title: Replication of TCF4 through association and linkage studies in late-onset Fuchs endothelial corneal dystrophy.
abstract: Fuchs endothelial corneal dystrophy (FECD) is a common, late-onset disorder of the corneal endothelium. Although progress has been made in understanding the genetic basis of FECD by studying large families in which the phenotype is transmitted in an autosomal dominant fashion, a recently reported genome-wide association study identified common alleles at a locus on chromosome 18 near TCF4 which confer susceptibility to FECD. Here, we report the findings of our independent validation study for TCF4 using the largest FECD dataset to date (450 FECD cases and 340 normal controls). Logistic regression with sex as a covariate was performed for three genetic models: dominant (DOM), additive (ADD), and recessive (REC). We found significant association with rs613872, the target marker reported by Baratz et al.(2010), for all three genetic models (DOM: P = 9.33×10(-35); ADD: P = 7.48×10(-30); REC: P = 5.27×10(-6)). To strengthen the association study, we also conducted a genome-wide linkage scan on 64 multiplex families, composed primarily of affected sibling pairs (ASPs), using both parametric and non-parametric two-point and multipoint analyses. The most significant linkage region localizes to chromosome 18 from 69.94cM to 85.29cM, with a peak multipoint HLOD = 2.5 at rs1145315 (75.58cM) under the DOM model, mapping 1.5 Mb proximal to rs613872. In summary, our study presents evidence to support the role of the intronic TCF4 single nucleotide polymorphism rs613872 in late-onset FECD through both association and linkage studies.
authors.affiliation: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina, United States of America. yiju.li@duke.edu
authors.forename: Yi-Ju
authors.initials: YJ
authors.lastname: Li
authors.forename: Mollie A
authors.initials: MA
authors.lastname: Minear
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Rimmler
authors.forename: Bei
authors.initials: B
authors.lastname: Zhao
authors.forename: Elmer
authors.initials: E
authors.lastname: Balajonda
authors.forename: Michael A
authors.initials: MA
authors.lastname: Hauser
authors.forename: R Rand
authors.initials: RR
authors.lastname: Allingham
authors.forename: Allen O
authors.initials: AO
authors.lastname: Eghrari
authors.forename: S Amer
authors.initials: SA
authors.lastname: Riazuddin
authors.forename: Nicholas
authors.initials: N
authors.lastname: Katsanis
authors.forename: John D
authors.initials: JD
authors.lastname: Gottsch
authors.forename: Simon G
authors.initials: SG
authors.lastname: Gregory
authors.forename: Gordon K
authors.initials: GK
authors.lastname: Klintworth
authors.forename: Natalie A
authors.initials: NA
authors.lastname: Afshari
mesh_terms: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D002887:Chromosomes, Human, Pair 18; D005642:Fuchs' Endothelial Dystrophy / Q000235:genetics*; D008040:Genetic Linkage; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D007438:Introns; D008957:Models, Genetic; D020641:Polymorphism, Single Nucleotide; D000073940:Transcription Factor 4; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D005819:Genetic Markers; C532096:TCF4 protein, human; D000073940:Transcription Factor 4; D014157:Transcription Factors