Association of Genetic Variation With Keratoconus

Question Which genetic loci are associated with keratoconus? Findings In this case-control genome-wide association study of a discovery cohort and 3 independent replication cohorts, a locus containing multiple variants across 6 protein-coding genes on chromosome 11 was associated with keratoconus. Several of these genes are likely involved in apoptotic pathways. Meaning This study of patients with keratoconus and control participants showed a potential role of genes involved in apoptotic pathways. 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 x 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& x202f;252& x202f;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 x 10(-8)), with a P value of 7.46 x 10(-9) at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 x 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 x 10(-6) in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 x 10(-7)). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 x 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. This case-control, genome-wide association study assesses genetic susceptibility regions for keratoconus via a genome-wide association study of a discovery cohort and 3 independent replication cohorts from the United States, Northern Ireland, and Australia.