title: Genome-wide association study of primary open angle glaucoma risk and quantitative traits.
abstract: OBJECTIVE
  Primary open angle glaucoma (POAG) is a characteristic optic neuropathy which progresses to irreversible vision loss. Few genes have been detected that influence POAG susceptibility and other genes are therefore likely to be involved. We analyzed carefully characterized POAG cases in a genome-wide association study (GWAS).
  
  
  METHODS
  We performed a GWAS in 387 POAG cases using public control data (WTCCC2). We also investigated the quantitative phenotypes, cup:disc ratio (CDR), central corneal thickness (CCT), and intra-ocular pressure (IOP). Promising single nucleotide polymorphisms (SNPs), based on various prioritisation criteria, were genotyped in a cohort of 294 further POAG cases and controls.
  
  
  RESULTS
  We found 2 GWAS significant results in the discovery stage for association, one of which which had multiple evidence in the gene 'neural precursor cell expressed, developmentally down-regulated 9' (NEDD9; rs11961171, p=8.55E-13) and the second on chromosome 16 with no supporting evidence. Taking into account all the evidence from risk and quantitative trait ocular phenotypes we chose 86 SNPs for replication in an independent sample. Our most significant SNP was not replicated (p=0.59). We found 4 nominally significant results in the replication cohort, but none passed correction for multiple testing. Two of these, for phenotypes CDR (rs4385494, discovery p=4.51x10-5, replication p=0.029) and CCT (rs17128941, discovery p=5.52x10-6, replication=0.027), show the consistent direction of effects between the discovery and replication data. We also assess evidence for previously associated known genes and find evidence for the genes 'transmembrane and coiled-coil domains 1' (TMCO1) and 'cyclin-dependent kinase inhibitor 2B' (CDKN2B).
  
  
  CONCLUSIONS
  Although we were unable to replicate any novel results for POAG risk, we did replicate two SNPs with consistent effects for CDR and CCT, though they do not withstand correction for multiple testing. There has been a range of publications in the last couple of years identifying POAG risk genes and genes involved in POAG related ocular traits. We found evidence for 3 known genes (TMCO1, CDKN2B, and S1 RNA binding domain 1 [SRBD1]) in this study. Novel rare variants, not detectable by GWAS, but by new methods such as exome sequencing may hold the key to unravelling the remaining contribution of genetics to complex diseases such as POAG.
authors.affiliation: Genetic Epidemiology and Genomic Informatics Group, Human Genetics, Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, UK.
authors.forename: Jane
authors.initials: J
authors.lastname: Gibson
authors.forename: Helen
authors.initials: H
authors.lastname: Griffiths
authors.forename: Gabriella
authors.initials: G
authors.lastname: De Salvo
authors.forename: Mick
authors.initials: M
authors.lastname: Cole
authors.forename: Aby
authors.initials: A
authors.lastname: Jacob
authors.forename: Alex
authors.initials: A
authors.lastname: Macleod
authors.forename: Yit
authors.initials: Y
authors.lastname: Yang
authors.forename: Geeta
authors.initials: G
authors.lastname: Menon
authors.forename: Angela
authors.initials: A
authors.lastname: Cree
authors.forename: Sarah
authors.initials: S
authors.lastname: Ennis
authors.forename: Andrew
authors.initials: A
authors.lastname: Lotery
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005136:Eye Proteins / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D005902:Glaucoma, Open-Angle / Q000235:genetics*; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D019655:Quantitative Trait, Heritable; D012307:Risk Factors; D014065:Tonometry, Ocular; D006113:United Kingdom
chemical_list: D005136:Eye Proteins