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PubMed · 40084664

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

Dongyu Wang·Alexandra Scalici·Yanbing Wang·Honghuang Lin·Achilleas Pitsillides·Nancy Heard-Costa·Carlos Cruchaga·Ellen Ziegemeier·Joshua C Bis·Myriam Fornage·Eric Boerwinkle·Philip L De Jager·Ellen Wijsman·Josée Dupuis·Alan E Renton·Sudha Seshadri·Alison M Goate·Alzheimer's Disease Neuroimaging Initiative (ADNI), The Alzheimer's Disease Sequencing Project·Anita L DeStefano·Gina M Peloso
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Abstract

BackgroundPrior studies examined variants within presenilin-2 (PSEN2), presenilin-1 (PSEN1), and amyloid precursor protein (APP) 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 PSEN2, PSEN1, APP within the participants from the ADSP.MethodsWe identified rare variants (MAF&#x2009;<&#x2009;1%) in PSEN2, PSEN1, and APP in 14,641 individuals with whole genome sequencing and 16,849 individuals with whole exome sequencing available (Ntotal&#x2009;=&#x2009;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 PSEN2, 25 in PSEN1, and 2 in APP. 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&#x2009;&#xb1;&#x2009;1.4 years earlier compared with noncarriers (p&#x2009;=&#x2009;7.8&#x2009;&#xd7;&#x2009;10-57). Additionally, we identified 197 rare variants (MAF&#x2009;<&#x2009;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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HumansAlzheimer DiseasePresenilin-2Presenilin-1Amyloid beta-Protein PrecursorGenetic VariationMaleExome SequencingFemaleGene FrequencyWhole Genome SequencingGenetic Predisposition to DiseaseAgedAlzheimer's diseasegenetic databasesgenetic profilewhole exome sequencingwhole genome sequencingJournal ArticleResearch Support, N.I.H., Extramural

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Dongyu Wang, Alexandra Scalici, Yanbing Wang, Honghuang Lin, Achilleas Pitsillides, Nancy Heard-Costa, Carlos Cruchaga, Ellen Ziegemeier, Joshua C Bis, Myriam Fornage, Eric Boerwinkle, Philip L De Jager, Ellen Wijsman, Jos&#xe9;e Dupuis, Alan E Renton, Sudha Seshadri, Alison M Goate, Alzheimer's Disease Neuroimaging Initiative (ADNI), The Alzheimer's Disease Sequencing Project, Anita L DeStefano, Gina M Peloso. 2025-03-14. Frequency of variants in Mendelian Alzheimer's disease genes within the Alzheimer's Disease Sequencing Project.. https://doi.org/10.1177/13872877251320375

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