Genetic association analysis of 77,539 genomes reveals rare disease etiologies.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
03 2023
03 2023
Historique:
received:
21
10
2022
accepted:
06
01
2023
pubmed:
18
3
2023
medline:
25
3
2023
entrez:
17
3
2023
Statut:
ppublish
Résumé
The genetic etiologies of more than half of rare diseases remain unknown. Standardized genome sequencing and phenotyping of large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient and powerful analytical methods. We built a compact database, the 'Rareservoir', containing the rare variant genotypes and phenotypes of 77,539 participants sequenced by the 100,000 Genomes Project. We then used the Bayesian genetic association method BeviMed to infer associations between genes and each of 269 rare disease classes assigned by clinicians to the participants. We identified 241 known and 19 previously unidentified associations. We validated associations with ERG, PMEPA1 and GPR156 by searching for pedigrees in other cohorts and using bioinformatic and experimental approaches. We provide evidence that (1) loss-of-function variants in the Erythroblast Transformation Specific (ETS)-family transcription factor encoding gene ERG lead to primary lymphoedema, (2) truncating variants in the last exon of transforming growth factor-β regulator PMEPA1 result in Loeys-Dietz syndrome and (3) loss-of-function variants in GPR156 give rise to recessive congenital hearing impairment. The Rareservoir provides a lightweight, flexible and portable system for synthesizing the genetic and phenotypic data required to study rare disease cohorts with tens of thousands of participants.
Identifiants
pubmed: 36928819
doi: 10.1038/s41591-023-02211-z
pii: 10.1038/s41591-023-02211-z
pmc: PMC10033407
doi:
Substances chimiques
PMEPA1 protein, human
0
Membrane Proteins
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
679-688Subventions
Organisme : NHLBI NIH HHS
ID : R01 HL161365
Pays : United States
Organisme : British Heart Foundation
ID : RE/18/1/34212
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/V037617/1
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 219506/Z/19/Z
Pays : United Kingdom
Organisme : NIDCD NIH HHS
ID : R01 DC016295
Pays : United States
Organisme : British Heart Foundation
ID : PG/17/33/32990
Pays : United Kingdom
Organisme : British Heart Foundation
ID : PG/20/16/35047
Pays : United Kingdom
Organisme : NICHD NIH HHS
ID : R03 HD111492
Pays : United States
Organisme : British Heart Foundation
ID : RG/17/7/33217
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/P011543/1
Pays : United Kingdom
Informations de copyright
© 2023. The Author(s).
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