Genome-wide analysis identified 17 new loci influencing intraocular pressure in Chinese population
|
摘要
Intraocular pressure(IOP) is a major risk factor for glaucoma. Genetic determinants of intraocular pressure can provide critical insights into the genetic architecture of glaucoma and, as a result, open new avenues for therapeutic intervention. We performed a genome-wide association study and replication analysis of 8,552 Chinese participants. In the genome-wide association study, we identified 51 loci that surpassed the significance of P<9×10~(-7), and we formally replicated these loci. A combined discovery and replication meta-analysis identified 21 genome-wide loci that surpassed the genome-wide significance of P<5×10~(-8), including 4 previously reported loci: rs145063132(7 p21.2, ETV1/DGKB), rs548030386(7 q31.2, ST7 near CAV1/CAV2), rs7047871(9 p24.2, GLIS3), and rs2472494(9 q31.1, ABCA1/SLC44 A1). Of the 17 newly identified loci, five were reported to have ocular related phenotypes: PTCH2(rs7525308 in 1 p34.1), LRIF1/DRAM2(rs1282146 in 1 p13.3), COLEC11(rs201143466 in 2 p25.3),SPTBN1(rs4514918 in 2 p16.2), and CRK(rs11078446 in 17 p13.3). The genetic loci identified in this study not only increase our understanding of the genes involved in intraocular pressure but also provide important genetic markers to improve future genetic screening and drug discovery for intraocular pressure disorders.
Intraocular pressure(IOP) is a major risk factor for glaucoma. Genetic determinants of intraocular pressure can provide critical insights into the genetic architecture of glaucoma and, as a result, open new avenues for therapeutic intervention. We performed a genome-wide association study and replication analysis of 8,552 Chinese participants. In the genome-wide association study, we identified 51 loci that surpassed the significance of P<9×10~(-7), and we formally replicated these loci. A combined discovery and replication meta-analysis identified 21 genome-wide loci that surpassed the genome-wide significance of P<5×10~(-8), including 4 previously reported loci: rs145063132(7 p21.2, ETV1/DGKB), rs548030386(7 q31.2, ST7 near CAV1/CAV2), rs7047871(9 p24.2, GLIS3), and rs2472494(9 q31.1, ABCA1/SLC44 A1). Of the 17 newly identified loci, five were reported to have ocular related phenotypes: PTCH2(rs7525308 in 1 p34.1), LRIF1/DRAM2(rs1282146 in 1 p13.3), COLEC11(rs201143466 in 2 p25.3),SPTBN1(rs4514918 in 2 p16.2), and CRK(rs11078446 in 17 p13.3). The genetic loci identified in this study not only increase our understanding of the genes involved in intraocular pressure but also provide important genetic markers to improve future genetic screening and drug discovery for intraocular pressure disorders.
Intraocular pressure(IOP) is a major risk factor for glaucoma. Genetic determinants of intraocular pressure can provide critical insights into the genetic architecture of glaucoma and, as a result, open new avenues for therapeutic intervention. We performed a genome-wide association study and replication analysis of 8,552 Chinese participants. In the genome-wide association study, we identified 51 loci that surpassed the significance of P<9×10~(-7), and we formally replicated these loci. A combined discovery and replication meta-analysis identified 21 genome-wide loci that surpassed the genome-wide significance of P<5×10~(-8), including 4 previously reported loci: rs145063132(7 p21.2, ETV1/DGKB), rs548030386(7 q31.2, ST7 near CAV1/CAV2), rs7047871(9 p24.2, GLIS3), and rs2472494(9 q31.1, ABCA1/SLC44 A1). Of the 17 newly identified loci, five were reported to have ocular related phenotypes: PTCH2(rs7525308 in 1 p34.1), LRIF1/DRAM2(rs1282146 in 1 p13.3), COLEC11(rs201143466 in 2 p25.3),SPTBN1(rs4514918 in 2 p16.2), and CRK(rs11078446 in 17 p13.3). The genetic loci identified in this study not only increase our understanding of the genes involved in intraocular pressure but also provide important genetic markers to improve future genetic screening and drug discovery for intraocular pressure disorders.
引文
Acott,T.S.,and Kelley,M.J.(2008).Extracellular matrix in the trabecular meshwork.Exp Eye Res 86,543-561.
Bailey,J.N.C.,Loomis,S.J.,Kang,J.H.,Allingham,R.R.,Gharahkhani,P.,Khor,C.C.,Burdon,K.P.,Aschard,H.,Chasman,D.I.,Igo,R.P.,et al.(2016).Genome-wide association analysis identifies TXNRD2,ATXN2and FOXC1 as susceptibility loci for primary open-angle glaucoma.Nat Genet 48,189-194.
