Exome-Based Rare-Variant Analyses in CKD.
genetic renal disease
human genetics
molecular genetics
Journal
Journal of the American Society of Nephrology : JASN
ISSN: 1533-3450
Titre abrégé: J Am Soc Nephrol
Pays: United States
ID NLM: 9013836
Informations de publication
Date de publication:
06 2019
06 2019
Historique:
received:
08
09
2018
accepted:
06
03
2019
pubmed:
16
5
2019
medline:
26
2
2020
entrez:
16
5
2019
Statut:
ppublish
Résumé
Studies have identified many common genetic associations that influence renal function and all-cause CKD, but these explain only a small fraction of variance in these traits. The contribution of rare variants has not been systematically examined. We performed exome sequencing of 3150 individuals, who collectively encompassed diverse CKD subtypes, and 9563 controls. To detect causal genes and evaluate the contribution of rare variants we used collapsing analysis, in which we compared the proportion of cases and controls carrying rare variants per gene. The analyses captured five established monogenic causes of CKD: variants in This study demonstrates that rare-variant collapsing analyses can validate known genes and identify candidate genes and modifiers for kidney disease. In so doing, these findings provide a motivation for larger-scale investigation of rare-variant risk contributions across major clinical CKD categories.
Sections du résumé
BACKGROUND
Studies have identified many common genetic associations that influence renal function and all-cause CKD, but these explain only a small fraction of variance in these traits. The contribution of rare variants has not been systematically examined.
METHODS
We performed exome sequencing of 3150 individuals, who collectively encompassed diverse CKD subtypes, and 9563 controls. To detect causal genes and evaluate the contribution of rare variants we used collapsing analysis, in which we compared the proportion of cases and controls carrying rare variants per gene.
RESULTS
The analyses captured five established monogenic causes of CKD: variants in
CONCLUSIONS
This study demonstrates that rare-variant collapsing analyses can validate known genes and identify candidate genes and modifiers for kidney disease. In so doing, these findings provide a motivation for larger-scale investigation of rare-variant risk contributions across major clinical CKD categories.
Identifiants
pubmed: 31085678
pii: ASN.2018090909
doi: 10.1681/ASN.2018090909
pmc: PMC6551770
doi:
Substances chimiques
COL4A4 protein, human
0
Collagen Type IV
0
Protein Kinase D2
0
TRPP Cation Channels
0
polycystic kidney disease 1 protein
0
Protein Kinases
EC 2.7.-
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
1109-1122Subventions
Organisme : NIDDK NIH HHS
ID : F30 DK116473
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK103184
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK115574
Pays : United States
Organisme : NIMHD NIH HHS
ID : R01 MD009223
Pays : United States
Informations de copyright
Copyright © 2019 by the American Society of Nephrology.
Références
N Engl J Med. 2009 Apr 2;360(14):1395-407
pubmed: 19332456
J Clin Invest. 2017 Sep 1;127(9):3558
pubmed: 28862642
PLoS Genet. 2013;9(8):e1003709
pubmed: 23990802
