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 (US) |
|---|---|
| Article number | 1864 |
| Journal | Nature communications |
| Volume | 9 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2018 |
ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Access to Document
Other files and links
Fingerprint
Dive into the research topics of 'Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases'. Together they form a unique fingerprint.Cite this
- APA
- Standard
- Harvard
- Vancouver
- Author
- BIBTEX
- RIS
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 journal › Article › peer-review
}
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, 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
N1 - Publisher Copyright: © 2018 The Author(s).
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 - http://www.scopus.com/inward/record.url?scp=85047061045&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047061045&partnerID=8YFLogxK
U2 - 10.1038/s41467-018-03646-6
DO - 10.1038/s41467-018-03646-6
M3 - Article
C2 - 29760442
AN - SCOPUS:85047061045
VL - 9
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1864
ER -