A phenome-wide association study of methylated GC-rich repeats identifies a GCC repeat expansion in AFF3 associated with intellectual disability.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
23 Sep 2024
23 Sep 2024
Historique:
received:
12
04
2023
accepted:
20
08
2024
medline:
24
9
2024
pubmed:
24
9
2024
entrez:
23
9
2024
Statut:
aheadofprint
Résumé
GC-rich tandem repeat expansions (TREs) are often associated with DNA methylation, gene silencing and folate-sensitive fragile sites, and underlie several congenital and late-onset disorders. Through a combination of DNA-methylation profiling and tandem repeat genotyping, we identified 24 methylated TREs and investigated their effects on human traits using phenome-wide association studies in 168,641 individuals from the UK Biobank, identifying 156 significant TRE-trait associations involving 17 different TREs. Of these, a GCC expansion in the promoter of AFF3 was associated with a 2.4-fold reduced probability of completing secondary education, an effect size comparable to several recurrent pathogenic microdeletions. In a cohort of 6,371 probands with neurodevelopmental problems of suspected genetic etiology, we observed a significant enrichment of AFF3 expansions compared with controls. With a population prevalence that is at least fivefold higher than the TRE that causes fragile X syndrome, AFF3 expansions represent a major cause of neurodevelopmental delay.
Identifiants
pubmed: 39313615
doi: 10.1038/s41588-024-01917-1
pii: 10.1038/s41588-024-01917-1
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : U.S. Department of Health & Human Services | NIH | National Institute on Aging (U.S. National Institute on Aging)
ID : AG075051
Organisme : U.S. Department of Health & Human Services | NIH | Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
ID : HD103782
Organisme : U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)
ID : NS120241
Organisme : Prinses Beatrix Spierfonds
ID : W.OR20-08
Organisme : U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute (NHLBI)
ID : Biodata Catalyst fellowship 5120339
Organisme : EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)
ID : 772376
Organisme : RCUK | MRC | Medical Research Foundation
ID : MR/S006753/1
Organisme : RCUK | Medical Research Council (MRC)
ID : MR/S006753/1
Investigateurs
A Tucci
(A)
J H Veldink
(JH)
Informations de copyright
© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.
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