@article {1340, title = {Association of polymorphisms in the hepatocyte growth factor gene promoter with keratoconus.}, journal = {Invest Ophthalmol Vis Sci}, volume = {52}, year = {2011}, month = {2011 Oct 31}, pages = {8514-9}, abstract = {

PURPOSE: Keratoconus is a progressive disorder of the cornea that can lead to severe visual impairment or blindness. Although several genomic regions have been linked to rare familial forms of keratoconus, no genes have yet been definitively identified for common forms of the disease.

METHODS: Two genome-wide association scans were undertaken in parallel. The first used pooled DNA from an Australian cohort, followed by typing of top-ranked single-nucleotide polymorphisms (SNPs) in individual DNA samples. The second was conducted in individually genotyped patients, and controls from the USA. Tag SNPs around the hepatocyte growth factor (HGF) gene were typed in three additional replication cohorts. Serum levels of HGF protein in normal individuals were assessed with ELISA and correlated with genotype.

RESULTS: The only SNP observed to be associated in both the pooled discovery and primary replication cohort was rs1014091, located upstream of the HGF gene. The nearby SNP rs3735520 was found to be associated in the individually typed discovery cohort (P = 6.1 {\texttimes} 10(-7)). Genotyping of tag SNPs around HGF revealed association at rs3735520 and rs17501108/rs1014091 in four of the five cohorts. Meta-analysis of all five datasets together yielded suggestive P values for rs3735520 (P = 9.9 {\texttimes} 10(-7)) and rs17501108 (P = 9.9 {\texttimes} 10(-5)). In addition, SNP rs3735520 was found to be associated with serum HGF level in normal individuals (P = 0.036).

CONCLUSIONS: Taken together, these results implicate genetic variation at the HGF locus with keratoconus susceptibility.

}, keywords = {Adult, Aged, Chromosomes, Human, Pair 7, Corneal Topography, Enzyme-Linked Immunosorbent Assay, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotype, Hepatocyte Growth Factor, Humans, Keratoconus, Middle Aged, Nucleic Acid Hybridization, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Sequence Tagged Sites}, issn = {1552-5783}, doi = {10.1167/iovs.11-8261}, author = {Burdon, Kathryn P and Macgregor, Stuart and Bykhovskaya, Yelena and Javadiyan, Sharhbanou and Li, Xiaohui and Laurie, Kate J and Muszynska, Dorota and Lindsay, Richard and Lechner, Judith and Haritunians, Talin and Henders, Anjali K and Dash, Durga and Siscovick, David and Anand, Seema and Aldave, Anthony and Coster, Douglas J and Szczotka-Flynn, Loretta and Mills, Richard A and Iyengar, Sudha K and Taylor, Kent D and Phillips, Tony and Montgomery, Grant W and Rotter, Jerome I and Hewitt, Alex W and Sharma, Shiwani and Rabinowitz, Yaron S and Willoughby, Colin and Craig, Jamie E} } @article {8631, title = {Association of Genetic Variation With Keratoconus.}, journal = {JAMA Ophthalmol}, volume = {138}, year = {2020}, month = {2020 02 01}, pages = {174-181}, 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 {\texttimes} 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 {\texttimes} 10-8), with a P value of 7.46 {\texttimes} 10-9 at rs61876744 in patatin-like phospholipase domain-containing 2 gene (PNPLA2) on chromosome 11 and a P value of 6.35 {\texttimes} 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 {\texttimes} 10-6 in mastermind-like transcriptional coactivator 2 (MAML2) on chromosome 11 (P = 3.91 {\texttimes} 10-7). The novel locus in PNPLA2 reached genome-wide significance in an analysis of all 4 cohorts (P = 2.45 {\texttimes} 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.

}, keywords = {Adult, Female, Fuchs{\textquoteright} Endothelial Dystrophy, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Keratoconus, Lipase, Logistic Models, Male, Middle Aged, Polymorphism, Single Nucleotide}, issn = {2168-6173}, doi = {10.1001/jamaophthalmol.2019.5293}, author = {McComish, Bennet J and Sahebjada, Srujana and Bykhovskaya, Yelena and Willoughby, Colin E and Richardson, Andrea J and Tenen, Abi and Charlesworth, Jac C and Macgregor, Stuart and Mitchell, Paul and Lucas, Sionne E M and Mills, Richard A and Mackey, David A and Li, Xiaohui and Wang, Jie Jin and Jensen, Richard A and Rotter, Jerome I and Taylor, Kent D and Hewitt, Alex W and Rabinowitz, Yaron S and Baird, Paul N and Craig, Jamie E and Burdon, Kathryn P} }