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PPIP5K2 and PCSK1 are Candidate Genetic Contributors to Familial Keratoconus.

ABSTRACT: Keratoconus (KC) is the most common corneal ectatic disorder affecting >300,000 people in the US. KC normally has its onset in adolescence, progressively worsening through the third to fourth decades of life. KC patients report significant impaired vision-related quality of life. Genetic factors play an important role in KC pathogenesis. To identify novel genes in familial KC patients, we performed whole exome and genome sequencing in a four-generation family. We identified potential variants in the PPIP5K2 and PCSK1 genes. Using in vitro cellular model and in vivo gene-trap mouse model, we found critical evidence to support the role of PPIP5K2 in normal corneal function and KC pathogenesis. The gene-trap mouse showed irregular corneal surfaces and pathological corneal thinning resembling KC. For the first time, we have integrated corneal tomography and pachymetry mapping into characterization of mouse corneal phenotypes which could be widely implemented in basic and translational research for KC diagnosis and therapy in the future.

SUBMITTER: Khaled ML

PROVIDER: S-EPMC6920454 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature

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PPIP5K2 and PCSK1 are Candidate Genetic Contributors to Familial Keratoconus.

Khaled Mariam Lofty ML Bykhovskaya Yelena Y Gu Chunfang C Liu Alice A Drewry Michelle D MD Chen Zhong Z Mysona Barbara A BA Parker Emily E McNabb Ryan P RP Yu Hongfang H Lu Xiaowen X Wang Jing J Li Xiaohui X Al-Muammar Abdulrahman A Rotter Jerome I JI Porter Louise F LF Estes Amy A Watsky Mitchell A MA Smith Sylvia B SB Xu Hongyan H Abu-Amero Khaled K KK Kuo Anthony A Shears Stephen B SB Rabinowitz Yaron S YS Liu Yutao Y

Scientific reports 20191218 1

Keratoconus (KC) is the most common corneal ectatic disorder affecting >300,000 people in the US. KC normally has its onset in adolescence, progressively worsening through the third to fourth decades of life. KC patients report significant impaired vision-related quality of life. Genetic factors play an important role in KC pathogenesis. To identify novel genes in familial KC patients, we performed whole exome and genome sequencing in a four-generation family. We identified potential variants in ...[more]

PMID: 31852976

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Project description:ImportanceKeratoconus 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.ObjectiveTo identify genetic susceptibility regions for keratoconus in the human genome.Design, setting, and participantsThis 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 measuresAssociations between keratoconus and 6 252 612 genetic variants were estimated using logistic regression after adjusting for ancestry using the first 3 principal components.ResultsThe 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 relevanceIn 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.

Dataset Information

PPIP5K2 and PCSK1 are Candidate Genetic Contributors to Familial Keratoconus.

Publications

PPIP5K2 and PCSK1 are Candidate Genetic Contributors to Familial Keratoconus.

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