Birtel,J.,Eisenberger,T.,Gliem,M.,Müller,P.L.,Herrmann,P.,Betz,C.,Zahnleiter,D.,Neuhaus,C.,Lenzner,S.,Holz,F.G.,et al.(2018).Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.Sci Rep 8,4824.
Boland,M.V.,Ervin,A.M.,Friedman,D.S.,Jampel,H.D.,Hawkins,B.S.,Vollenweider,D.,Chelladurai,Y.,Ward,D.,Suarez-Cuervo,C.,and Robinson,K.A.(2013).Comparative effectiveness of treatments for open-angle glaucoma:a systematic review for the U.S.Preventive Services Task Force.Ann Intern Med 158,271.
Bulik-Sullivan,B.K.,Loh,P.R.,Finucane,H.K.,Ripke,S.,Yang,J.,Yang,J.,Patterson,N.,Daly,M.J.,Price,A.L.,and Neale,B.M.(2015).LDScore regression distinguishes confounding from polygenicity in genome-wide association studies.Nat Genet 47,291-295.
Caspers,M.,Czogalla,K.J.,Liphardt,K.,Müller,J.,Westhofen,P.,Watzka,M.,and Oldenburg,J.(2015).Two enzymes catalyze vitamin K 2,3-epoxide reductase activity in mouse:VKORC1 is highly expressed in exocrine tissues while VKORC1L1 is highly expressed in brain.Thrombosis Res 135,977-983.
Chen,C.S.,Alonso,J.L.,Ostuni,E.,Whitesides,G.M.,and Ingber,D.E.(2003).Cell shape provides global control of focal adhesion assembly.Biochem Biophys Res Commun 307,355-361.
Chen,Y.,Lin,Y.,Vithana,E.N.,Jia,L.,Zuo,X.,Wong,T.Y.,Chen,L.J.,Zhu,X.,Tam,P.O.S.,Gong,B.,et al.(2014).Common variants near ABCA1 and in PMM2 are associated with primary open-angle glaucoma.Nat Genet 46,1115-1119.
Choquet,H.,Thai,K.K.,Yin,J.,Hoffmann,T.J.,Kvale,M.N.,Banda,Y.,Schaefer,C.,Risch,N.,Nair,K.S.,Melles,R.,et al.(2017).A large multi-ethnic genome-wide association study identifies novel genetic loci for intraocular pressure.Nat Commun 8,2108.
Cimbalistiene,L.,Lehnert,W.,Huoponen,K.,and Kucinskas,V.(2007).First reported case of lysinuric protein intolerance(LPI)in Lithuania,confirmed biochemically and by DNA analysis.J Appl Genet 48,277-280.
Collaborative Normal-Tension Glaucoma Study Group.(1998).The effectiveness of intraocular pressure reduction in the treatment of normaltension glaucoma.Am J Ophthalmol 126,498-505.
Collins,T.N.,Mao,Y.,Li,H.,Bouaziz,M.,Hong,A.,Feng,G.S.,Wang,F.,Quilliam,L.A.,Chen,L.,Park,T.,et al.(2018).Crk proteins transduce FGF signaling to promote lens fiber cell elongation.eLife 7,e32586.
Das,S.,Forer,L.,Sch?nherr,S.,Sidore,C.,Locke,A.E.,Kwong,A.,Vrieze,S.I.,Chew,E.Y.,Levy,S.,McGue,M.,et al.(2016).Nextgeneration genotype imputation service and methods.Nat Genet 48,1284-1287.
Delaneau,O.,Zagury,J.F.,and Marchini,J.(2013).Improved wholechromosome phasing for disease and population genetic studies.Nat Methods 10,5-6.
El-Asrag,M.E.,Sergouniotis,P.I.,McKibbin,M.,Plagnol,V.,Sheridan,E.,Waseem,N.,Abdelhamed,Z.,McKeefry,D.,Van Schil,K.,Poulter,J.A.,et al.(2015).Biallelic mutations in the autophagy regulator DRAM2cause retinal dystrophy with early macular involvement.Am J Human Genets 96,948-954.
Fuxman Bass,J.I.,Diallo,A.,Nelson,J.,Soto,J.M.,Myers,C.L.,and Walhout,A.J.M.(2013).Using networks to measure similarity between genes:association index selection.Nat Methods 10,1169-1176.
Gharahkhani,P.,Burdon,K.P.,Fogarty,R.,Sharma,S.,Hewitt,A.W.,Martin,S.,Law,M.H.,Cremin,K.,Bailey,J.N.C.,Loomis,S.J.,et al.(2014).Common variants near ABCA1,AFAP1 and GMDS confer risk of primary open-angle glaucoma.Nat Genet 46,1120-1125.
