant variants in the ADSP was 0.3%. We observed that 79.5% of the variant carriers were cases compared to 3.9% were controls. In those with AD, the mean age of onset of AD among carriers of these clinically-relevant variants was 19.6 ± 1.4 years earlier compared with noncarriers (p = 7.8 × 10 ). Additionally, we identified 197 rare variants (MAF < 1%) within ADSP participants not reported in known clinical databases.ConclusionsA small proportion of individuals in the ADSP are carriers of a previously-reported clinically-relevant variant allele for AD and these participants have significantly earlier age of AD onset compared to noncarriers.
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ISSN:1875-8908
1875-8908
DOI:10.1177/13872877251320375