Resequencing of candidate genes for Keratoconus reveals a role for Ehlers-Danlos Syndrome genes.
Journal
European journal of human genetics : EJHG
ISSN: 1476-5438
Titre abrégé: Eur J Hum Genet
Pays: England
ID NLM: 9302235
Informations de publication
Date de publication:
12 2021
12 2021
Historique:
received:
06
08
2019
accepted:
26
02
2021
revised:
22
01
2021
pubmed:
20
3
2021
medline:
23
3
2022
entrez:
19
3
2021
Statut:
ppublish
Résumé
The involvement of genetic factors in the pathogenesis of KC has long been recognized but the identification of variants affecting the underlying protein functions has been challenging. In this study, we selected 34 candidate genes for KC based on previous whole-exome sequencing (WES) and the literature, and resequenced them in 745 KC patients and 810 ethnically matched controls from Belgium, France and Italy. Data analysis was performed using the single variant association test as well as gene-based mutation burden and variance components tests. In our study, we detected enrichment of genetic variation across multiple gene-based tests for the genes COL2A1, COL5A1, TNXB, and ZNF469. The top hit in the single variant association test was obtained for a common variant in the COL12A1 gene. These associations were consistently found across independent subpopulations. Interestingly, COL5A1, TNXB, ZNF469 and COL12A1 are all known Ehlers-Danlos Syndrome (EDS) genes. Though the co-occurrence of KC and EDS has been reported previously, this study is the first to demonstrate a consistent role of genetic variants in EDS genes in the etiology of KC. In conclusion, our data show a shared genetic etiology between KC and EDS, and clearly confirm the currently disputed role of ZNF469 in disease susceptibility for KC.
Identifiants
pubmed: 33737726
doi: 10.1038/s41431-021-00849-2
pii: 10.1038/s41431-021-00849-2
pmc: PMC8633318
doi:
Substances chimiques
COL2A1 protein, human
0
COL5A1 protein, human
0
Collagen Type II
0
Collagen Type V
0
Tenascin
0
Transcription Factors
0
ZNF469 protein, human
0
tenascin X
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1745-1755Informations de copyright
© 2021. The Author(s), under exclusive licence to European Society of Human Genetics.
Références
Rabinowitz YS. Keratoconus. Surv Ophthalmol. 1998;42:297–319.
pubmed: 9493273
doi: 10.1016/S0039-6257(97)00119-7
Godefrooij DA, de Wit GA, Uiterwaal CS, Imhof SM, Wisse RP. Age-specific incidence and prevalence of keratoconus: a nationwide registration study. Am J Ophthalmol. 2017;175:169–72.
pubmed: 28039037
doi: 10.1016/j.ajo.2016.12.015
Tuft SJ, Hassan H, George S, Frazer DG, Willoughby CE, Liskova P. Keratoconus in 18 pairs of twins. Acta Ophthalmol. 2012;90:e482–6.
pubmed: 22682160
doi: 10.1111/j.1755-3768.2012.02448.x
Wang Y, Rabinowitz YS, Rotter JI, Yang H. Genetic epidemiological study of keratoconus: evidence for major gene determination. Am J Med Genet. 2000;93:403–9.
pubmed: 10951465
doi: 10.1002/1096-8628(20000828)93:5<403::AID-AJMG11>3.0.CO;2-A
Szczotka-Flynn L, Slaughter M, McMahon T, Barr J, Edrington T, Fink B, et al. Disease severity and family history in keratoconus. Br J Ophthalmol. 2008;92:1108–11.
pubmed: 18653604
doi: 10.1136/bjo.2007.130294
Morrow GL, Stein RM, Racine JS, Siegel-Bartelt J. Computerized videokeratography of keratoconus kindreds. Can J Ophthalmol J canadien d’ophtalmologie. 1997;32:233–43.
Kriszt A, Losonczy G, Berta A, Vereb G, Takacs L. Segregation analysis suggests that keratoconus is a complex non-mendelian disease. Acta Ophthalmol. 2014;92:e562–8.
pubmed: 24629050
doi: 10.1111/aos.12389
Lu Y, Vitart V, Burdon KP, Khor CC, Bykhovskaya Y, Mirshahi A, et al. Genome-wide association analyses identify multiple loci associated with central corneal thickness and keratoconus. Nat Genet. 2013;45:155–63.
pubmed: 23291589
pmcid: 3720123
doi: 10.1038/ng.2506
Toriello HV, Glover TW, Takahara K, Byers PH, Miller DE, Higgins JV, et al. A translocation interrupts the COL5A1 gene in a patient with Ehlers-Danlos syndrome and hypomelanosis of Ito. Nat Genet. 1996;13:361–5.
pubmed: 8673139
doi: 10.1038/ng0796-361
Segev F, Heon E, Cole WG, Wenstrup RJ, Young F, Slomovic AR, et al. Structural abnormalities of the cornea and lid resulting from collagen V mutations. Investig Ophthalmol Vis Sci. 2006;47:565–73.