Heijl,A.,Leske,M.C.,Bengtsson,B.,Hyman,L.,and Hussein,M.(2002).Reduction of intraocular pressure and glaucoma progression:results from the early manifest glaucoma trial.Arch Ophthalmol 120,1268-1279.
Huang,D.W.,Sherman,B.T.,and Lempicki,R.A.(2009).Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.Nat Protoc 4,44-57.
Hysi,P.G.,Cheng,C.Y.,Springelkamp,H.,Macgregor,S.,Bailey,J.N.C.,Wojciechowski,R.,Vitart,V.,Nag,A.,Hewitt,A.W.,H?hn,R.,et al.(2014).Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma.Nat Genet 46,1126-1130.
Kahn,B.M.,Corman,T.S.,Lovelace,K.,Hong,M.,Krauss,R.S.,and Epstein,D.J.(2017).Prenatal ethanol exposure in mice phenocopies Cdon mutation by impeding Shh function in the etiology of optic nerve hypoplasia.Dis Model Mech 10,29-37.
Khawaja,A.P.,Cooke Bailey,J.N.,Wareham,N.J.,Scott,R.A.,Simcoe,M.,Igo,R.P.,Song,Y.E.,Wojciechowski,R.,Cheng,C.Y.,Khaw,P.T.,et al.(2018).Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary openangle glaucoma.Nat Genet 50,778-782.
Kim,M.S.,Pinto,S.M.,Getnet,D.,Nirujogi,R.S.,Manda,S.S.,Chaerkady,R.,Madugundu,A.K.,Kelkar,D.S.,Isserlin,R.,Jain,S.,et al.(2014).A draft map of the human proteome.Nature 509,575-581.
Lee,J.,Cox,B.D.,Daly,C.M.S.,Lee,C.,Nuckels,R.J.,Tittle,R.K.,Uribe,R.A.,and Gross,J.M.(2012).An ENU mutagenesis screen in zebrafish for visual system mutants identifies a novel splice-acceptor site mutation in patched2 that results in colobomas.Invest Ophthalmol Vis Sci 53,8214-8221.
Liu,X.Z.,Xia,X.J.,Xu,L.R,Pandya,A.,Liang,C.Y.,Blanton,S.H.,Brown,S.D.,Steel,K.P.,and Nance,W.E.(2000).Mutations in connexin31 underlie recessive as well as dominant non-syndromic hearing loss.Human Mol Genets 9,63-67.
López-Bigas,N.,Olivé,M.,Rabionet,R.,Ben-David,O.,Martínez-Matos,J.A.,Bravo,O.,Banchs,I.,Volpini,V.,Gasparini,P.,Avraham,K.B.,et al.(2001).Connexin 31(GJB3)is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment.Human Mol Genets 10,947-952.
Lu,C.,Kasik,J.,Stephan,D.A.,Yang,S.,Sperling,M.A.,and Menon,R.K.(2001).Grtp1,a novel gene regulated by growth hormone.Endocrinology 142,4568-4571.
Lu,T.Y.,Doherty,J.,and Freeman,M.R.(2014).DRK/DOS/SOS converge with Crk/Mbc/dCed-12 to activate Rac1 during glial engulfment of axonal debris.Proc Natl Acad Sci USA 111,12544-12549.
MacGregor,S.,Ong,J.S.,An,J.,Han,X.,Zhou,T.,Siggs,O.M.,Law,M.H.,Souzeau,E.,Sharma,S.,Lynn,D.J.,et al.(2018).Genome-wide association study of intraocular pressure uncovers new pathways to glaucoma.Nat Genet 50,1067-1071.
Morrison,J.C.,Johnson,E.C.,Cepurna,W.,and Jia,L.(2005).Understanding mechanisms of pressure-induced optic nerve damage.Prog Retinal Eye Res 24,217-240.
Motoyama,J.,Heng,H.,Crackower,M.A.,Takabatake,T.,Takeshima,K.,Tsui,L.C.,and Hui,C.(1998).Overlapping and non-overlapping Ptch2expression with Shh during mouse embryogenesis.Mech Dev 78,81-84.
Oddoux,S.,Brocard,J.,Schweitzer,A.,Szentesi,P.,Giannesini,B.,Brocard,J.,Fauré,J.,Pernet-Gallay,K.,Bendahan,D.,Lunardi,J.,et al.(2009).Triadin deletion induces impaired skeletal muscle function.JBiol Chem 284,34918-34929.
Ozel,A.B.,Moroi,S.E.,Reed,D.M.,Nika,M.,Schmidt,C.M.,Akbari,S.,Scott,K.,Rozsa,F.,Pawar,H.,Musch,D.C.,et al.(2014).Genomewide association study and meta-analysis of intraocular pressure.Hum Genet 133,41-57.
Quigley,H.A.,and Broman,A.T.(2006).The number of people with glaucoma worldwide in 2010 and 2020.Br J Ophthalmol 90,262-267.
Rooryck,C.,Diaz-Font,A.,Osborn,D.P.S.,Chabchoub,E.,HernandezHernandez,V.,Shamseldin,H.,Kenny,J.,Waters,A.,Jenkins,D.,Kaissi,A.A.,et al.(2011).Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.Nat Genet 43,197-203.
Roux-Buisson,N.,Cacheux,M.,Fourest-Lieuvin,A.,Fauconnier,J.,Brocard,J.,Denjoy,I.,Durand,P.,Guicheney,P.,Kyndt,F.,Leenhardt,A.,et al.(2012).Absence of triadin,a protein of the calcium release complex,is responsible for cardiac arrhythmia with sudden death in human.Human Mol Genets 21,2759-2767.
Sanfilippo,P.G.,Hewitt,A.W.,Hammond,C.J.,and Mackey,D.A.(2010).The heritability of ocular traits.Survey Ophthalmol 55,561-583.
Sarfarazi,M.,Akarsu,N.A.,Hossain,A.,Turacli,E.M.,Aktan,G.S.,Barsoum-Homsy,M.,Chevrette,L.,and Sayli,S.B.(1995).Assignment of a locus(GLC3A)for primary congenital glaucoma(Buphthalmos)to2p21 and evidence for genetic heterogeneity.Genomics 30,171-177.
Sergouniotis,P.I.,McKibbin,M.,Robson,A.G.,Bolz,H.J.,De Baere,E.,Müller,P.L.,Heller,R.,El-Asrag,M.E.,Van Schil,K.,Plagnol,V.,et al.(2015).Disease expression in autosomal recessive retinal dystrophy associated with mutations in the DRAM2 gene.Invest Ophthalmol Vis Sci 56,8083-8090.
Smits,N.C.,Kobayashi,T.,Srivastava,P.K.,Skopelja,S.,Ivy,J.A.,Elwood,D.J.,Stan,R.V.,Tsongalis,G.J.,Sellke,F.W.,Gross,P.L.,et al.(2017).HS3ST1 genotype regulates antithrombin’s inflammomodulatory tone and associates with atherosclerosis.Matrix Biol 63,69-90.
Springelkamp,H.,Iglesias,A.I.,Mishra,A.,H?hn,R.,Wojciechowski,R.,Khawaja,A.P.,Nag,A.,Wang,Y.X.,Wang,J.J.,Cuellar-Partida,G.,et al.(2017).New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics..Hum Mol Genet 26,ddw399.
Szklarczyk,D.,Franceschini,A.,Kuhn,M.,Simonovic,M.,Roth,A.,Minguez,P.,Doerks,T.,Stark,M.,Muller,J.,Bork,P.,et al.(2011).The STRING database in 2011:functional interaction networks of proteins,globally integrated and scored.Nucl Acids Res 39,D561-D568.
Tang,Y.,Katuri,V.,Dillner,A.,Mishra,B.,Deng,C.X.,and Mishra,L.(2003).Disruption of transforming growth factor-beta signaling in ELFbeta-spectrin-deficient mice.Science 299,574-577.
van Koolwijk,L.M.E.,Ramdas,W.D.,Ikram,M.K.,Jansonius,N.M.,Pasutto,F.,Hysi,P.G.,Macgregor,S.,Janssen,S.F.,Hewitt,A.W.,Viswanathan,A.C.,et al.(2012).Common genetic determinants of intraocular pressure and primary open-angle glaucoma.PLoS Genet 8,e1002611.
Vranka,J.A.,and Acott,T.S.(2017).Pressure-induced expression changes in segmental flow regions of the human trabecular meshwork.Exp Eye Res 158,67-72.
Vranka,J.A.,Kelley,M.J.,Acott,T.S.,and Keller,K.E.(2015).Extracellular matrix in the trabecular meshwork:intraocular pressure regulation and dysregulation in glaucoma.Exp Eye Res 133,112-125.
Wang,K.,Li,M.,and Hakonarson,H.(2010).ANNOVAR:functional annotation of genetic variants from high-throughput sequencing data.Nucleic Acids Res 38,e164.
