title: Genome-wide association study identifies three novel loci in Fuchs endothelial corneal dystrophy.
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.
authors.affiliation: Shiley Eye Institute, University of California, La Jolla, California 92093, USA.
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Afshari
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Robert P
authors.initials: RP
authors.lastname: Igo
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Nathan J
authors.initials: NJ
authors.lastname: Morris
authors.affiliation: Department of Ophthalmology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Dwight
authors.initials: D
authors.lastname: Stambolian
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia.
authors.forename: Shiwani
authors.initials: S
authors.lastname: Sharma
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: V Lakshmi
authors.initials: VL
authors.lastname: Pulagam
authors.affiliation: Michigan Cornea Consultants, PC, Southfield, Michigan 48034, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Dunn
authors.affiliation: Department of Ophthalmology, University of Iowa, College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Stamler
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Truitt
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27701, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Rimmler
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia.
authors.forename: Abraham
authors.initials: A
authors.lastname: Kuot
authors.affiliation: Davis Duehr Dean Clinic, Madison, Wisconsin 53715, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Croasdale
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27701, USA.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Qin
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia.|Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania 7000, Australia.
authors.forename: Kathryn P
authors.identifier: 0000-0001-8217-1249
authors.initials: KP
authors.lastname: Burdon
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: S Amer
authors.initials: SA
authors.lastname: Riazuddin
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia.
authors.forename: Richard
authors.initials: R
authors.lastname: Mills
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia.|Department of Pathology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia.
authors.forename: Sonja
authors.initials: S
authors.lastname: Klebe
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27701, USA.
authors.forename: Mollie A
authors.initials: MA
authors.lastname: Minear
authors.affiliation: Shiley Eye Institute, University of California, La Jolla, California 92093, USA.
authors.forename: Jiagang
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Duke University Eye Center, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Elmer
authors.initials: E
authors.lastname: Balajonda
authors.affiliation: Central Pennsylvania Eye Institute, Hershey, Pennsylvania 17033, USA.
authors.forename: George O
authors.initials: GO
authors.lastname: Rosenwasser
authors.affiliation: Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Keith H
authors.initials: KH
authors.lastname: Baratz
authors.affiliation: Department of Ophthalmology, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA.
authors.forename: V Vinod
authors.initials: VV
authors.lastname: Mootha
authors.affiliation: Department of Ophthalmology, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: Sanjay V
authors.identifier: 0000-0001-6694-1530
authors.initials: SV
authors.lastname: Patel
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27701, USA.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Gregory
authors.affiliation: Computational and Statistical Genomics Branch, National Human Genome Research Institute, National Institutes of Health and Johns Hopkins University, Baltimore, Maryland 21224, USA.
authors.forename: Joan E
authors.identifier: 0000-0002-9153-2920
authors.initials: JE
authors.lastname: Bailey-Wilson
authors.affiliation: Price Vision Group, Indianapolis, Indiana 46260, USA.
authors.forename: Marianne O
authors.initials: MO
authors.lastname: Price
authors.affiliation: Price Vision Group, Indianapolis, Indiana 46260, USA.
authors.forename: Francis W
authors.initials: FW
authors.lastname: Price
authors.affiliation: Department of Ophthalmology, Flinders Medical Centre, Flinders University, Adelaide, South Australia 5042, Australia.
authors.forename: Jamie E
authors.initials: JE
authors.lastname: Craig
authors.affiliation: Department of Ophthalmology, University of Iowa, College of Medicine, Iowa City, Iowa 52242, USA.
authors.forename: John H
authors.initials: JH
authors.lastname: Fingert
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Gottsch
authors.affiliation: Stein Eye Institute, University of California, Los Angeles, California 90095, USA.
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Aldave
authors.affiliation: Duke University Eye Center, Duke University Medical Center, Durham, North Carolina 27710, USA.|Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Klintworth
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA.|Department of Ophthalmology and Visual Sciences, Case Western Reserve University and University Hospitals Eye Institute, Cleveland, Ohio 44106, USA.
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Lass
authors.affiliation: Duke Molecular Physiology Institute, Duke University Medical Center, Durham, North Carolina 27701, USA.|Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina 27710, USA.
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Li
authors.affiliation: Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, Ohio 44106, USA.|Department of Ophthalmology and Visual Sciences, Case Western Reserve University and University Hospitals Eye Institute, Cleveland, Ohio 44106, USA.
authors.forename: Sudha K
authors.initials: SK
authors.lastname: Iyengar
mesh_terms: D005642:Fuchs' Endothelial Dystrophy / Q000235:genetics*; D056426:Genetic Loci; D055106:Genome-Wide Association Study; D006801:Humans; D012372:ROC Curve; D015203:Reproducibility of Results; D012307:Risk Factors