Association of Genetic Variation With Keratoconus

Abstract

IMPORTANCE Keratoconus is a condition in which the cornea progressively thins and protrudes in a conical shape, severely affecting refraction and vision. It is a major indication for corneal transplant. To discover new genetic loci associated with keratoconus and better understand the causative mechanism of this disease, we performed a genome-wide association study on patients with keratoconus. OBJECTIVE To identify genetic susceptibility regions for keratoconus in the human genome. DESIGN, SETTING, AND PARTICIPANTS This study was conducted with data from eye clinics in Australia, the United States, and Northern Ireland. The discovery cohort of individuals with keratoconus and control participants from Australia was genotyped using the Illumina HumanCoreExome single-nucleotide polymorphism array. After quality control and data cleaning, genotypes were imputed against the 1000 Genomes Project reference panel (phase III; version 5), and association analyses were completed using PLINK version 1.90. Single-nucleotide polymorphisms with P < 1.00 × 10 −6 were assessed for replication in 3 additional cohorts. Control participants were drawn from the cohorts of the Blue Mountains Eye Study and a previous study of glaucoma. Replication cohorts were from a previous keratoconus genome-wide association study data set from the United States, a cohort of affected and control participants from Australia and Northern Ireland, and a case-control cohort from Victoria, Australia. Data were collected from January 2006 to March 2019. MAIN OUTCOMES AND MEASURES Associations between keratoconus and 6 252 612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components. RESULTS The discovery cohort included 522 affected individuals and 655 control participants, while the replication cohorts included 818 affected individuals (222 from the United States, 331 from Australia and Northern Ireland, and 265 from Victoria, Australia) and 3858 control participants (2927 from the United States, 229 from Australia and Northern Ireland, and 702 from Victoria, Australia). Two novel loci reached genome-wide significance (defined as P < 5.00 × 10 −8), with a P value of 7.46 × 10 −9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 × 10 −12 at rs138380, 2.2 kb upstream of casein kinase I isoform epsilon gene (CSNK1E) on chromosome 22. One additional locus was identified with a P value less than 1.00 × 10 −6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 × 10 −7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 × 10 −8). CONCLUSIONS AND RELEVANCE In this relatively large keratoconus genome-wide association study, we identified a genome-wide significant locus for keratoconus in the region of PNPLA2 on chromosome 11.

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

“…The discovery analysis identified 22 GWAS-significant associations (Supplementary Data 2), including six loci previously associated with keratoconus (FOXO1 17 , COL5A1 17 , FNDC3B 17 , ZNF469 17 , LOX 23 and near PNPLA2 24 ), four that were previously associated with CCT 16,18 but not keratoconus, and 12 entirely novel loci. Among the novel keratoconus loci, the most significant association was found at a gene-poor region on chr21q2 (p = 1.34 × 10 −13 for rs76747345).…”

“…Previous association with keratoconus and CCT. We collected evidence of previous associations with keratoconus and CCT by querying the GWAS catalog 104 and looking up reports in peer-reviewed articles 16,17,20,24,105 for genomic markers and regions associated with either. We specifically looked for genome-wide significance level of association.…”

“…Genome-wide association analysis of this cohort has been described previously 24 . In brief, participants with keratoconus were ascertained through the eye clinic of Flinders Medical Centre, Adelaide; optometry and ophthalmology clinics in Adelaide and Melbourne; or an Australia-wide invitation to members of Keratoconus Australia, a community-based support group for patients.…”

Replication of the Association Between Keratoconus and Polymorphisms in PNPLA2 and MAML2 in a Han Chinese Population

“…Identifying the genetic risk factors for KC has proved challenging. Recently, well-powered GWAS for keratoconus and central corneal thickness have uncovered many risk loci, but most of them were performed in western populations (Burdon et al, 2011 ; Li et al, 2012 ; Lu et al, 2013 ; Cuellar-Partida et al, 2015 ; Khawaja et al, 2019 ; McComish et al, 2019 ). Some of those reported KC susceptibility loci have been further investigated in a Han Chinese cohort, including by our group (Wang et al, 2013 , 2018 ; Hao et al, 2015 ; Zhang et al, 2018 ).…”

“…Two novel loci showed genome-wide significance, rs61876744 in the PNPLA2 gene on chr11, and rs138380 in the CSNK1E gene on chr22. They also reported a suggestive association signal from rs10831500, which was close to the MAML2 gene on chr11 (McComish et al, 2019). However, given the potential genetic heterogeneity underlying KC etiology, it still remains unclear whether these newly identified SNPs are still in association with KC risk in other populations.…”