. 2017 Mar 30:8:14898.

doi: 10.1038/ncomms14898.

Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy

Natalie A Afshari¹, Robert P Igo Jr², Nathan J Morris², Dwight Stambolian³, Shiwani Sharma⁴, V Lakshmi Pulagam², Steven Dunn⁵, John F Stamler⁶, Barbara J Truitt², Jacqueline Rimmler⁷, Abraham Kuot⁴, Christopher R Croasdale⁸, Xuejun Qin⁷, Kathryn P Burdon^{4

9}, S Amer Riazuddin¹⁰, Richard Mills⁴, Sonja Klebe^{4

11}, Mollie A Minear⁷, Jiagang Zhao¹, Elmer Balajonda¹², George O Rosenwasser¹³, Keith H Baratz¹⁴, V Vinod Mootha¹⁵, Sanjay V Patel¹⁴, Simon G Gregory⁷, Joan E Bailey-Wilson¹⁶, Marianne O Price¹⁷, Francis W Price Jr¹⁷, Jamie E Craig⁴, John H Fingert⁶, John D Gottsch¹⁰, Anthony J Aldave¹⁸, Gordon K Klintworth^{12

19}, Jonathan H Lass^{2

20}, Yi-Ju Li^{7

21}, Sudha K Iyengar^{2

20}

Affiliations

¹ Shiley Eye Institute, University of California, La Jolla, California 92093, USA.
² Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
³ Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
⁴ Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia.
⁵ Michigan Cornea Consultants, PC, Southfield, Michigan 48034, USA.
⁶ Department of Ophthalmology, University of Iowa, College of Medicine, Iowa City, Iowa 52242, USA.
⁷ Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27701, USA.
⁸ Davis Duehr Dean Clinic, Madison, Wisconsin 53715, USA.
⁹ Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia.
¹⁰ The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
¹¹ Department of Pathology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia.
¹² Duke University Eye Center, Duke University Medical Center, Durham, North Carolina 27710, USA.
¹³ Central Pennsylvania Eye Institute, Hershey, Pennsylvania 17033, USA.
¹⁴ Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota 55905, USA.
¹⁵ Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
¹⁶ Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health and Johns Hopkins University, Baltimore, Maryland 21224, USA.
¹⁷ Price Vision Group, Indianapolis, Indiana 46260, USA.
¹⁸ Stein Eye Institute, University of California, Los Angeles, California 90095, USA.
¹⁹ Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
²⁰ Department of Ophthalmology and Visual Sciences, Case Western Reserve University and University Hospitals Eye Institute, Cleveland, Ohio 44106, USA.
²¹ Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina 27710, USA.

PMID: 28358029
PMCID: PMC5379100
DOI: 10.1038/ncomms14898

Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy

Natalie A Afshari et al. Nat Commun. 2017.

. 2017 Mar 30:8:14898.

doi: 10.1038/ncomms14898.

Authors

Affiliations

¹ Shiley Eye Institute, University of California, La Jolla, California 92093, USA.
² Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
³ Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
⁴ Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia.
⁵ Michigan Cornea Consultants, PC, Southfield, Michigan 48034, USA.
⁶ Department of Ophthalmology, University of Iowa, College of Medicine, Iowa City, Iowa 52242, USA.
⁷ Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27701, USA.
⁸ Davis Duehr Dean Clinic, Madison, Wisconsin 53715, USA.
⁹ Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia.
¹⁰ The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
¹¹ Department of Pathology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia.
¹² Duke University Eye Center, Duke University Medical Center, Durham, North Carolina 27710, USA.
¹³ Central Pennsylvania Eye Institute, Hershey, Pennsylvania 17033, USA.
¹⁴ Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota 55905, USA.
¹⁵ Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
¹⁶ Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health and Johns Hopkins University, Baltimore, Maryland 21224, USA.
¹⁷ Price Vision Group, Indianapolis, Indiana 46260, USA.
¹⁸ Stein Eye Institute, University of California, Los Angeles, California 90095, USA.
¹⁹ Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
²⁰ Department of Ophthalmology and Visual Sciences, Case Western Reserve University and University Hospitals Eye Institute, Cleveland, Ohio 44106, USA.
²¹ Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina 27710, USA.

PMID: 28358029
PMCID: PMC5379100
DOI: 10.1038/ncomms14898

Abstract

The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal organization are highly heritable. To understand the genetic aetiology of Fuchs endothelial corneal dystrophy (FECD), the most prevalent corneal disorder requiring transplantation, we conducted a genome-wide association study (GWAS) on 1,404 FECD cases and 2,564 controls of European ancestry, followed by replication and meta-analysis, for a total of 2,075 cases and 3,342 controls. We identify three novel loci meeting genome-wide significance (P<5 × 10^-8): KANK4 rs79742895, LAMC1 rs3768617 and LINC00970/ATP1B1 rs1200114. We also observe an overwhelming effect of the established TCF4 locus. Interestingly, we detect differential sex-specific association at LAMC1, with greater risk in women, and TCF4, with greater risk in men. Combining GWAS results with biological evidence we expand the knowledge of common FECD loci from one to four, and provide a deeper understanding of the underlying pathogenic basis of FECD.

PubMed Disclaimer

Conflict of interest statement

The authors declare no competing financial interests.

Figures

**Figure 1. Results from GWAS for FECD.**
Negative log P values (vertical axis) from 8,680,745 SNPs are shown. The red horizontal line marks genome-wide significance (P=5 × 10⁻⁸). Negative log P values are condensed above P=10⁻¹². Vertical grey lines are chromosome boundaries. The genomic control parameter was 1.033, indicating adequate control of test statistic inflation from population stratification (Supplementary Fig. 2).

**Figure 2. ROC curves for FECD status.**
Curves are shown from genetic risk scores based on all replicated loci (black), rs784257 in *TCF4* only (blue) and all loci except rs784257 (magenta).

See this image and copyright information in PMC

References

1. Eye Bank Association of America. 2015 Eye Banking Statistical Report (Eye Bank Association of America, Washington, DC, 2016).
1. Fuchs E. Dystrophia epithelialis corneae. Arch. Clin. Exp. Ophthalmol. 76, 478–508 (1910).
1. Musch D. C., Niziol L. M., Stein J. D., Kamyar R. M. & Sugar A. Prevalence of corneal dystrophies in the United States: estimates from claims data. Invest. Ophthalmol. Vis. Sci. 52, 6959–6963 (2011). - PMC - PubMed
1. Gottsch J. D. et al. Inheritance of a novel COL8A2 mutation defines a distinct early-onset subtype of Fuchs corneal dystrophy. Invest. Ophthalmol. Vis. Sci. 46, 1934–1939 (2005). - PubMed
1. Krachmer J. H., Purcell J. J. Jr, Young C. W. & Bucher K. D. Corneal endothelial dystrophy. A study of 64 families. Arch. Ophthalmol. 96, 2036–2039 (1978). - PubMed

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions

Supplementary concepts

Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
- scite Smart Citations
Medical
- MedlinePlus Health Information
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy

Affiliations

Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

MeSH terms

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Miscellaneous