doi: 10.1167/iovs.05-0771
Li X, Bykhovskaya Y, Canedo AL, Haritunians T, Siscovick D, Aldave AJ, et al. Genetic association of COL5A1 variants in keratoconus patients suggests a complex connection between corneal thinning and keratoconus. Investig Ophthalmol Vis Sci. 2013;54:2696–704.
doi: 10.1167/iovs.13-11601
Sahebjada S, Schache M, Richardson AJ, Snibson G, MacGregor S, Daniell M, et al. Evaluating the association between keratoconus and the corneal thickness genes in an independent Australian population. Investig Ophthalmol Vis Sci. 2013;54:8224–8.
doi: 10.1167/iovs.13-12982
Hao XD, Chen P, Chen ZL, Li SX, Wang Y. Evaluating the association between keratoconus and reported genetic loci in a Han Chinese population. Ophthalmic Genet. 2015;36:132–6.
pubmed: 25675348
doi: 10.3109/13816810.2015.1005317
Liskova P, Dudakova L, Krepelova A, Klema J, Hysi PG. Replication of SNP associations with keratoconus in a Czech cohort. PloS One. 2017;12:e0172365.
pubmed: 28207827
pmcid: 5313182
doi: 10.1371/journal.pone.0172365
Rohrbach M, Spencer HL, Porter LF, Burkitt-Wright EM, Burer C, Janecke A, et al. ZNF469 frequently mutated in the brittle cornea syndrome (BCS) is a single exon gene possibly regulating the expression of several extracellular matrix components. Mol Genet Metab. 2013;109:289–95.
pubmed: 23680354
pmcid: 3925994
doi: 10.1016/j.ymgme.2013.04.014
Moskvina V, Holmans P, Schmidt KM, Craddock N. Design of case-controls studies with unscreened controls. Ann Hum Genet. 2005;69:566–76.
pubmed: 16138915
doi: 10.1111/j.1529-8817.2005.00175.x
Boyle EA, O’Roak BJ, Martin BK, Kumar A, Shendure J. MIPgen: optimized modeling and design of molecular inversion probes for targeted resequencing. Bioinformatics 2014;30:2670–2.
pubmed: 24867941
pmcid: 4155255
doi: 10.1093/bioinformatics/btu353
Udar N, Atilano SR, Brown DJ, Holguin B, Small K, Nesburn AB, et al. SOD1: a candidate gene for keratoconus. Investig Ophthalmol Vis Sci. 2006;47:3345–51.
doi: 10.1167/iovs.05-1500
O’Roak BJ, Vives L, Fu W, Egertson JD, Stanaway IB, Phelps IG, et al. Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders. Science 2012;338:1619–22.
pubmed: 23160955
pmcid: 3528801
doi: 10.1126/science.1227764
Dutta D, Gagliano Taliun SA, Weinstock JS, Zawistowski M, Sidore C, Fritsche LG, et al. Meta-MultiSKAT: Multiple phenotype meta-analysis for region-based association test. Genet Epidemiol. 2019;43:800–14.
pubmed: 31433078
pmcid: 7006736
doi: 10.1002/gepi.22248
Li B, Leal SM. Methods for detecting associations with rare variants for common diseases: application to analysis of sequence data. Am J Hum Genet. 2008;83:311–21.
pubmed: 18691683
pmcid: 2842185
doi: 10.1016/j.ajhg.2008.06.024
Liu DJ, Leal SM. A novel adaptive method for the analysis of next-generation sequencing data to detect complex trait associations with rare variants due to gene main effects and interactions. PLoS Genet. 2010;6:e1001156.
pubmed: 20976247
pmcid: 2954824
doi: 10.1371/journal.pgen.1001156
Price AL, Kryukov GV, de Bakker PI, Purcell SM, Staples J, Wei LJ, et al. Pooled association tests for rare variants in exon-resequencing studies. Am J Hum Genet. 2010;86:832–8.
pubmed: 20471002
pmcid: 3032073
doi: 10.1016/j.ajhg.2010.04.005
Ionita-Laza I, Lee S, Makarov V, Buxbaum JD, Lin X. Sequence kernel association tests for the combined effect of rare and common variants. Am J Hum Genet. 2013;92:841–53.
pubmed: 23684009
pmcid: 3675243
doi: 10.1016/j.ajhg.2013.04.015
Neale BM, Rivas MA, Voight BF, Altshuler D, Devlin B, Orho-Melander M, et al. Testing for an unusual distribution of rare variants. PLoS Genet. 2011;7:e1001322.
pubmed: 21408211
pmcid: 3048375
doi: 10.1371/journal.pgen.1001322
San Lucas FA, Wang G, Scheet P, Peng B. Integrated annotation and analysis of genetic variants from next-generation sequencing studies with variant tools. Bioinformatics 2012;28:421–2.
pubmed: 22138362
doi: 10.1093/bioinformatics/btr667
Storey JD, Tibshirani R. Statistical significance for genomewide studies. Proc Natl Acad Sci USA. 2003;100:9440–5.
