title: A genome-wide association study identifies a potential novel gene locus for keratoconus, one of the commonest causes for corneal transplantation in developed countries.
abstract: Keratoconus is a condition in which the cornea progressively thins over time, and is a major cause for cornea transplantation. To identify keratoconus susceptibility regions, we performed a comprehensive genome-wide association study (GWAS) using a discovery and replication design. A discovery panel of 222 keratoconus Caucasian patients and 3324 Caucasian controls was genotyped using Illumina 370K beadchips. Further associated and fine-mapping single nucleotide polymorphisms (SNPs) (n= 4905) were genotyped in an independent replication case-control panel of 304 cases and 518 controls and a family panel of 307 subjects in 70 families. Logistic regression models implemented in PLINK were performed to test associations in case-control samples with and without principal component (PC) adjustments. Generalized estimation equation models accounting for familial correlations implemented in GWAF were used for association testing in families. No genome-wide associations were identified in the discovery GWAS panel. From the initial testing without adjustments for PCs, the top three SNPs located at 3p26 (rs6442925), 2q21.3 (rs4954218) and 19q13.3 (rs1428642) were identified with unadjusted P-values of 6.5 × 10(-8), 2.4 × 10(-7) and 3.1 × 10(-7), respectively. After adjustments for PCs, rs1428642 became the most significant through the genome with a P-value of 1.4 × 10(-6), while rs6442925 and rs4954218 were less significant (P= 1.9 × 10(-5) and 2.6 × 10(-4)). SNP rs4954218 was confirmed in two independent replication panels with P-values of 0.004 and 0.009, respectively. Meta-analysis revealed a highest association at rs4954218 with adjusted P= 1.6 × 10(-7) (unadjusted P= 1.2 × 10(-9)). These findings suggest SNP rs4954218, located near the RAB3GAP1 gene, previously reported to be associated with corneal malformation, is a potential susceptibility locus for keratoconus.
authors: Cornea Genetic Eye Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
authors: Xiaohui
authors: X
authors: Li
authors: Yelena
authors: Y
authors: Bykhovskaya
authors: Talin
authors: T
authors: Haritunians
authors: David
authors: D
authors: Siscovick
authors: Anthony
authors: A
authors: Aldave
authors: Loretta
authors: L
authors: Szczotka-Flynn
authors: Sudha K
authors: SK
authors: Iyengar
authors: Jerome I
authors: JI
authors: Rotter
authors: Kent D
authors: KD
authors: Taylor
authors: Yaron S
authors: YS
authors: Rabinowitz
mesh_terms: D016022:Case-Control Studies; D002889:Chromosomes, Human, Pair 2; D015331:Cohort Studies; D016039:Corneal Transplantation; D019049:Developed Countries; D055106:Genome-Wide Association Study; D006801:Humans; D007640:Keratoconus / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide