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

Adriana I. Iglesias, Aniket Mishra, Veronique Vitart, Yelena Bykhovskaya, René Höhn, Henriët 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 Siscovick, Paul Mitchell, Yih Chung Tham, Jonathan L. Haines, Lisa S. Kearns & 124 others Caroline Hayward, Yuan Shi, Elisabeth M. Van Leeuwen, Kent D. Taylor, Jie Jin Wang, Elena Rochtchina, John Attia, Rodney Scott, Elizabeth G. Holliday, Paul N. Baird, Jing Xie, Michael Inouye, Ananth Viswanathan, Xueling Sim, Pieter Bonnemaijer, Jerome I. Rotter, Nicholas G. Martin, Tanja Zeller, Richard A. Mills, Sandra E. Staffieri, Jost B. Jonas, Irene Schmidtmann, Thibaud Boutin, Jae H. Kang, Sionne E.M. Lucas, Tien Yin Wong, Manfred E. Beutel, James F. Wilson, R. Rand Allingham, Murray H. Brilliant, Donald L. Budenz, William G. Christen, John Fingert, David S. Friedman, Douglas Gaasterland, Terry Gaasterland, Michael A. Hauser, Peter Kraft, Richard K. Lee, Paul R. Lichter, Yutao Liu, Stephanie J. Loomis, Sayoko E. Moroi, Margaret A. Pericak-Vance, Anthony Realini, Julia E. Richards, Joel S. Schuman, William K. Scott, Kuldev Singh, Arthur J. Sit, Douglas Vollrath, Robert N. Weinreb, Gadi Wollstein, Donald J. Zack, Kang Zhang, Peter Donnelly, Ines Barroso, Jenefer M. Blackwell, Elvira Bramon, Matthew A. Brown, Juan P. Casas, Aiden Corvin, Panos Deloukas, Audrey Duncanson, Janusz Jankowski, Hugh S. Markus, Christopher G. Mathew, Colin N.A. Palmer, Robert 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 Pearson, Amy Strange, Zhan Su, Damjan Vukcevic, Cordelia Langford, Sarah E. Hunt, Sarah Edkins, Rhian Gwilliam, Hannah Blackburn, Suzannah J. Bumpstead, Serge Dronov, Matthew Gillman, Emma Gray, Naomi Hammond, Alagurevathi Jayakumar, Owen T. McCann, Jennifer Liddle, Simon C. Potter, Radhi Ravindrarajah, Michelle Ricketts, Matthew Waller, Paul Weston, Sara Widaa, Pamela Whittaker, André G. Uitterlinden, Eranga N. Vithana, Paul J. Foster, Pirro G. Hysi, Alex 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 E. Craig, Yaron S. Rabinowitz, Janey L. Wiggs, Kathryn P. Burdon, Cornelia M. Van Duijn, Stuart MacGregor

Research output: Contribution to journalArticle

2 Citations (Scopus)

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 languageEnglish (US)
Article number1864
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

eye diseases
Eye Diseases
genome
Genome-Wide Association Study
Keratoconus
Genes
genes
Connective Tissue
Loeys-Dietz Syndrome
glaucoma
connective tissue
Temazepam
Tissue
Myopia
Glaucoma
Cornea
myopia
Extracellular Matrix
Meta-Analysis
disorders

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Iglesias, A. I., Mishra, A., Vitart, V., Bykhovskaya, Y., Höhn, R., Springelkamp, H., ... 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]. https://doi.org/10.1038/s41467-018-03646-6

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

In: Nature Communications, Vol. 9, No. 1, 1864, 01.12.2018.

