04581nas a2200541 4500008004100000022001400041245005500055210005400110260001500164300001200179490000800191520308300199653001003282653001103292653003303303653003803336653003403374653001103408653001603419653001103435653002003446653000903466653001603475653003603491100002403527700002303551700002403574700002503598700002603623700001503649700002503664700002203689700001903711700002303730700002203753700002103775700001603796700001903812700002303831700002203854700002003876700002003896700002503916700001903941700002003960700002303980856003604003 2020 eng d a2168-617300aAssociation of Genetic Variation With Keratoconus.0 aAssociation of Genetic Variation With Keratoconus c2020 02 01 a174-1810 v1383 a

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.

10aAdult10aFemale10aFuchs' Endothelial Dystrophy10aGenetic Predisposition to Disease10aGenome-Wide Association Study10aHumans10aKeratoconus10aLipase10aLogistic Models10aMale10aMiddle Aged10aPolymorphism, Single Nucleotide1 aMcComish, Bennet, J1 aSahebjada, Srujana1 aBykhovskaya, Yelena1 aWilloughby, Colin, E1 aRichardson, Andrea, J1 aTenen, Abi1 aCharlesworth, Jac, C1 aMacgregor, Stuart1 aMitchell, Paul1 aLucas, Sionne, E M1 aMills, Richard, A1 aMackey, David, A1 aLi, Xiaohui1 aWang, Jie, Jin1 aJensen, Richard, A1 aRotter, Jerome, I1 aTaylor, Kent, D1 aHewitt, Alex, W1 aRabinowitz, Yaron, S1 aBaird, Paul, N1 aCraig, Jamie, E1 aBurdon, Kathryn, P uhttps://chs-nhlbi.org/node/8631