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

Blue Mountains Eye Study—GWAS group; NEIGHBORHOOD Consortium; Wellcome Trust Case Control Consortium 2; Emmanuelle Souzeau

doi:10.1038/s41467-018-03646-6

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

Blue Mountains Eye Study—GWAS group
, NEIGHBORHOOD Consortium
, Wellcome Trust Case Control Consortium 2
, Emmanuelle Souzeau

Science and Engineering Office

Research output: Contribution to journal › Article › peer-review

79 Citations (Scopus)

381 Downloads (Pure)

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
Number of pages	11
Journal	Nature Communications
Volume	9
Issue number	1
Early online date	14 May 2018
DOIs	https://doi.org/10.1038/s41467-018-03646-6
Publication status	Published - 1 Dec 2018

Keywords

ADAMTS Proteins/genetics
Asian Continental Ancestry Group
Cornea/abnormalities
Corneal Diseases/ethnology
Corneal Dystrophies, Hereditary/ethnology
Decorin/genetics
Ehlers-Danlos Syndrome/ethnology
European Continental Ancestry Group
Eye Diseases, Hereditary/ethnology
Fibrillin-1/genetics
Gene Expression
Genome, Human
Genome-Wide Association Study
Glaucoma, Open-Angle/ethnology
Humans
Keratoconus/ethnology
Loeys-Dietz Syndrome/ethnology
Lumican/genetics
Marfan Syndrome/ethnology
Mendelian Randomization Analysis
Myopia/ethnology
Polymorphism, Single Nucleotide
Proteoglycans/genetics
Quantitative Trait Loci
Quantitative Trait, Heritable
Transforming Growth Factor beta2/genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-018-03646-6Licence: CC BY

Final Published VersionFinal published version, 1.32 MBLicence: CC BY
Final Published Version (Author Correction)Final published version, 889 KBLicence: CC BY

Cite this

@article{ef334248fdee41cd808c073b7db84e71,

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.",

keywords = "ADAMTS Proteins/genetics, Asian Continental Ancestry Group, Cornea/abnormalities, Corneal Diseases/ethnology, Corneal Dystrophies, Hereditary/ethnology, Decorin/genetics, Ehlers-Danlos Syndrome/ethnology, European Continental Ancestry Group, Eye Diseases, Hereditary/ethnology, Fibrillin-1/genetics, Gene Expression, Genome, Human, Genome-Wide Association Study, Glaucoma, Open-Angle/ethnology, Humans, Keratoconus/ethnology, Loeys-Dietz Syndrome/ethnology, Lumican/genetics, Marfan Syndrome/ethnology, Mendelian Randomization Analysis, Myopia/ethnology, Polymorphism, Single Nucleotide, Proteoglycans/genetics, Quantitative Trait Loci, Quantitative Trait, Heritable, Transforming Growth Factor beta2/genetics",

author = "\{Blue Mountains Eye Study—GWAS group\} and \{NEIGHBORHOOD Consortium\} and \{Wellcome Trust Case Control Consortium 2\} and 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 Pola{\v s}ek 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 Scott, \{William K.\} and Peter Donnelly and Palmer, \{Colin N.A.\} and Emmanuelle Souzeau",

year = "2018",

month = dec,

day = "1",

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

language = "English",

volume = "9",

pages = "1864",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Cross-ancestry genome-wide association analysis of corneal thickness strengthens link between complex and Mendelian eye diseases. / Blue Mountains Eye Study—GWAS group; NEIGHBORHOOD Consortium; Wellcome Trust Case Control Consortium 2 et al.
In: Nature Communications, Vol. 9, No. 1, 1864, 01.12.2018, p. 1864.

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 - Blue Mountains Eye Study—GWAS group

AU - NEIGHBORHOOD Consortium

AU - Wellcome Trust Case Control Consortium 2

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 - Scott, William K.

AU - Donnelly, Peter

AU - Palmer, Colin N.A.

AU - Souzeau, Emmanuelle

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.

KW - ADAMTS Proteins/genetics

KW - Asian Continental Ancestry Group

KW - Cornea/abnormalities

KW - Corneal Diseases/ethnology

KW - Corneal Dystrophies, Hereditary/ethnology

KW - Decorin/genetics

KW - Ehlers-Danlos Syndrome/ethnology

KW - European Continental Ancestry Group

KW - Eye Diseases, Hereditary/ethnology

KW - Fibrillin-1/genetics

KW - Gene Expression

KW - Genome, Human

KW - Genome-Wide Association Study

KW - Glaucoma, Open-Angle/ethnology

KW - Humans

KW - Keratoconus/ethnology

KW - Loeys-Dietz Syndrome/ethnology

KW - Lumican/genetics

KW - Marfan Syndrome/ethnology

KW - Mendelian Randomization Analysis

KW - Myopia/ethnology

KW - Polymorphism, Single Nucleotide

KW - Proteoglycans/genetics

KW - Quantitative Trait Loci

KW - Quantitative Trait, Heritable

KW - Transforming Growth Factor beta2/genetics

UR - https://www.scopus.com/pages/publications/85047061045

U2 - 10.1038/s41467-018-03646-6

DO - 10.1038/s41467-018-03646-6

M3 - Article

C2 - 29760442

AN - SCOPUS:85047061045

SN - 2041-1723

VL - 9

SP - 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

Abstract

Keywords

UN SDGs

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