03084nas a2200361   4500008004100000022001400041245017300055210006900228260001600297300001000313490000700323520191100330653002502241653003102266653001902297653002802316653002402344653003402368653001102402653001602413653003602429100001602465700002402481700002302505700002102528700002002549700002802569700002202597700002202619700002002641700002502661856003602686       2012                        eng d  a1460-208300aA genome-wide association study identifies a potential novel gene locus for keratoconus, one of the commonest causes for corneal transplantation in developed countries.0 agenomewide association study identifies a potential novel gene l  c2012 Jan 15  a421-90 v213 a<p>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.</p>10aCase-Control Studies10aChromosomes, Human, Pair 210aCohort Studies10aCorneal Transplantation10aDeveloped Countries10aGenome-Wide Association Study10aHumans10aKeratoconus10aPolymorphism, Single Nucleotide1 aLi, Xiaohui1 aBykhovskaya, Yelena1 aHaritunians, Talin1 aSiscovick, David1 aAldave, Anthony1 aSzczotka-Flynn, Loretta1 aIyengar, Sudha, K1 aRotter, Jerome, I1 aTaylor, Kent, D1 aRabinowitz, Yaron, S  uhttps://chs-nhlbi.org/node/1555