Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Adriana I. Iglesias; Aniket Mishra; Véronique Vitart; Yelena Bykhovskaya; René Höhn; Henriette Springelkamp; Gabriel Cuellar-Partida; Puya Gharahkhani; Jessica N.Cooke Bailey; Colin E. Willoughby; Xiaohui Li; Seyhan Yazar; Abhishek Nag; Anthony P. Khawaja; Ozren Polašek; David S. Siscovick; Paul G. Mitchell; Yih Chung Tham; Jonathan L. Haines; Lisa S. Kearns; Caroline Hayward; Yuan Shi; Elisabeth M. Van Leeuwen; Kent D. Taylor; Jiejin Wang; Elena Rochtchina; John R. Attia; Rodney J. Scott; Elizabeth G. Holliday; Tien Yin Wong; Paul N. Baird; Jing Xie; Michael Inouye; Ananth C. Viswanathan; Xueling Sim; Pieter W.M. Bonnemaijer; Jerome I. Rotter; Nicholas G. Martin; Tanja Zeller; Richard A.D. Mills; Emmanuelle Souzeau; Sandra Elfride Staffieri; Jost Bruno Jonas; Irene Schmidtmann; Thibaud S. Boutin; Jaehee Kang; Sionne E.M. Lucas; Manfred E. Beutel; James F. Wilson; Peter J. Donnelly; Inês Barroso; Jenefer Mary Blackwell; Elvira Bramon; Matthew A. Brown; Juan Pablo Casas; Aiden Corvin; Panos Deloukas; Audrey Duncanson; Janusz Jankowski; Hugh Stephen Markus; Christopher G. Mathew; Colin Neil Palmer; Robert J. Plomin; Anna Rautanen; Stephen J. Sawcer; Richard C. Trembath; Nicholas W. Wood; Chris C.A. Spencer; Gavin Band; Céline Bellenguez; Colin Freeman; Garrett Hellenthal; Eleni Giannoulatou; Matti Pirinen; Richard D. Pearson; Amy Strange; Zhan Su; Damjan Vukcevic; Cordelia F. Langford; Sarah E. Hunt; Sarah J. Edkins; Rhian G. Gwilliam; Hannah Blackburn; Suzannah J. Bumpstead; Serge Dronov; Matthew W. Gillman; Emma Gray; Naomi Hammond; Alagurevathi Jayakumar; Owen T. McCann; Jennifer Liddle; Simon C. Potter; Rathi Sri Ravindrarajah; Michelle Ricketts; Matthew J. Waller; Paul Weston; Sara Widaa; Pamela Whittaker; Robert Rand Allingham; Murray H. Brilliant; Donald L. Budenz; William Gerard Christen; John H. Fingert; David Steven Friedman; Douglas E. Gaasterland; Terry M. Gaasterland; Michael A. Hauser; Peter Kraft; Richard K. Lee; Paul R. Lichter; Yutao Liu; Stephanie J. Loomis; Sayoko E. Moroi; Brian W. Kunkle; Anthony T. Realini; Julia E. Richards; Joel S. Schuman; William K. Scott; Kuldev Singh; Arthur J. Sit; Arthur J. Sit; Robert N. Weinreb; Gadi Wollstein; Donald J. Zack; Donald J. Zack; André G. Uitterlinden; Eranga Nishanthie Vithana; Paul J. Foster; Pirro G. Hysi; A. W. Hewitt; Chiea Chuen Khor; Louis R. Pasquale; Grant W. Montgomery; Caroline C.W. Klaver; Tin Aung; Norbert Pfeiffer; David A. Mackey; Christopher J. Hammond; Ching Yu Cheng; Jamie Evan Craig; Yaron S. Rabinowitz; Janey L. Wiggs; Kathryn P. Burdon; Cornelia M. Van Duijn; Stuart MacGregor