Weinreb,R.N.,Aung,T.,and Medeiros,F.A.(2014).The pathophysiology and treatment of glaucoma.JAMA 311,1901-1911.
Weinreb,R.N.,Leung,C.K.S.,Crowston,J.G.,Medeiros,F.A.,Friedman,D.S.,Wiggs,J.L.,and Martin,K.R.(2016).Primary open-angle glaucoma.Nat Rev Dis Primers 2,16067.
Westhofen,P.,Watzka,M.,Marinova,M.,Hass,M.,Kirfel,G.,Müller,J.,Bevans,C.G.,Müller,C.R.,and Oldenburg,J.(2011).Human vitamin K 2,3-epoxide reductase complex subunit 1-like 1(VKORC1L1)mediates vitamin K-dependent intracellular antioxidant function.J Biol Chem 286,15085-15094.
Wolfs,R.C.,Klaver,C.C.,Ramrattan,R.S.,van Duijn,C.M.,Hofman,A.,and de Jong,P.T.(1998).Genetic risk of primary open-angle glaucoma.Population-based familial aggregation study.Arch Ophthalmol 116,1640-1645.
Yang,J.,Weedon,M.N.,Purcell,S.,Lettre,G.,Estrada,K.,Willer,C.J.,Smith,A.V.,Ingelsson,E.,O’Connell,J.R.,Mangino,M.,et al.(2011).Genomic inflation factors under polygenic inheritance.Eur J Hum Genet 19,807-812.
Yoon,J.H.,Her,S.,Kim,M.,Jang,I.S.,and Park,J.(2012).The expression of damage-regulated autophagy modulator 2(DRAM2)contributes to autophagy induction.Mol Biol Rep 39,1087-1093.
Zuberi,K.,Franz,M.,Rodriguez,H.,Montojo,J.,Lopes,C.T.,Bader,G.D.,and Morris,Q.(2013).GeneMANIA prediction server 2013 update.Nucleic Acids Res 41,W115-W122.
Bailey,J.N.C.,Loomis,S.J.,Kang,J.H.,Allingham,R.R.,Gharahkhani,P.,Khor,C.C.,Burdon,K.P.,Aschard,H.,Chasman,D.I.,Igo,R.P.,et al.(2016).Genome-wide association analysis identifies TXNRD2,ATXN2and FOXC1 as susceptibility loci for primary open-angle glaucoma.Nat Genet 48,189-194.
Birtel,J.,Eisenberger,T.,Gliem,M.,Müller,P.L.,Herrmann,P.,Betz,C.,Zahnleiter,D.,Neuhaus,C.,Lenzner,S.,Holz,F.G.,et al.(2018).Clinical and genetic characteristics of 251 consecutive patients with macular and cone/cone-rod dystrophy.Sci Rep 8,4824.
Boland,M.V.,Ervin,A.M.,Friedman,D.S.,Jampel,H.D.,Hawkins,B.S.,Vollenweider,D.,Chelladurai,Y.,Ward,D.,Suarez-Cuervo,C.,and Robinson,K.A.(2013).Comparative effectiveness of treatments for open-angle glaucoma:a systematic review for the U.S.Preventive Services Task Force.Ann Intern Med 158,271.
Bulik-Sullivan,B.K.,Loh,P.R.,Finucane,H.K.,Ripke,S.,Yang,J.,Yang,J.,Patterson,N.,Daly,M.J.,Price,A.L.,and Neale,B.M.(2015).LDScore regression distinguishes confounding from polygenicity in genome-wide association studies.Nat Genet 47,291-295.
Caspers,M.,Czogalla,K.J.,Liphardt,K.,Müller,J.,Westhofen,P.,Watzka,M.,and Oldenburg,J.(2015).Two enzymes catalyze vitamin K 2,3-epoxide reductase activity in mouse:VKORC1 is highly expressed in exocrine tissues while VKORC1L1 is highly expressed in brain.Thrombosis Res 135,977-983.
Chen,C.S.,Alonso,J.L.,Ostuni,E.,Whitesides,G.M.,and Ingber,D.E.(2003).Cell shape provides global control of focal adhesion assembly.Biochem Biophys Res Commun 307,355-361.
Chen,Y.,Lin,Y.,Vithana,E.N.,Jia,L.,Zuo,X.,Wong,T.Y.,Chen,L.J.,Zhu,X.,Tam,P.O.S.,Gong,B.,et al.(2014).Common variants near ABCA1 and in PMM2 are associated with primary open-angle glaucoma.Nat Genet 46,1115-1119.