Research output: Contribution to journalArticle

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, D, Mitchell, P, Tham, YC, Haines, JL, Kearns, LS, Hayward, C, Shi, Y, Van Leeuwen, EM, Taylor, KD, Wang, JJ, Rochtchina, E, Attia, J, Scott, R, Holliday, EG, Baird, PN, Xie, J, Inouye, M, Viswanathan, A, Sim, X, Bonnemaijer, P, Rotter, JI, Martin, NG, Zeller, T, Mills, RA, Staffieri, SE, Jonas, JB, Schmidtmann, I, Boutin, T, Kang, JH, Lucas, SEM, Wong, TY, Beutel, ME, Wilson, JF, Allingham, RR, Brilliant, MH, Budenz, DL, Christen, WG, Fingert, J, Friedman, DS, Gaasterland, D, Gaasterland, T, Hauser, MA, Kraft, P, Lee, RK, Lichter, PR, Liu, Y, Loomis, SJ, Moroi, SE, Pericak-Vance, MA, Realini, A, Richards, JE, Schuman, JS, Scott, WK, Singh, K, Sit, AJ, Vollrath, D, Weinreb, RN, Wollstein, G, Zack, DJ, Zhang, K, Donnelly, P, Barroso, I, Blackwell, JM, Bramon, E, Brown, MA, Casas, JP, Corvin, A, Deloukas, P, Duncanson, A, Jankowski, J, Markus, HS, Mathew, CG, Palmer, CNA, Plomin, R, Rautanen, A, Sawcer, SJ, Trembath, RC, Wood, NW, Spencer, CCA, Band, G, Bellenguez, C, Freeman, C, Hellenthal, G, Giannoulatou, E, Pirinen, M, Pearson, R, Strange, A, Su, Z, Vukcevic, D, Langford, C, Hunt, SE, Edkins, S, Gwilliam, R, Blackburn, H, Bumpstead, SJ, Dronov, S, Gillman, M, Gray, E, Hammond, N, Jayakumar, A, McCann, OT, Liddle, J, Potter, SC, Ravindrarajah, R, Ricketts, M, Waller, M, Weston, P, Widaa, S, Whittaker, P, 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. https://doi.org/10.1038/s41467-018-03646-6
Iglesias, Adriana I. ; Mishra, Aniket ; Vitart, Veronique ; Bykhovskaya, Yelena ; Höhn, René ; Springelkamp, Henriët ; Cuellar-Partida, Gabriel ; Gharahkhani, Puya ; Bailey, Jessica N.Cooke ; Willoughby, Colin E. ; Li, Xiaohui ; Yazar, Seyhan ; Nag, Abhishek ; Khawaja, Anthony P. ; Polašek, Ozren ; Siscovick, David ; Mitchell, Paul ; Tham, Yih Chung ; Haines, Jonathan L. ; Kearns, Lisa S. ; Hayward, Caroline ; Shi, Yuan ; Van Leeuwen, Elisabeth M. ; Taylor, Kent D. ; Wang, Jie Jin ; Rochtchina, Elena ; Attia, John ; Scott, Rodney ; Holliday, Elizabeth G. ; Baird, Paul N. ; Xie, Jing ; Inouye, Michael ; Viswanathan, Ananth ; Sim, Xueling ; Bonnemaijer, Pieter ; Rotter, Jerome I. ; Martin, Nicholas G. ; Zeller, Tanja ; Mills, Richard A. ; Staffieri, Sandra E. ; Jonas, Jost B. ; Schmidtmann, Irene ; Boutin, Thibaud ; Kang, Jae H. ; Lucas, Sionne E.M. ; Wong, Tien Yin ; Beutel, Manfred E. ; Wilson, James F. ; Allingham, R. Rand ; Brilliant, Murray H. ; Budenz, Donald L. ; Christen, William G. ; Fingert, John ; Friedman, David S. ; Gaasterland, Douglas ; Gaasterland, Terry ; Hauser, Michael A. ; Kraft, Peter ; Lee, Richard K. ; Lichter, Paul R. ; Liu, Yutao ; Loomis, Stephanie J. ; Moroi, Sayoko E. ; Pericak-Vance, Margaret A. ; Realini, Anthony ; Richards, Julia E. ; Schuman, Joel S. ; Scott, William K. ; Singh, Kuldev ; Sit, Arthur J. ; Vollrath, Douglas ; Weinreb, Robert N. ; Wollstein, Gadi ; Zack, Donald J. ; Zhang, Kang ; Donnelly, Peter ; Barroso, Ines ; Blackwell, Jenefer M. ; Bramon, Elvira ; Brown, Matthew A. ; Casas, Juan P. ; Corvin, Aiden ; Deloukas, Panos ; Duncanson, Audrey ; Jankowski, Janusz ; Markus, Hugh S. ; Mathew, Christopher G. ; Palmer, Colin N.A. ; Plomin, Robert ; Rautanen, Anna ; Sawcer, Stephen J. ; Trembath, Richard C. ; Wood, Nicholas W. ; Spencer, Chris C.A. ; Band, Gavin ; Bellenguez, Céline ; Freeman, Colin ; Hellenthal, Garrett ; Giannoulatou, Eleni ; Pirinen, Matti ; Pearson, Richard ; Strange, Amy ; Su, Zhan ; Vukcevic, Damjan ; Langford, Cordelia ; Hunt, Sarah E. ; Edkins, Sarah ; Gwilliam, Rhian ; Blackburn, Hannah ; Bumpstead, Suzannah J. ; Dronov, Serge ; Gillman, Matthew ; Gray, Emma ; Hammond, Naomi ; Jayakumar, Alagurevathi ; McCann, Owen T. ; Liddle, Jennifer ; Potter, Simon C. ; Ravindrarajah, Radhi ; Ricketts, Michelle ; Waller, Matthew ; Weston, Paul ; Widaa, Sara ; Whittaker, Pamela ; Uitterlinden, André G. ; Vithana, Eranga N. ; Foster, Paul J. ; Hysi, Pirro G. ; Hewitt, Alex W. ; Khor, Chiea Chuen ; Pasquale, Louis R. ; Montgomery, Grant W. ; Klaver, Caroline C.W. ; Aung, Tin ; Pfeiffer, Norbert ; MacKey, David A. ; Hammond, Christopher J. ; Cheng, Ching Yu ; Craig, Jamie E. ; Rabinowitz, Yaron S. ; Wiggs, Janey L. ; Burdon, Kathryn P. ; Van Duijn, Cornelia M. ; MacGregor, Stuart. / Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases. In: Nature Communications. 2018 ; Vol. 9, No. 1.
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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 Veronique Vitart and Yelena Bykhovskaya and Ren{\'e} H{\"o}hn and Henri{\"e}t 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 Polašek and David Siscovick and Paul Mitchell 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 Wang, {Jie Jin} and Elena Rochtchina and John Attia and Rodney Scott and Holliday, {Elizabeth G.} and Baird, {Paul N.} and Jing Xie and Michael Inouye and Ananth Viswanathan and Xueling Sim and Pieter Bonnemaijer and Rotter, {Jerome I.} and Martin, {Nicholas G.} and Tanja Zeller and Mills, {Richard A.} and Staffieri, {Sandra E.} and Jonas, {Jost B.} and Irene Schmidtmann and Thibaud Boutin and Kang, {Jae H.} and Lucas, {Sionne E.M.} and Wong, {Tien Yin} and Beutel, {Manfred E.} and Wilson, {James F.} and Allingham, {R. Rand} and Brilliant, {Murray H.} and Budenz, {Donald L.} and Christen, {William G.} and John Fingert and Friedman, {David S.} and Douglas Gaasterland and Terry Gaasterland 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 Pericak-Vance, {Margaret A.} and Anthony Realini and Richards, {Julia E.} and Schuman, {Joel S.} and Scott, {William K.} and Kuldev Singh and Sit, {Arthur J.} and Douglas Vollrath and Weinreb, {Robert N.} and Gadi Wollstein and Zack, {Donald J.} and Kang Zhang and Peter Donnelly and Ines Barroso and Blackwell, {Jenefer M.} and Elvira Bramon and Brown, {Matthew A.} and Casas, {Juan P.} and Aiden Corvin and Panos Deloukas and Audrey Duncanson and Janusz Jankowski and Markus, {Hugh S.} and Mathew, {Christopher G.} and Palmer, {Colin N.A.} and Robert Plomin 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 Richard Pearson and Amy Strange and Zhan Su and Damjan Vukcevic and Cordelia Langford and Hunt, {Sarah E.} and Sarah Edkins and Rhian Gwilliam and Hannah Blackburn and Bumpstead, {Suzannah J.} and Serge Dronov and Matthew Gillman and Emma Gray and Naomi Hammond and Alagurevathi Jayakumar and McCann, {Owen T.} and Jennifer Liddle and Potter, {Simon C.} and Radhi Ravindrarajah and Michelle Ricketts and Matthew Waller and Paul Weston and Sara Widaa and Pamela Whittaker and Uitterlinden, {Andr{\'e} G.} and Vithana, {Eranga N.} and Foster, {Paul J.} and Hysi, {Pirro G.} and Hewitt, {Alex 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 E.} and Rabinowitz, {Yaron S.} and Wiggs, {Janey L.} and Burdon, {Kathryn P.} and {Van Duijn}, {Cornelia M.} and Stuart MacGregor",
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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, Veronique