doi:10.1038/s41467-018-03646-6

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

Adriana I. Iglesias, Aniket Mishra, Véronique Vitart, Yelena Bykhovskaya, René Höhn, Henriette Springelkamp, Gabriel Cuellar-Partida, Puya Gharahkhani, Jessica N.Cooke Bailey, Colin E. Willoughby, Xiaohui Li, Seyhan Yazar, Abhishek Nag, Anthony P. Khawaja, Ozren Polašek, David S. Siscovick, Paul G. Mitchell, Yih Chung Tham, Jonathan L. Haines, Lisa S. KearnsCaroline Hayward, Yuan Shi, Elisabeth M. Van Leeuwen, Kent D. Taylor, Jiejin Wang, Elena Rochtchina, John R. Attia, Rodney J. Scott, Elizabeth G. Holliday, Tien Yin Wong, Paul N. Baird, Jing Xie, Michael Inouye, Ananth C. Viswanathan, Xueling Sim, Pieter W.M. Bonnemaijer, Jerome I. Rotter, Nicholas G. Martin, Tanja Zeller, Richard A.D. Mills, Emmanuelle Souzeau, Sandra Elfride Staffieri, Jost Bruno Jonas, Irene Schmidtmann, Thibaud S. Boutin, Jaehee Kang, Sionne E.M. Lucas, Manfred E. Beutel, James F. Wilson, Peter J. Donnelly, Inês Barroso, Jenefer Mary Blackwell, Elvira Bramon, Matthew A. Brown, Juan Pablo Casas, Aiden Corvin, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh Stephen Markus, Christopher G. Mathew, Colin Neil Palmer, Robert J. Plomin, Anna Rautanen, Stephen J. Sawcer, Richard C. Trembath, Nicholas W. Wood, Chris C.A. Spencer, Gavin Band, Céline Bellenguez, Colin Freeman, Garrett Hellenthal, Eleni Giannoulatou, Matti Pirinen, Richard D. Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia F. Langford, Sarah E. Hunt, Sarah J. Edkins, Rhian G. Gwilliam, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Matthew W. Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T. McCann, Jennifer Liddle, Simon C. Potter, Rathi Sri Ravindrarajah, Michelle Ricketts, Matthew J. Waller, Paul Weston, Sara Widaa, Pamela Whittaker, Robert Rand Allingham, Murray H. Brilliant, Donald L. Budenz, William Gerard Christen, John H. Fingert, David Steven Friedman, Douglas E. Gaasterland, Terry M. Gaasterland, Michael A. Hauser, Peter Kraft, Richard K. Lee, Paul R. Lichter, Yutao Liu, Stephanie J. Loomis, Sayoko E. Moroi, Brian W. Kunkle, Anthony T. Realini, Julia E. Richards, Joel S. Schuman, William K. Scott, Kuldev Singh, Arthur J. Sit, Arthur J. Sit, Robert N. Weinreb, Gadi Wollstein, Donald J. Zack, Donald J. Zack, André G. Uitterlinden, Eranga Nishanthie Vithana, Paul J. Foster, Pirro G. Hysi, A. W. Hewitt, Chiea Chuen Khor, Louis R. Pasquale, Grant W. Montgomery, Caroline C.W. Klaver, Tin Aung, Norbert Pfeiffer, David A. Mackey, Christopher J. Hammond, Ching Yu Cheng, Jamie Evan Craig, Yaron S. Rabinowitz, Janey L. Wiggs, Kathryn P. Burdon, Cornelia M. Van Duijn, Stuart MacGregor

College of Medicine and Public Health

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Abstract

Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10^-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

Original language	English
Article number	1864
Pages (from-to)	1864-1864
Number of pages	1
Journal	Nature Communications
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41467-018-03646-6
Publication status	Published - 1 Dec 2018

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Iglesias_Cross-Ancestry_P2019Final published version, 1.32 MBLicence: CC BY

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Iglesias, A. I., Mishra, A., Vitart, V., Bykhovskaya, Y., Höhn, R., Springelkamp, H., Cuellar-Partida, G., Gharahkhani, P., Bailey, J. N. C., Willoughby, C. E., Li, X., Yazar, S., Nag, A., Khawaja, A. P., Polašek, O., Siscovick, D. S., Mitchell, P. G., Tham, Y. C., Haines, J. L., ... MacGregor, S. (2018). Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases. Nature Communications, 9(1), 1864-1864. Article 1864. https://doi.org/10.1038/s41467-018-03646-6