Choquet,H.,Thai,K.K.,Yin,J.,Hoffmann,T.J.,Kvale,M.N.,Banda,Y.,Schaefer,C.,Risch,N.,Nair,K.S.,Melles,R.,et al.(2017).A large multi-ethnic genome-wide association study identifies novel genetic loci for intraocular pressure.Nat Commun 8,2108.
Cimbalistiene,L.,Lehnert,W.,Huoponen,K.,and Kucinskas,V.(2007).First reported case of lysinuric protein intolerance(LPI)in Lithuania,confirmed biochemically and by DNA analysis.J Appl Genet 48,277-280.
Collaborative Normal-Tension Glaucoma Study Group.(1998).The effectiveness of intraocular pressure reduction in the treatment of normaltension glaucoma.Am J Ophthalmol 126,498-505.
Collins,T.N.,Mao,Y.,Li,H.,Bouaziz,M.,Hong,A.,Feng,G.S.,Wang,F.,Quilliam,L.A.,Chen,L.,Park,T.,et al.(2018).Crk proteins transduce FGF signaling to promote lens fiber cell elongation.eLife 7,e32586.
Das,S.,Forer,L.,Sch?nherr,S.,Sidore,C.,Locke,A.E.,Kwong,A.,Vrieze,S.I.,Chew,E.Y.,Levy,S.,McGue,M.,et al.(2016).Nextgeneration genotype imputation service and methods.Nat Genet 48,1284-1287.
Delaneau,O.,Zagury,J.F.,and Marchini,J.(2013).Improved wholechromosome phasing for disease and population genetic studies.Nat Methods 10,5-6.
El-Asrag,M.E.,Sergouniotis,P.I.,McKibbin,M.,Plagnol,V.,Sheridan,E.,Waseem,N.,Abdelhamed,Z.,McKeefry,D.,Van Schil,K.,Poulter,J.A.,et al.(2015).Biallelic mutations in the autophagy regulator DRAM2cause retinal dystrophy with early macular involvement.Am J Human Genets 96,948-954.
Fuxman Bass,J.I.,Diallo,A.,Nelson,J.,Soto,J.M.,Myers,C.L.,and Walhout,A.J.M.(2013).Using networks to measure similarity between genes:association index selection.Nat Methods 10,1169-1176.
Gharahkhani,P.,Burdon,K.P.,Fogarty,R.,Sharma,S.,Hewitt,A.W.,Martin,S.,Law,M.H.,Cremin,K.,Bailey,J.N.C.,Loomis,S.J.,et al.(2014).Common variants near ABCA1,AFAP1 and GMDS confer risk of primary open-angle glaucoma.Nat Genet 46,1120-1125.
Heijl,A.,Leske,M.C.,Bengtsson,B.,Hyman,L.,and Hussein,M.(2002).Reduction of intraocular pressure and glaucoma progression:results from the early manifest glaucoma trial.Arch Ophthalmol 120,1268-1279.
Huang,D.W.,Sherman,B.T.,and Lempicki,R.A.(2009).Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources.Nat Protoc 4,44-57.
Hysi,P.G.,Cheng,C.Y.,Springelkamp,H.,Macgregor,S.,Bailey,J.N.C.,Wojciechowski,R.,Vitart,V.,Nag,A.,Hewitt,A.W.,H?hn,R.,et al.(2014).Genome-wide analysis of multi-ancestry cohorts identifies new loci influencing intraocular pressure and susceptibility to glaucoma.Nat Genet 46,1126-1130.
Kahn,B.M.,Corman,T.S.,Lovelace,K.,Hong,M.,Krauss,R.S.,and Epstein,D.J.(2017).Prenatal ethanol exposure in mice phenocopies Cdon mutation by impeding Shh function in the etiology of optic nerve hypoplasia.Dis Model Mech 10,29-37.
Khawaja,A.P.,Cooke Bailey,J.N.,Wareham,N.J.,Scott,R.A.,Simcoe,M.,Igo,R.P.,Song,Y.E.,Wojciechowski,R.,Cheng,C.Y.,Khaw,P.T.,et al.(2018).Genome-wide analyses identify 68 new loci associated with intraocular pressure and improve risk prediction for primary openangle glaucoma.Nat Genet 50,778-782.
Kim,M.S.,Pinto,S.M.,Getnet,D.,Nirujogi,R.S.,Manda,S.S.,Chaerkady,R.,Madugundu,A.K.,Kelkar,D.S.,Isserlin,R.,Jain,S.,et al.(2014).A draft map of the human proteome.Nature 509,575-581.
Lee,J.,Cox,B.D.,Daly,C.M.S.,Lee,C.,Nuckels,R.J.,Tittle,R.K.,Uribe,R.A.,and Gross,J.M.(2012).An ENU mutagenesis screen in zebrafish for visual system mutants identifies a novel splice-acceptor site mutation in patched2 that results in colobomas.Invest Ophthalmol Vis Sci 53,8214-8221.