AU - Bykhovskaya, Yelena

AU - Höhn, René

AU - Springelkamp, Henriët

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

AU - Mitchell, Paul

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, Jie Jin

AU - Rochtchina, Elena

AU - Attia, John

AU - Scott, Rodney

AU - Holliday, Elizabeth G.

AU - Baird, Paul N.

AU - Xie, Jing

AU - Inouye, Michael

AU - Viswanathan, Ananth

AU - Sim, Xueling

AU - Bonnemaijer, Pieter

AU - Rotter, Jerome I.

AU - Martin, Nicholas G.

AU - Zeller, Tanja

AU - Mills, Richard A.

AU - Staffieri, Sandra E.

AU - Jonas, Jost B.

AU - Schmidtmann, Irene

AU - Boutin, Thibaud

AU - Kang, Jae H.

AU - Lucas, Sionne E.M.

AU - Wong, Tien Yin

AU - Beutel, Manfred E.

AU - Wilson, James F.

AU - Allingham, R. Rand

AU - Brilliant, Murray H.

AU - Budenz, Donald L.

AU - Christen, William G.

AU - Fingert, John

AU - Friedman, David S.

AU - Gaasterland, Douglas

AU - Gaasterland, Terry

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 - Pericak-Vance, Margaret A.

AU - Realini, Anthony

AU - Richards, Julia E.

AU - Schuman, Joel S.

AU - Scott, William K.

AU - Singh, Kuldev

AU - Sit, Arthur J.

AU - Vollrath, Douglas

AU - Weinreb, Robert N.

AU - Wollstein, Gadi

AU - Zack, Donald J.

AU - Zhang, Kang

AU - Donnelly, Peter

AU - Barroso, Ines

AU - Blackwell, Jenefer M.

AU - Bramon, Elvira

AU - Brown, Matthew A.

AU - Casas, Juan P.

AU - Corvin, Aiden

AU - Deloukas, Panos

AU - Duncanson, Audrey

AU - Jankowski, Janusz

AU - Markus, Hugh S.

AU - Mathew, Christopher G.

AU - Palmer, Colin N.A.

AU - Plomin, Robert

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

AU - Strange, Amy

AU - Su, Zhan

AU - Vukcevic, Damjan

AU - Langford, Cordelia

AU - Hunt, Sarah E.

AU - Edkins, Sarah

AU - Gwilliam, Rhian

AU - Blackburn, Hannah

AU - Bumpstead, Suzannah J.

AU - Dronov, Serge

AU - Gillman, Matthew

AU - Gray, Emma

AU - Hammond, Naomi

AU - Jayakumar, Alagurevathi

AU - McCann, Owen T.

AU - Liddle, Jennifer

AU - Potter, Simon C.

AU - Ravindrarajah, Radhi

AU - Ricketts, Michelle

AU - Waller, Matthew

AU - Weston, Paul

AU - Widaa, Sara

AU - Whittaker, Pamela

AU - Uitterlinden, André G.

AU - Vithana, Eranga N.

AU - Foster, Paul J.

AU - Hysi, Pirro G.

AU - Hewitt, Alex 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 E.

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.

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