Pathogenic variants in the Longitudinal Early-onset Alzheimer's Disease Study cohort.
APP
Alzheimer's disease
C9ORF7
GRN
MAPT
PSEN1
PSEN2
dementia
early onset
genetics
sequencing
Journal
Alzheimer's & dementia : the journal of the Alzheimer's Association
ISSN: 1552-5279
Titre abrégé: Alzheimers Dement
Pays: United States
ID NLM: 101231978
Informations de publication
Date de publication:
11 2023
11 2023
Historique:
revised:
28
08
2023
received:
20
04
2023
accepted:
29
08
2023
medline:
30
11
2023
pubmed:
6
10
2023
entrez:
6
10
2023
Statut:
ppublish
Résumé
One goal of the Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is to investigate the genetic etiology of early onset (40-64 years) cognitive impairment. Toward this goal, LEADS participants are screened for known pathogenic variants. LEADS amyloid-positive early-onset Alzheimer's disease (EOAD) or negative early-onset non-AD (EOnonAD) cases were whole exome sequenced (N = 299). Pathogenic variant frequency in APP, PSEN1, PSEN2, GRN, MAPT, and C9ORF72 was assessed for EOAD and EOnonAD. Gene burden testing was performed in cases compared to similar-age cognitively normal controls in the Parkinson's Progression Markers Initiative (PPMI) study. Previously reported pathogenic variants in the six genes were identified in 1.35% of EOAD (3/223) and 6.58% of EOnonAD (5/76). No genes showed enrichment for carriers of rare functional variants in LEADS cases. Results suggest that LEADS is enriched for novel genetic causative variants, as previously reported variants are not observed in most cases. Sequencing identified eight cognitively impaired pathogenic variant carriers. Pathogenic variants were identified in PSEN1, GRN, MAPT, and C9ORF72. Rare variants were not enriched in APP, PSEN1/2, GRN, and MAPT. The Longitudinal Early-onset Alzheimer's Disease Study (LEADS) is a key resource for early-onset Alzheimer's genetic research.
Substances chimiques
Amyloid beta-Protein Precursor
0
C9orf72 Protein
0
Presenilin-1
0
Presenilin-2
0
Types de publication
Journal Article
Review
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
S64-S73Subventions
Organisme : NIH HHS
ID : P30AG062422
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG010133
Pays : United States
Organisme : NIA NIH HHS
ID : U24 AG072122
Pays : United States
Organisme : NIH HHS
ID : P30AG013854
Pays : United States
Organisme : NIH HHS
ID : P50AG005681
Pays : United States
Organisme : NIH HHS
ID : U01AG057195
Pays : United States
Organisme : NIH HHS
ID : P30AG062421
Pays : United States
Organisme : NIH HHS
ID : P50AG008702
Pays : United States
Organisme : NIH HHS
ID : P50AG025688
Pays : United States
Organisme : NIH HHS
ID : P50AG005146
Pays : United States
Organisme : NIH HHS
ID : P30AG010124
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG066515
Pays : United States
Organisme : NIA NIH HHS
ID : U01 AG016976
Pays : United States
Organisme : NIH HHS
ID : U24AG021886
Pays : United States
Organisme : NIH HHS
ID : P50AG047366
Pays : United States
Organisme : NIH HHS
ID : R56AG057195
Pays : United States
Organisme : NIH HHS
ID : P50AG023501
Pays : United States
Organisme : NIH HHS
ID : U01AG016976
Pays : United States
Organisme : NIH HHS
ID : P30AG010133
Pays : United States
Organisme : NIH HHS
ID : P30AG066506
Pays : United States
Organisme : NIA NIH HHS
ID : P30 AG072976
Pays : United States
Organisme : NIH HHS
ID : R56AG057195
Pays : United States
Organisme : NIH HHS
ID : U01AG057195
Pays : United States
Organisme : NIH HHS
ID : U24AG021886
Pays : United States
Organisme : NIH HHS
ID : U01AG016976
Pays : United States
Organisme : NIH HHS
ID : P30AG010133
Pays : United States
Organisme : NIH HHS
ID : P50AG008702
Pays : United States
Organisme : NIH HHS
ID : P50AG025688
Pays : United States
Organisme : NIH HHS
ID : P50AG005146
Pays : United States
Organisme : NIH HHS
ID : P30AG062421
Pays : United States
Organisme : NIH HHS
ID : P30AG062422
Pays : United States
Organisme : NIH HHS
ID : P50AG023501
Pays : United States
Organisme : NIH HHS
ID : P30AG010124
Pays : United States
Organisme : NIH HHS
ID : P30AG066506
Pays : United States
Organisme : NIH HHS
ID : P30AG013854
Pays : United States
Organisme : NIH HHS
ID : P50AG005681
Pays : United States
Organisme : NIH HHS
ID : P50AG047366
Pays : United States
Organisme : Alzheimer's Association
ID : LEADS GENETICS-19-639372
Pays : United States
Organisme : Alzheimer's Association
ID : AARG-22-926940
Pays : United States
Organisme : Alzheimer's Association
ID : LDRFP-21-818464
Pays : United States
Informations de copyright
© 2023 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.