J Nephrol. 2003 Jul-Aug;16(4):511-5
pubmed: 14696752
Nat Genet. 2010 May;42(5):376-84
pubmed: 20383146
Lancet. 2017 Mar 25;389(10075):1238-1252
pubmed: 27887750
J Am Soc Nephrol. 2011 Nov;22(11):1991-6
pubmed: 21997397
Hum Mol Genet. 2017 Aug 1;26(15):2949-2960
pubmed: 28486600
Lancet Neurol. 2017 Feb;16(2):135-143
pubmed: 28102150
Genome Res. 2017 Oct;27(10):1715-1729
pubmed: 28864458
Nat Rev Nephrol. 2016 Mar;12(3):133-46
pubmed: 26750453
Ann Neurol. 2005 Jan;57(1):60-6
pubmed: 15622536
Nat Genet. 2018 Nov;50(11):1593-1599
pubmed: 30349118
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Science. 2010 Aug 13;329(5993):841-5
pubmed: 20647424
Sci Rep. 2017 Apr 28;7:45040
pubmed: 28452372
Hum Genet. 2010 Sep;128(3):345-50
pubmed: 20635188
Am J Hum Genet. 2017 Nov 2;101(5):789-802
pubmed: 29100090
N Engl J Med. 2019 Jan 10;380(2):142-151
pubmed: 30586318
Nat Genet. 2003 Jun;34(2):154-6
pubmed: 12730697
Hum Mutat. 1999;13(3):210-20
pubmed: 10090476
Curr Drug Targets. 2018;19(9):1058-1067
pubmed: 29210646
PLoS One. 2015 Jun 01;10(6):e0127791
pubmed: 26030142
Am J Hum Genet. 2017 Nov 2;101(5):803-814
pubmed: 29100091
Clin Kidney J. 2015 Dec;8(6):690-4
pubmed: 26613025
Trends Endocrinol Metab. 2016 Apr;27(4):204-215
pubmed: 26947522
J Am Soc Nephrol. 2015 Nov;26(11):2882-90
pubmed: 25788523
Nat Genet. 2009 Jun;41(6):712-7
pubmed: 19430482
Ann Intern Med. 2018 Jan 16;168(2):100-109
pubmed: 29204651
Nat Genet. 1993 Jul;4(3):314-20
pubmed: 8358442
Semin Nephrol. 2015 May;35(3):222-36
pubmed: 26215860
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
Kidney Int. 2014 Dec;86(6):1253-9
pubmed: 25229338
Orphanet J Rare Dis. 2014 Jun 30;9:98
pubmed: 24980890
Nat Rev Drug Discov. 2018 Mar;17(3):167-181
pubmed: 29348681
Science. 2015 Mar 27;347(6229):1436-41
pubmed: 25700176
Genet Med. 2015 May;17(5):405-24
pubmed: 25741868
Proc Natl Acad Sci U S A. 2018 Mar 27;115(13):3446-3451
pubmed: 29531077
Am J Hum Genet. 2014 May 1;94(5):784-9
pubmed: 24791903
PLoS Genet. 2009 Jun;5(6):e1000504
pubmed: 19503597
Am J Hum Genet. 2012 Nov 2;91(5):839-48
pubmed: 23103226
Circ Genom Precis Med. 2018 Jun;11(6):e002098
pubmed: 29899045
Am J Hum Genet. 2016 Sep 1;99(3):527-539
pubmed: 27545677
Nat Genet. 2015 May;47(5):512-7
pubmed: 25848748
Nat Methods. 2010 Apr;7(4):248-9
pubmed: 20354512
Am J Hum Genet. 2014 Jul 3;95(1):5-23
pubmed: 24995866
Am J Respir Crit Care Med. 2017 Jul 1;196(1):82-93
pubmed: 28099038
Nephrol Dial Transplant. 2016 Jun;31(6):961-70
pubmed: 26346198
Ann Neurol. 2016 Apr;79(4):522-34
pubmed: 26704558
J Am Soc Nephrol. 2013 Sep;24(9):1484-91
pubmed: 23766536
Hum Mutat. 2014 Jan;35(1):36-40
pubmed: 24285566
Lancet. 2016 Oct 8;388(10053):1459-1544
pubmed: 27733281
Circ Cardiovasc Genet. 2010 Dec;3(6):523-30
pubmed: 20884846
Arch Neurol. 2005 Jan;62(1):37-41
pubmed: 15642848
Nat Commun. 2016 Jan 21;7:10023
pubmed: 26831199
Nephron. 2015;130(4):293-301
pubmed: 26202451
Genome Biol. 2016 Jan 18;17:9
pubmed: 26781712
Bioinformatics. 2010 Nov 15;26(22):2867-73
pubmed: 20926424
J Am Soc Nephrol. 1997 Dec;8(12):1942-5
pubmed: 9402097
G Ital Nefrol. 2015;32 Suppl 64:
pubmed: 26479061
PLoS Genet. 2017 Nov 29;13(11):e1007104
pubmed: 29186148
Am J Hum Genet. 2019 Feb 7;104(2):299-309
pubmed: 30686509