Family-based exome sequencing identifies rare coding variants in age-related macular degeneration.
Journal
Human molecular genetics
ISSN: 1460-2083
Titre abrégé: Hum Mol Genet
Pays: England
ID NLM: 9208958
Informations de publication
Date de publication:
29 07 2020
29 07 2020
Historique:
received:
15
01
2020
revised:
18
03
2020
accepted:
26
03
2020
pubmed:
5
4
2020
medline:
24
8
2021
entrez:
5
4
2020
Statut:
ppublish
Résumé
Genome-wide association studies (GWAS) have identified 52 independent variants at 34 genetic loci that are associated with age-related macular degeneration (AMD), the most common cause of incurable vision loss in the elderly worldwide. However, causal genes at the majority of these loci remain unknown. In this study, we performed whole exome sequencing of 264 individuals from 63 multiplex families with AMD and analyzed the data for rare protein-altering variants in candidate target genes at AMD-associated loci. Rare coding variants were identified in the CFH, PUS7, RXFP2, PHF12 and TACC2 genes in three or more families. In addition, we detected rare coding variants in the C9, SPEF2 and BCAR1 genes, which were previously suggested as likely causative genes at respective AMD susceptibility loci. Identification of rare variants in the CFH and C9 genes in our study validated previous reports of rare variants in complement pathway genes in AMD. We then extended our exome-wide analysis and identified rare protein-altering variants in 13 genes outside the AMD-GWAS loci in three or more families. Two of these genes, SCN10A and KIR2DL4, are of interest because variants in these genes also showed association with AMD in case-control cohorts, albeit not at the level of genome-wide significance. Our study presents the first large-scale, exome-wide analysis of rare variants in AMD. Further independent replications and molecular investigation of candidate target genes, reported here, would assist in gaining novel insights into mechanisms underlying AMD pathogenesis.
Identifiants
pubmed: 32246154
pii: 5815551
doi: 10.1093/hmg/ddaa057
pmc: PMC7390936
doi:
Substances chimiques
KIR2DL4 protein, human
0
NAV1.8 Voltage-Gated Sodium Channel
0
Receptors, KIR2DL4
0
SCN10A protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Intramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2022-2034Informations de copyright
© The Author(s) 2020. Published by Oxford University Press.
Références
Bioinformatics. 2014 Aug 1;30(15):2114-20
pubmed: 24695404
Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19444-9
pubmed: 23115331
Prog Retin Eye Res. 2015 May;46:1-30
pubmed: 25668385
J Med Genet. 2015 Jul;52(7):484-92
pubmed: 25986072
J Exp Zool B Mol Dev Evol. 2015 Nov;324(7):605-13
pubmed: 26173401
Lancet Glob Health. 2014 Feb;2(2):e106-16
pubmed: 25104651
Bioinformatics. 2010 Sep 15;26(18):2336-7
pubmed: 20634204
JAMA Ophthalmol. 2016 Mar;134(3):287-93
pubmed: 26767664
Prog Retin Eye Res. 2018 Nov;67:56-86
pubmed: 29729972
Annu Rev Genomics Hum Genet. 2009;10:19-43
pubmed: 19405847
JAMA Ophthalmol. 2015 Jul;133(7):785-91
pubmed: 25880396
Bioinformatics. 2009 Jul 15;25(14):1754-60
pubmed: 19451168
Proc Natl Acad Sci U S A. 2007 Oct 9;104(41):16227-32
pubmed: 17884985
Genet Epidemiol. 1994;11(1):51-67
pubmed: 8013888
JAMA Ophthalmol. 2017 Oct 1;135(10):1037-1044
pubmed: 28859202
Science. 2005 Apr 15;308(5720):419-21
pubmed: 15761120
Mol Cell Biol. 2017 Feb 15;37(5):
pubmed: 27956701
Mol Immunol. 2017 Apr;84:65-76
pubmed: 27939104
Proc Natl Acad Sci U S A. 2005 May 17;102(20):7227-32
