Epigenomic and transcriptomic analyses define core cell types, genes and targetable mechanisms for kidney disease.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
07 2022
07 2022
Historique:
received:
13
08
2021
accepted:
09
05
2022
pubmed:
18
6
2022
medline:
16
7
2022
entrez:
17
6
2022
Statut:
ppublish
Résumé
More than 800 million people suffer from kidney disease, yet the mechanism of kidney dysfunction is poorly understood. In the present study, we define the genetic association with kidney function in 1.5 million individuals and identify 878 (126 new) loci. We map the genotype effect on the methylome in 443 kidneys, transcriptome in 686 samples and single-cell open chromatin in 57,229 kidney cells. Heritability analysis reveals that methylation variation explains a larger fraction of heritability than gene expression. We present a multi-stage prioritization strategy and prioritize target genes for 87% of kidney function loci. We highlight key roles of proximal tubules and metabolism in kidney function regulation. Furthermore, the causal role of SLC47A1 in kidney disease is defined in mice with genetic loss of Slc47a1 and in human individuals carrying loss-of-function variants. Our findings emphasize the key role of bulk and single-cell epigenomic information in translating genome-wide association studies into identifying causal genes, cellular origins and mechanisms of complex traits.
Identifiants
pubmed: 35710981
doi: 10.1038/s41588-022-01097-w
pii: 10.1038/s41588-022-01097-w
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
950-962Subventions
Organisme : NIDDK NIH HHS
ID : P30 DK050306
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK105821
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK087635
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK076077
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
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