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title = "Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases",

abstract = "Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.",

author = "Iglesias, {Adriana I.} and Aniket Mishra and V{\'e}ronique Vitart and Yelena Bykhovskaya and Ren{\'e} H{\"o}hn and Henriette Springelkamp and Gabriel Cuellar-Partida and Puya Gharahkhani and Bailey, {Jessica N.Cooke} and Willoughby, {Colin E.} and Xiaohui Li and Seyhan Yazar and Abhishek Nag and Khawaja, {Anthony P.} and Ozren Pola{\v s}ek and Siscovick, {David S.} and Mitchell, {Paul G.} and Tham, {Yih Chung} and Haines, {Jonathan L.} and Kearns, {Lisa S.} and Caroline Hayward and Yuan Shi and {Van Leeuwen}, {Elisabeth M.} and Taylor, {Kent D.} and Jiejin Wang and Elena Rochtchina and Attia, {John R.} and Scott, {Rodney J.} and Holliday, {Elizabeth G.} and Wong, {Tien Yin} and Baird, {Paul N.} and Jing Xie and Michael Inouye and Viswanathan, {Ananth C.} and Xueling Sim and Bonnemaijer, {Pieter W.M.} and Rotter, {Jerome I.} and Martin, {Nicholas G.} and Tanja Zeller and Mills, {Richard A.D.} and Emmanuelle Souzeau and Staffieri, {Sandra Elfride} and Jonas, {Jost Bruno} and Irene Schmidtmann and Boutin, {Thibaud S.} and Jaehee Kang and Lucas, {Sionne E.M.} and Beutel, {Manfred E.} and Wilson, {James F.} and Donnelly, {Peter J.} and In{\^e}s Barroso and Blackwell, {Jenefer Mary} and Elvira Bramon and Brown, {Matthew A.} and Casas, {Juan Pablo} and Aiden Corvin and Panos Deloukas and Audrey Duncanson and Janusz Jankowski and Markus, {Hugh Stephen} and Mathew, {Christopher G.} and Palmer, {Colin Neil} and Plomin, {Robert J.} and Anna Rautanen and Sawcer, {Stephen J.} and Trembath, {Richard C.} and Wood, {Nicholas W.} and Spencer, {Chris C.A.} and Gavin Band and C{\'e}line Bellenguez and Colin Freeman and Garrett Hellenthal and Eleni Giannoulatou and Matti Pirinen and Pearson, {Richard D.} and Amy Strange and Zhan Su and Damjan Vukcevic and Langford, {Cordelia F.} and Hunt, {Sarah E.} and Edkins, {Sarah J.} and Gwilliam, {Rhian G.} and Hannah Blackburn and Bumpstead, {Suzannah J.} and Serge Dronov and Gillman, {Matthew W.} and Emma Gray and Naomi Hammond and Alagurevathi Jayakumar and McCann, {Owen T.} and Jennifer Liddle and Potter, {Simon C.} and Ravindrarajah, {Rathi Sri} and Michelle Ricketts and Waller, {Matthew J.} and Paul Weston and Sara Widaa and Pamela Whittaker and Allingham, {Robert Rand} and Brilliant, {Murray H.} and Budenz, {Donald L.} and Christen, {William Gerard} and Fingert, {John H.} and Friedman, {David Steven} and Gaasterland, {Douglas E.} and Gaasterland, {Terry M.} and Hauser, {Michael A.} and Peter Kraft and Lee, {Richard K.} and Lichter, {Paul R.} and Yutao Liu and Loomis, {Stephanie J.} and Moroi, {Sayoko E.} and Kunkle, {Brian W.} and Realini, {Anthony T.} and Richards, {Julia E.} and Schuman, {Joel S.} and Scott, {William K.} and Kuldev Singh and Sit, {Arthur J.} and Sit, {Arthur J.} and Weinreb, {Robert N.} and Gadi Wollstein and Zack, {Donald J.} and Zack, {Donald J.} and Uitterlinden, {Andr{\'e} G.} and Vithana, {Eranga Nishanthie} and Foster, {Paul J.} and Hysi, {Pirro G.} and Hewitt, {A. W.} and Khor, {Chiea Chuen} and Pasquale, {Louis R.} and Montgomery, {Grant W.} and Klaver, {Caroline C.W.} and Tin Aung and Norbert Pfeiffer and Mackey, {David A.} and Hammond, {Christopher J.} and Cheng, {Ching Yu} and Craig, {Jamie Evan} and Rabinowitz, {Yaron S.} and Wiggs, {Janey L.} and Burdon, {Kathryn P.} and {Van Duijn}, {Cornelia M.} and Stuart MacGregor",

year = "2018",

month = dec,

day = "1",

doi = "10.1038/s41467-018-03646-6",

language = "English",

volume = "9",

pages = "1864--1864",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature",