Liu,X.Z.,Xia,X.J.,Xu,L.R,Pandya,A.,Liang,C.Y.,Blanton,S.H.,Brown,S.D.,Steel,K.P.,and Nance,W.E.(2000).Mutations in connexin31 underlie recessive as well as dominant non-syndromic hearing loss.Human Mol Genets 9,63-67.
López-Bigas,N.,Olivé,M.,Rabionet,R.,Ben-David,O.,Martínez-Matos,J.A.,Bravo,O.,Banchs,I.,Volpini,V.,Gasparini,P.,Avraham,K.B.,et al.(2001).Connexin 31(GJB3)is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment.Human Mol Genets 10,947-952.
Lu,C.,Kasik,J.,Stephan,D.A.,Yang,S.,Sperling,M.A.,and Menon,R.K.(2001).Grtp1,a novel gene regulated by growth hormone.Endocrinology 142,4568-4571.
Lu,T.Y.,Doherty,J.,and Freeman,M.R.(2014).DRK/DOS/SOS converge with Crk/Mbc/dCed-12 to activate Rac1 during glial engulfment of axonal debris.Proc Natl Acad Sci USA 111,12544-12549.
MacGregor,S.,Ong,J.S.,An,J.,Han,X.,Zhou,T.,Siggs,O.M.,Law,M.H.,Souzeau,E.,Sharma,S.,Lynn,D.J.,et al.(2018).Genome-wide association study of intraocular pressure uncovers new pathways to glaucoma.Nat Genet 50,1067-1071.
Morrison,J.C.,Johnson,E.C.,Cepurna,W.,and Jia,L.(2005).Understanding mechanisms of pressure-induced optic nerve damage.Prog Retinal Eye Res 24,217-240.
Motoyama,J.,Heng,H.,Crackower,M.A.,Takabatake,T.,Takeshima,K.,Tsui,L.C.,and Hui,C.(1998).Overlapping and non-overlapping Ptch2expression with Shh during mouse embryogenesis.Mech Dev 78,81-84.
Oddoux,S.,Brocard,J.,Schweitzer,A.,Szentesi,P.,Giannesini,B.,Brocard,J.,Fauré,J.,Pernet-Gallay,K.,Bendahan,D.,Lunardi,J.,et al.(2009).Triadin deletion induces impaired skeletal muscle function.JBiol Chem 284,34918-34929.
Ozel,A.B.,Moroi,S.E.,Reed,D.M.,Nika,M.,Schmidt,C.M.,Akbari,S.,Scott,K.,Rozsa,F.,Pawar,H.,Musch,D.C.,et al.(2014).Genomewide association study and meta-analysis of intraocular pressure.Hum Genet 133,41-57.
Quigley,H.A.,and Broman,A.T.(2006).The number of people with glaucoma worldwide in 2010 and 2020.Br J Ophthalmol 90,262-267.
Rooryck,C.,Diaz-Font,A.,Osborn,D.P.S.,Chabchoub,E.,HernandezHernandez,V.,Shamseldin,H.,Kenny,J.,Waters,A.,Jenkins,D.,Kaissi,A.A.,et al.(2011).Mutations in lectin complement pathway genes COLEC11 and MASP1 cause 3MC syndrome.Nat Genet 43,197-203.
Roux-Buisson,N.,Cacheux,M.,Fourest-Lieuvin,A.,Fauconnier,J.,Brocard,J.,Denjoy,I.,Durand,P.,Guicheney,P.,Kyndt,F.,Leenhardt,A.,et al.(2012).Absence of triadin,a protein of the calcium release complex,is responsible for cardiac arrhythmia with sudden death in human.Human Mol Genets 21,2759-2767.
Sanfilippo,P.G.,Hewitt,A.W.,Hammond,C.J.,and Mackey,D.A.(2010).The heritability of ocular traits.Survey Ophthalmol 55,561-583.
Sarfarazi,M.,Akarsu,N.A.,Hossain,A.,Turacli,E.M.,Aktan,G.S.,Barsoum-Homsy,M.,Chevrette,L.,and Sayli,S.B.(1995).Assignment of a locus(GLC3A)for primary congenital glaucoma(Buphthalmos)to2p21 and evidence for genetic heterogeneity.Genomics 30,171-177.
Sergouniotis,P.I.,McKibbin,M.,Robson,A.G.,Bolz,H.J.,De Baere,E.,Müller,P.L.,Heller,R.,El-Asrag,M.E.,Van Schil,K.,Plagnol,V.,et al.(2015).Disease expression in autosomal recessive retinal dystrophy associated with mutations in the DRAM2 gene.Invest Ophthalmol Vis Sci 56,8083-8090.
