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

Nature Communications
Adriana I IglesiasStuart Macgregor

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.

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Citations

Mar 22, 2019·Nature Communications·Erna V IvarsdottirKari Stefansson
Mar 15, 2020·Molecular Biology and Evolution·Michael R McGowenAnd Stephen J Rossiter
Dec 5, 2019·Communications Biology·Pieter W M BonnemaijerCornelia M van Duijn
Dec 20, 2019·JAMA Ophthalmology·Bennet J McComishKathryn P Burdon
Jan 6, 2021·Genes·Ryan ZukermanThomas A Ciulla
Mar 29, 2020·American Journal of Ophthalmology·Fumihiko MabuchiUNKNOWN Japan Glaucoma Society Omics Group (JGS-OG)
Feb 27, 2021·Frontiers in Bioengineering and Biotechnology·Elizabeth M BoazakC Ross Ethier
Jan 12, 2020·Communications Biology·Pieter W M BonnemaijerCornelia M van Duijn
Mar 20, 2021·European Journal of Human Genetics : EJHG·Erik FransenGuy Van Camp
Dec 15, 2020·Experimental Eye Research·Yelena Bykhovskaya, Yaron S Rabinowitz
May 13, 2021·Ophthalmic Genetics·Mahdiyeh Harati-SadeghRamin Saravani
Jun 2, 2021·Annual Review of Vision Science·Zihe XuAnthony P Khawaja
Aug 10, 2021·Disease Models & Mechanisms·Chloe M StantonVeronique Vitart

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Software Mentioned

Affymetrix
CoJo
liftOver
Online Mendelian Inheritance in Man ( OMIM )
DEPICT
Ingenuity Pathway Analysis ( IPA )
INRICH
Genome
GCTA
HaploReg

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