number = "1",

}

Iglesias, AI, Mishra, A, Vitart, V, Bykhovskaya, Y, Höhn, R, Springelkamp, H, Cuellar-Partida, G, Gharahkhani, P, Bailey, JNC, Willoughby, CE, Li, X, Yazar, S, Nag, A, Khawaja, AP, Polašek, O, Siscovick, DS, Mitchell, PG, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, Van Leeuwen, EM, Taylor, KD, Wang, J, Rochtchina, E, Attia, JR, Scott, RJ, Holliday, EG, Wong, TY, Baird, PN, Xie, J, Inouye, M, Viswanathan, AC, Sim, X, Bonnemaijer, PWM, Rotter, JI, Martin, NG, Zeller, T, Mills, RAD , Souzeau, E, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, TS, Kang, J, Lucas, SEM, Beutel, ME, Wilson, JF, Donnelly, PJ, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CN, Plomin, RJ, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, RD, Strange, A, Su, Z, Vukcevic, D, Langford, CF, Hunt, SE, Edkins, SJ, Gwilliam, RG, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, MW, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, RS, Ricketts, M, Waller, MJ, Weston, P, Widaa, S, Whittaker, P, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, JH, Friedman, DS, Gaasterland, DE, Gaasterland, TM, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Kunkle, BW, Realini, AT, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Sit, AJ, Weinreb, RN, Wollstein, G, Zack, DJ, Zack, DJ, Uitterlinden, AG, Vithana, EN, Foster, PJ, Hysi, PG, Hewitt, AW, Khor, CC, Pasquale, LR, Montgomery, GW, Klaver, CCW, Aung, T, Pfeiffer, N, Mackey, DA, Hammond, CJ, Cheng, CY, Craig, JE, Rabinowitz, YS, Wiggs, JL, Burdon, KP, Van Duijn, CM & MacGregor, S 2018, 'Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases', Nature Communications, vol. 9, no. 1, 1864, pp. 1864-1864. https://doi.org/10.1038/s41467-018-03646-6

TY - JOUR

T1 - Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

AU - Iglesias, Adriana I.

AU - Mishra, Aniket

AU - Vitart, Véronique

AU - Bykhovskaya, Yelena

AU - Höhn, René

AU - Springelkamp, Henriette

AU - Cuellar-Partida, Gabriel

AU - Gharahkhani, Puya

AU - Bailey, Jessica N.Cooke

AU - Willoughby, Colin E.

AU - Li, Xiaohui

AU - Yazar, Seyhan

AU - Nag, Abhishek

AU - Khawaja, Anthony P.

AU - Polašek, Ozren

AU - Siscovick, David S.

AU - Mitchell, Paul G.

AU - Tham, Yih Chung

AU - Haines, Jonathan L.

AU - Kearns, Lisa S.

AU - Hayward, Caroline

AU - Shi, Yuan

AU - Van Leeuwen, Elisabeth M.

AU - Taylor, Kent D.

AU - Wang, Jiejin

AU - Rochtchina, Elena

AU - Attia, John R.

AU - Scott, Rodney J.

AU - Holliday, Elizabeth G.

AU - Wong, Tien Yin

AU - Baird, Paul N.

AU - Xie, Jing

AU - Inouye, Michael

AU - Viswanathan, Ananth C.

AU - Sim, Xueling

AU - Bonnemaijer, Pieter W.M.

AU - Rotter, Jerome I.

AU - Martin, Nicholas G.

AU - Zeller, Tanja

AU - Mills, Richard A.D.

AU - Souzeau, Emmanuelle

AU - Staffieri, Sandra Elfride

AU - Jonas, Jost Bruno

AU - Schmidtmann, Irene

AU - Boutin, Thibaud S.

AU - Kang, Jaehee

AU - Lucas, Sionne E.M.

AU - Beutel, Manfred E.

AU - Wilson, James F.

AU - Donnelly, Peter J.

AU - Barroso, Inês

AU - Blackwell, Jenefer Mary

AU - Bramon, Elvira

AU - Brown, Matthew A.

AU - Casas, Juan Pablo

AU - Corvin, Aiden

AU - Deloukas, Panos

AU - Duncanson, Audrey

AU - Jankowski, Janusz

AU - Markus, Hugh Stephen

AU - Mathew, Christopher G.

AU - Palmer, Colin Neil

AU - Plomin, Robert J.