Smits,N.C.,Kobayashi,T.,Srivastava,P.K.,Skopelja,S.,Ivy,J.A.,Elwood,D.J.,Stan,R.V.,Tsongalis,G.J.,Sellke,F.W.,Gross,P.L.,et al.(2017).HS3ST1 genotype regulates antithrombin’s inflammomodulatory tone and associates with atherosclerosis.Matrix Biol 63,69-90.
Springelkamp,H.,Iglesias,A.I.,Mishra,A.,H?hn,R.,Wojciechowski,R.,Khawaja,A.P.,Nag,A.,Wang,Y.X.,Wang,J.J.,Cuellar-Partida,G.,et al.(2017).New insights into the genetics of primary open-angle glaucoma based on meta-analyses of intraocular pressure and optic disc characteristics..Hum Mol Genet 26,ddw399.
Szklarczyk,D.,Franceschini,A.,Kuhn,M.,Simonovic,M.,Roth,A.,Minguez,P.,Doerks,T.,Stark,M.,Muller,J.,Bork,P.,et al.(2011).The STRING database in 2011:functional interaction networks of proteins,globally integrated and scored.Nucl Acids Res 39,D561-D568.
Tang,Y.,Katuri,V.,Dillner,A.,Mishra,B.,Deng,C.X.,and Mishra,L.(2003).Disruption of transforming growth factor-beta signaling in ELFbeta-spectrin-deficient mice.Science 299,574-577.
van Koolwijk,L.M.E.,Ramdas,W.D.,Ikram,M.K.,Jansonius,N.M.,Pasutto,F.,Hysi,P.G.,Macgregor,S.,Janssen,S.F.,Hewitt,A.W.,Viswanathan,A.C.,et al.(2012).Common genetic determinants of intraocular pressure and primary open-angle glaucoma.PLoS Genet 8,e1002611.
Vranka,J.A.,and Acott,T.S.(2017).Pressure-induced expression changes in segmental flow regions of the human trabecular meshwork.Exp Eye Res 158,67-72.
Vranka,J.A.,Kelley,M.J.,Acott,T.S.,and Keller,K.E.(2015).Extracellular matrix in the trabecular meshwork:intraocular pressure regulation and dysregulation in glaucoma.Exp Eye Res 133,112-125.
Wang,K.,Li,M.,and Hakonarson,H.(2010).ANNOVAR:functional annotation of genetic variants from high-throughput sequencing data.Nucleic Acids Res 38,e164.
Weinreb,R.N.,Aung,T.,and Medeiros,F.A.(2014).The pathophysiology and treatment of glaucoma.JAMA 311,1901-1911.
Weinreb,R.N.,Leung,C.K.S.,Crowston,J.G.,Medeiros,F.A.,Friedman,D.S.,Wiggs,J.L.,and Martin,K.R.(2016).Primary open-angle glaucoma.Nat Rev Dis Primers 2,16067.
Westhofen,P.,Watzka,M.,Marinova,M.,Hass,M.,Kirfel,G.,Müller,J.,Bevans,C.G.,Müller,C.R.,and Oldenburg,J.(2011).Human vitamin K 2,3-epoxide reductase complex subunit 1-like 1(VKORC1L1)mediates vitamin K-dependent intracellular antioxidant function.J Biol Chem 286,15085-15094.
Wolfs,R.C.,Klaver,C.C.,Ramrattan,R.S.,van Duijn,C.M.,Hofman,A.,and de Jong,P.T.(1998).Genetic risk of primary open-angle glaucoma.Population-based familial aggregation study.Arch Ophthalmol 116,1640-1645.
Yang,J.,Weedon,M.N.,Purcell,S.,Lettre,G.,Estrada,K.,Willer,C.J.,Smith,A.V.,Ingelsson,E.,O’Connell,J.R.,Mangino,M.,et al.(2011).Genomic inflation factors under polygenic inheritance.Eur J Hum Genet 19,807-812.
Yoon,J.H.,Her,S.,Kim,M.,Jang,I.S.,and Park,J.(2012).The expression of damage-regulated autophagy modulator 2(DRAM2)contributes to autophagy induction.Mol Biol Rep 39,1087-1093.
Zuberi,K.,Franz,M.,Rodriguez,H.,Montojo,J.,Lopes,C.T.,Bader,G.D.,and Morris,Q.(2013).GeneMANIA prediction server 2013 update.Nucleic Acids Res 41,W115-W122.