pubmed: 12883005
pmcid: 170937
doi: 10.1073/pnas.1530509100
Lee S, Abecasis GR, Boehnke M, Lin X. Rare-variant association analysis: study designs and statistical tests. Am J Hum Genet. 2014;95:5–23.
pubmed: 24995866
pmcid: 4085641
doi: 10.1016/j.ajhg.2014.06.009
Landers JA, Hewitt AW, Dimasi DP, Charlesworth JC, Straga T, Mills RA, et al. Heritability of central corneal thickness in nuclear families. Investig Ophthalmol Vis Sci. 2009;50:4087–90.
doi: 10.1167/iovs.08-3271
Swierkowska J, Gajecka M. Genetic factors influencing the reduction of central corneal thickness in disorders affecting the eye. Ophthalmic Genet. 2017;38:501–10.
pubmed: 28453375
doi: 10.1080/13816810.2017.1313993
Iglesias AI, Mishra A, Vitart V, Bykhovskaya Y, Hohn R, Springelkamp H, et al. Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases. Nat Commun. 2018;9:1864.
pubmed: 29760442
pmcid: 5951816
doi: 10.1038/s41467-018-03646-6
Brady AF, Demirdas S, Fournel-Gigleux S, Ghali N, Giunta C, Kapferer-Seebacher I, et al. The Ehlers-Danlos syndromes, rare types. Am J Med Genet Part C Semin Med Genet. 2017;175:70–115.
pubmed: 28306225
doi: 10.1002/ajmg.c.31550
Graham SE, Nielsen JB, Zawistowski M, Zhou W, Fritsche LG, Gabrielsen ME, et al. Sex-specific and pleiotropic effects underlying kidney function identified from GWAS meta-analysis. Nat Commun. 2019;10:1847.
pubmed: 31015462
pmcid: 6478837
doi: 10.1038/s41467-019-09861-z
Huyghe JR, Bien SA, Harrison TA, Kang HM, Chen S, Schmit SL, et al. Discovery of common and rare genetic risk variants for colorectal cancer. Nat Genet. 2019;51:76–87.
pubmed: 30510241
doi: 10.1038/s41588-018-0286-6
Zweers MC, Bristow J, Steijlen PM, Dean WB, Hamel BC, Otero M, et al. Haploinsufficiency of TNXB is associated with hypermobility type of Ehlers-Danlos syndrome. Am J Hum Genet. 2003;73:214–7.
pubmed: 12865992
pmcid: 1180584
doi: 10.1086/376564
Schalkwijk J, Zweers MC, Steijlen PM, Dean WB, Taylor G, van Vlijmen IM, et al. A recessive form of the Ehlers-Danlos syndrome caused by tenascin-X deficiency. N Engl J Med. 2001;345:1167–75.
pubmed: 11642233
doi: 10.1056/NEJMoa002939
Nielsen JB, Thorolfsdottir RB, Fritsche LG, Zhou W, Skov MW, Graham SE, et al. Biobank-driven genomic discovery yields new insight into atrial fibrillation biology. Nat Genet. 2018;50:1234–9.
pubmed: 30061737
pmcid: 6530775
doi: 10.1038/s41588-018-0171-3
Zou Y, Zwolanek D, Izu Y, Gandhy S, Schreiber G, Brockmann K, et al. Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice. Hum Mol Genet. 2014;23:2339–52.
pubmed: 24334604
doi: 10.1093/hmg/ddt627
Kuming BS, Joffe L. Ehlers-Danlos syndrome associated with keratoconus. A case report. South Afr Med J. 1977;52:403–5.
Woodward EG, Morris MT. Joint hypermobility in keratoconus. Ophthalmic Physiol Opt. 1990;10:360–2.
pubmed: 2263369
doi: 10.1111/j.1475-1313.1990.tb00882.x
Street DA, Vinokur ET, Waring GO 3rd, Pollak SJ, Clements SD, Perkins JV. Lack of association between keratoconus, mitral valve prolapse, and joint hypermobility. Ophthalmology. 1991;98:170–6.
pubmed: 2008274
doi: 10.1016/S0161-6420(91)32320-0
Knowlton RG, Weaver EJ, Struyk AF, Knobloch WH, King RA, Norris K, et al. Genetic linkage analysis of hereditary arthro-ophthalmopathy (Stickler syndrome) and the type II procollagen gene. Am J Hum Genet. 1989;45:681–8.
pubmed: 2573273
pmcid: 1683441
Walter K, Tansek M, Tobias ES, Ikegawa S, Coucke P, Hyland J, et al. COL2A1-related skeletal dysplasias with predominant metaphyseal involvement. Am J Med Genet Part A. 2007;143A:161–7.
pubmed: 17163530
doi: 10.1002/ajmg.a.31516
McComish BJ, Sahebjada S, Bykhovskaya Y, Willoughby CE, Richardson AJ, Tenen A, et al. Association of genetic variation with keratoconus. JAMA Ophthalmol. 2020;138:174–81.
pubmed: 31855235
doi: 10.1001/jamaophthalmol.2019.5293