AU - Rautanen, Anna

AU - Sawcer, Stephen J.

AU - Trembath, Richard C.

AU - Wood, Nicholas W.

AU - Spencer, Chris C.A.

AU - Band, Gavin

AU - Bellenguez, Céline

AU - Freeman, Colin

AU - Hellenthal, Garrett

AU - Giannoulatou, Eleni

AU - Pirinen, Matti

AU - Pearson, Richard D.

AU - Strange, Amy

AU - Su, Zhan

AU - Vukcevic, Damjan

AU - Langford, Cordelia F.

AU - Hunt, Sarah E.

AU - Edkins, Sarah J.

AU - Gwilliam, Rhian G.

AU - Blackburn, Hannah

AU - Bumpstead, Suzannah J.

AU - Dronov, Serge

AU - Gillman, Matthew W.

AU - Gray, Emma

AU - Hammond, Naomi

AU - Jayakumar, Alagurevathi

AU - McCann, Owen T.

AU - Liddle, Jennifer

AU - Potter, Simon C.

AU - Ravindrarajah, Rathi Sri

AU - Ricketts, Michelle

AU - Waller, Matthew J.

AU - Weston, Paul

AU - Widaa, Sara

AU - Whittaker, Pamela

AU - Allingham, Robert Rand

AU - Brilliant, Murray H.

AU - Budenz, Donald L.

AU - Christen, William Gerard

AU - Fingert, John H.

AU - Friedman, David Steven

AU - Gaasterland, Douglas E.

AU - Gaasterland, Terry M.

AU - Hauser, Michael A.

AU - Kraft, Peter

AU - Lee, Richard K.

AU - Lichter, Paul R.

AU - Liu, Yutao

AU - Loomis, Stephanie J.

AU - Moroi, Sayoko E.

AU - Kunkle, Brian W.

AU - Realini, Anthony T.

AU - Richards, Julia E.

AU - Schuman, Joel S.

AU - Scott, William K.

AU - Singh, Kuldev

AU - Sit, Arthur J.

AU - Weinreb, Robert N.

AU - Wollstein, Gadi

AU - Zack, Donald J.

AU - Uitterlinden, André G.

AU - Vithana, Eranga Nishanthie

AU - Foster, Paul J.

AU - Hysi, Pirro G.

AU - Hewitt, A. W.

AU - Khor, Chiea Chuen

AU - Pasquale, Louis R.

AU - Montgomery, Grant W.

AU - Klaver, Caroline C.W.

AU - Aung, Tin

AU - Pfeiffer, Norbert

AU - Mackey, David A.

AU - Hammond, Christopher J.

AU - Cheng, Ching Yu

AU - Craig, Jamie Evan

AU - Rabinowitz, Yaron S.

AU - Wiggs, Janey L.

AU - Burdon, Kathryn P.

AU - Van Duijn, Cornelia M.

AU - MacGregor, Stuart

PY - 2018/12/1

Y1 - 2018/12/1

N2 - Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

AB - Central corneal thickness (CCT) is a highly heritable trait associated with complex eye diseases such as keratoconus and glaucoma. We perform a genome-wide association meta-analysis of CCT and identify 19 novel regions. In addition to adding support for known connective tissue-related pathways, pathway analyses uncover previously unreported gene sets. Remarkably, >20% of the CCT-loci are near or within Mendelian disorder genes. These included FBN1, ADAMTS2 and TGFB2 which associate with connective tissue disorders (Marfan, Ehlers-Danlos and Loeys-Dietz syndromes), and the LUM-DCN-KERA gene complex involved in myopia, corneal dystrophies and cornea plana. Using index CCT-increasing variants, we find a significant inverse correlation in effect sizes between CCT and keratoconus (r =-0.62, P = 5.30 × 10-5) but not between CCT and primary open-angle glaucoma (r =-0.17, P = 0.2). Our findings provide evidence for shared genetic influences between CCT and keratoconus, and implicate candidate genes acting in collagen and extracellular matrix regulation.

UR - https://doi.org/10.1038/s41467-018-07819-1

UR - http://www.scopus.com/inward/record.url?scp=85047061045&partnerID=8YFLogxK

U2 - 10.1038/s41467-018-03646-6

DO - 10.1038/s41467-018-03646-6

M3 - Article

SN - 2041-1723

VL - 9

SP - 1864

EP - 1864

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 1864

ER -

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases

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