pubmed: 15870199
Science. 2005 Apr 15;308(5720):385-9
pubmed: 15761122
Neuron. 2014 Feb 19;81(4):779-86
pubmed: 24559672
Ophthalmology. 2013 Apr;120(4):844-51
pubmed: 23332590
Am J Hum Genet. 2003 Jun;72(6):1359-69
pubmed: 12730828
Hum Mol Genet. 2005 Aug 1;14(15):2257-64
pubmed: 15987700
Biol Reprod. 2010 Mar;82(3):580-90
pubmed: 19889948
Am J Hum Genet. 2005 Jul;77(1):149-53
pubmed: 15895326
Annu Rev Genomics Hum Genet. 2014;15:151-71
pubmed: 24773320
Nat Genet. 2016 Feb;48(2):134-43
pubmed: 26691988
Clin Genet. 2013 Aug;84(2):160-6
pubmed: 23713713
Arch Ophthalmol. 1998 Dec;116(12):1646-51
pubmed: 9869796
Nat Genet. 2011 Oct 23;43(12):1232-6
pubmed: 22019782
Prog Retin Eye Res. 2010 Mar;29(2):95-112
pubmed: 19961953
Physiol Rev. 2013 Jan;93(1):405-80
pubmed: 23303914
Adv Protein Chem Struct Biol. 2016;104:157-231
pubmed: 27038375
Ophthalmology. 2018 Sep;125(9):1433-1443
pubmed: 29706360
PLoS One. 2014 Apr 15;9(4):e94165
pubmed: 24736606
Am J Ophthalmol. 1997 Feb;123(2):199-206
pubmed: 9186125
J Comp Neurol. 2008 Jun 20;508(6):940-51
pubmed: 18399542
Sci Rep. 2016 Aug 30;6:31531
pubmed: 27572114
Ophthalmology. 2012 Dec;119(12):2526-36
pubmed: 23009893
Genome Res. 2010 Sep;20(9):1297-303
pubmed: 20644199
Invest Ophthalmol Vis Sci. 2008 Nov;49(11):5077-82
pubmed: 18515573
Mol Biol Cell. 2011 Apr;22(7):921-30
pubmed: 21307337
Nat Genet. 2013 Nov;45(11):1371-4
pubmed: 24036950
Hum Mol Genet. 2005 Nov 1;14(21):3227-36
pubmed: 16174643
Nat Genet. 2019 Apr;51(4):606-610
pubmed: 30742112
Ophthalmology. 2000 Dec;107(12):2224-32
pubmed: 11097601
Annu Rev Genomics Hum Genet. 2000;1:387-407
pubmed: 11701635
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
Annu Rev Genomics Hum Genet. 2006;7:277-300
pubmed: 16824023
Am J Hum Genet. 2003 Sep;73(3):540-50
pubmed: 12900797
Invest Ophthalmol Vis Sci. 2011 Nov 11;52(12):8828-34
pubmed: 22003108
Nucleic Acids Res. 2010 Sep;38(16):e164
pubmed: 20601685
Arch Ophthalmol. 2004 Apr;122(4):564-72
pubmed: 15078675
Hum Mol Genet. 2014 Oct 1;23(19):5283-93
pubmed: 24847005
Nat Genet. 2013 Jul;45(7):813-7
pubmed: 23685748
Cell Rep. 2020 Jan 28;30(4):1246-1259.e6
pubmed: 31995762
Arch Ophthalmol. 1998 Aug;116(8):1082-8
pubmed: 9715689
Nat Genet. 2011 May;43(5):491-8
pubmed: 21478889
Mol Cell Biol. 2003 Nov;23(22):7947-56
pubmed: 14585956
Am J Hum Genet. 2005 Sep;77(3):389-407
pubmed: 16080115
Ophthalmology. 2018 Mar;125(3):398-406
pubmed: 29224928
Hum Mol Genet. 2016 Nov 15;25(22):5027-5034
pubmed: 28173125
Genome Biol. 2017 Apr 27;18(1):77
pubmed: 28449691
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
PLoS One. 2016 Mar 23;11(3):e0152047
pubmed: 27007659
Science. 2005 Apr 15;308(5720):421-4
pubmed: 15761121
Am J Hum Genet. 2004 Mar;74(3):482-94
pubmed: 14968411
Hum Mol Genet. 2000 May 22;9(9):1329-49
pubmed: 10814715
Bioinformatics. 2014 Oct;30(19):2828-9
pubmed: 24894501
Nature. 2009 Oct 8;461(7265):747-53
pubmed: 19812666
Surv Ophthalmol. 1995 Mar-Apr;39(5):367-74
pubmed: 7604360
J Clin Invest. 2014 Apr;124(4):1430-8
pubmed: 24691477
Biol Reprod. 2011 Oct;85(4):690-701
pubmed: 21715716
Nature. 2003 Dec 18;426(6968):789-96
pubmed: 14685227
Annu Rev Vis Sci. 2015 Nov 24;1:73-96
pubmed: 28532374
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Nucleic Acids Res. 2014 Jan;42(Database issue):D1001-6
pubmed: 24316577
Invest Ophthalmol Vis Sci. 2014 Jun 06;55(7):4455-60
pubmed: 24906858
Nat Genet. 2013 Nov;45(11):1366-70
pubmed: 24036952
Nat Genet. 2013 Nov;45(11):1375-9
pubmed: 24036949
Hum Mol Genet. 2014 Nov 1;23(21):5827-37
pubmed: 24899048