Références
Wingo TS, Lah JJ, Levey AI, Cutler DJ. Autosomal recessive causes likely in early-onset Alzheimer disease. Arch Neurol. 2012;69:59-64.
Greaves CV, Rohrer JD. An update on genetic frontotemporal dementia. J Neurol. 2019;266:2075-2086.
Apostolova LG, Aisen P, Eloyan A, et al. The longitudinal early-onset Alzheimer's disease study (LEADS): framework and methodology. Alzheimers Dement. 2021;17:2043-2055.
Jack CR Jr, Knopman DS, Chetelat G, et al. Suspected non-Alzheimer disease pathophysiology-concept and controversy. Nat Rev Neurol. 2016;12:117-124.
Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res. 1975;12:189-198.
Cruts M, Gijselinck I, Van Langenhove T, van der Zee J, Van Broeckhoven C. Current insights into the C9orf72 repeat expansion diseases of the FTLD/ALS spectrum. Trends Neurosci. 2013;36:450-459.
Van der Auwera GA, Carneiro MO, Hartl C, et al. From FastQ data to high confidence variant calls: The Genome Analysis Toolkit best practices pipeline. Curr Protoc Bioinformatics. 2013;43:11.10.1-11.10.33.
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38:e164.
Backenroth D, Homsy J, Murillo LR, et al. CANOES: detecting rare copy number variants from whole exome sequencing data. Nucleic Acids Res. 2014;42:e97.
Krumm N, Sudmant PH, Ko A, et al. Copy number variation detection and genotyping from exome sequence data. Genome Res. 2012;22:1525-1532.
O'Roak BJ, Vives L, Girirajan S, et al. Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations. Nature. 2012;485:246-250.
Mills SM, Mallmann J, Santacruz AM, et al. Preclinical trials in autosomal dominant AD: implementation of the DIAN-TU trial. Rev Neurol (Paris). 2013;169:737-743.
Moulder KL, Snider BJ, Mills SL, et al. Dominantly Inherited Alzheimer Network: facilitating research and clinical trials. Alzheimers Res Ther. 2013;5:48.
Landrum MJ, Chitipiralla S, Brown GR, et al. ClinVar: improvements to accessing data. Nucleic Acids Res. 2020;48:D835-D844.
Landrum MJ, Kattman BL. ClinVar at five years: delivering on the promise. Hum Mutat. 2018;39:1623-1630.
Landrum MJ, Lee JM, Benson M, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018;46:D1062.
Stenson PD, Ball EV, Mort M, et al. Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat. 2003;21:577-581.
Fokkema I, Kroon M, Lopez Hernandez JA, et al. The LOVD3 platform: efficient genome-wide sharing of genetic variants. Eur J Hum Genet. 2021;29:1796-1803.
Kopanos C, Tsiolkas V, Kouris A, et al. VarSome: the human genomic variant search engine. Bioinformatics. 2019;35:1978-1980.
Marek K, Chowdhury S, Siderowf A, et al. The Parkinson's progression markers initiative (PPMI)-establishing a PD biomarker cohort. Ann Clin Transl Neurol. 2018;5:1460-1477.
Lee S, Emond MJ, Bamshad MJ, et al. Optimal unified approach for rare-variant association testing with application to small-sample case-control whole-exome sequencing studies. Am J Hum Genet. 2012;91:224-237.
Purcell S, Neale B, Todd-Brown K, et al. PLINK: a tool set for whole-genome association and population-based linkage analyses. Am J Hum Genet. 2007;81:559-575.
Chang CC, Chow CC, Tellier LC, Vattikuti S, Purcell SM, Lee JJ. Second-generation PLINK: rising to the challenge of larger and richer datasets. Gigascience. 2015;4:7.
Gudmundsson S, Singer-Berk M, Watts NA, et al. Variant interpretation using population databases: lessons from gnomAD. Hum Mutat. 2022;43:1012-1030.
Payami H, Kaye J, Heston LL, Bird TD, Schellenberg GD. Apolipoprotein E genotype and Alzheimer's disease. Lancet. 1993;342:738.
Rademakers R, Cruts M, Van Broeckhoven C. Genetics of early-onset Alzheimer dementia. Scientific World Journal. 2003;3:497-519.
Sorbi S, Nacmias B, Forleo P, Piacentini S, Latorraca S, Amaducci L. Epistatic effect of APP717 mutation and apolipoprotein E genotype in familial Alzheimer's disease. Ann Neurol. 1995;38:124-127.
Ayodele T, Rogaeva E, Kurup JT, Beecham G, Reitz C. Early-Onset Alzheimer's disease: what is missing in research? Curr Neurol Neurosci Rep. 2021;21:4.
Kirola L, Mukherjee A, Mutsuddi M. Recent updates on the genetics of Amyotrophic lateral dclerosis and frontotemporal dementia. Mol Neurobiol. 2022;59:5673-5694.