April 2014
Volume 55, Issue 13
ARVO Annual Meeting Abstract  |   April 2014
Common variants in TCF4 and three novel genes increase susceptibility to Fuchs Dystrophy
Author Affiliations & Notes
  • Sudha K Iyengar
    Case Western Reserve University and University Hospitals Eye Institute, Cleveland, OH
  • Yi-Ju Li
    Duke University Medical Center, Durham, NC
  • Robert P Igo
    Case Western Reserve University and University Hospitals Eye Institute, Cleveland, OH
  • Kathryn P Burdon
    Flinders University, Flinders Medical Centre,, Adelaide, SA, Australia
  • John H Fingert
    The University of Iowa, Iowa City, IA
  • John Gottsch
    Johns Hopkins University School of Medicine, Baltimore, MD
  • Gordon K Klintworth
    Duke University Medical Center, Durham, NC
  • Jonathan H Lass
    Case Western Reserve University and University Hospitals Eye Institute, Cleveland, OH
  • Natalie A Afshari
    University of California at San Diego, San Diego, CA
  • Footnotes
    Commercial Relationships Sudha Iyengar, None; Yi-Ju Li, None; Robert Igo, None; Kathryn Burdon, None; John Fingert, None; John Gottsch, None; Gordon Klintworth, None; Jonathan Lass, None; Natalie Afshari, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science April 2014, Vol.55, 4070. doi:
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      Sudha K Iyengar, Yi-Ju Li, Robert P Igo, Kathryn P Burdon, John H Fingert, John Gottsch, Gordon K Klintworth, Jonathan H Lass, Natalie A Afshari, FECD Genetics Consortium; Common variants in TCF4 and three novel genes increase susceptibility to Fuchs Dystrophy. Invest. Ophthalmol. Vis. Sci. 2014;55(13):4070.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: To find common susceptibility variants for Fuchs Endothelial Corneal Dystrophy (FECD) using a genome-wide association study.

Methods: We conducted a genome-wide association study in 1404 severe FECD cases and 2564 controls of European ancestry using the Illumina Omni 2.5 chip. After imputing our markers to the 1000 Genomes, the primary analyses consisted of association testing via logistic regression, controlling for population structure via six principal components, and covariates age and sex. Genome-wide significant markers at six loci were validated in three independent replication samples (N=671 cases and N=778 controls) via a fixed-effects meta analysis. We also conducted sensitivity analysis for histopathology validated cases, and determined whether female versus male gender showed differences in odds ratios at the best loci. Genetic risk scores were calculated based on the most significantly associated SNP from each of the four replicated regions (AUC).

Results: We identified six genomic regions on chromosomes 1, 11 and 18 containing SNPs with genomewide significant associations (p < 5 × 10-8). Four of these regions showed strong evidence in the replication cohorts. The previously identified locus at TCF4 (Baratz et al 2010, NEJM), encoding the transcription factor E2-2, displayed strong association in both discovery and replication cohorts (most significant SNP rs784257; pcombined = 2.5 × 10-200), with large effect sizes in both the discovery (OR = 5.77, 95% CI = [5.05, 6.60]) and replication (OR = 3.89 (95% CI = [3.30, 4.59]) samples. Replication was also successful at three additional loci (pcombined= 1.2 × 10-14, pcombined = 9.9 × 10-19, pcombined= 6.9 × 10-16). TCF4 showed genome-wide significance in the sex-specific analysis. Sensitivity analysis of histopathology validated cases confirmed all loci. The AUC for severe FECD cases vs. controls was 0.79, showing strong predictive value compared to other complex traits analyzed by GWAS. Predictive value was primarily through genotypes at rs784257 near TCF4; the AUC without rs784257 was only 0.562.

Conclusions: The FECD Genetics Consortium has conducted the largest genome-wide association study to date on FECD, leading to confirmation of the role of TCF4 on FECD, and identification of three novel validated loci. Further analyses of these genes should help elucidate different pathways in FECD pathogenesis.

Keywords: 539 genetics • 480 cornea: basic science • 481 cornea: endothelium  

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