Genome-wide association study of primary open angle glaucoma risk and quantitative traits.

paper Cited Public

Authors: Gibson, Jane; Griffiths, Helen; De Salvo, Gabriella; Cole, Mick; Jacob, Aby; Macleod, Alex; Yang, Yit; Menon, Geeta; Cree, Angela; Ennis, Sarah; Lotery, Andrew
Year: 2012
Journal: Molecular vision
PMID: 22605921
PMCID: PMC3351427

PURPOSE: 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.

#	Section	Preview
0	Introduction	Primary open angle glaucoma (POAG) is the most common subtype of glaucoma, which can be regarded as…
1	Introduction	[8]. Association studies detect more common causes of disease and, more recently, several replicated…
2	Introduction	There have also been recent successes in identifying genes associated with quantitative ocular…
3	Introduction	Genome-wide association studies (GWAS) have been performed in a wide range of complex diseases,…
4	Methods — Patient samples and phenotypes	Three hundred and eighty seven (387) primary open angle patients from a cohort of patients being…
5	Methods — Patient samples and phenotypes	The quantitative ocular traits analyzed were; intraocular pressure (IOP) taken as the maximum…
6	Methods — Genotyping and QC	The discovery sample was genotyped using the Affymetrix SNP 6.0 array (Affymetrix, Santa Clara, CA)…
7	Methods — Genotyping and QC	Quality control steps involved removing cases and SNPs with a high degree of missingness, and…
8	Methods — Genotyping and QC	A Hardy–Weinberg equilibrium (HWE) test (in the WTCCC2 control data) identified SNPs with large…
9	Methods — Statistical analysis	We analyzed the data for risk using allelic χ2, and further subdivided our cases into NTG and HTG…
10	Methods — Statistical analysis	GWA studies are prone to detection of false positives; to ensure that the most promising signals…
11	Methods — Statistical analysis	This multi-pronged approach gave a total of 86 SNPs to test in the replication cohort. All analysis…
12	Results — GWAS results	There were two SNPs with GWAS significance (p<1×10−8) in the risk analysis, the most significant…
13	Results — Quantitative traits	The quantitative ocular traits are summarized in Table 2. As expected for POAG cases the IOP was…
14	Results — Replication results	For replication 86 SNPs were genotyped in the 294 new cases, 50 controls, as well as the discovery…
15	Results — Replication results	SNPs were analyzed for association to the phenotype which led to their inclusion in the replication…
16	Results — Replication results	been collected for the 50 Southampton controls, enabling a similar quantitative analysis in controls…
17	Results — Previously published POAG genes	Included in our replication data were 3 SNPs near published POAG risk genes which showed strong…
18	Results — Previously published POAG genes	We found no association evidence for SNPs within MYOC, as expected, since patients with MYOC…
19	Discussion	We report two SNPs highly significant in our discovery data for the phenotypes CCT and CDR. Both…

Name	Type
1948 British birth cohort local	cohort
86 SNPs local	variant
Affymetrix SNP 6.0 array local	drug
age-related macular degeneration	phenotype
AKAP13 local	gene
AMD	phenotype
ATOH7 local	gene
average CDR local	phenotype
bipolar disorder	phenotype
blindness	phenotype
CARD10 local	gene
cases	cohort
Caucasian cohort	cohort
CAV1	gene
CAV1 variant local	variant
CAV2 local	gene
CCT local	phenotype
CDKN2B	gene
CDKN2B-AS1 local	gene
CDR local	phenotype
central corneal thickness local	phenotype
Central Corneal Thickness local	phenotype
COL5A1	gene
common variants	cohort
controls	cohort
Crohn’s disease	phenotype
Cup:Disc Ratio local	phenotype
diabetes	phenotype
discovery data local	cohort
discovery sample	cohort
Elovl5	gene
genes involved in eye development and maintenance local	gene
genetic variants	cohort
glaucoma local	phenotype
glaucoma cases local	cohort
Goldman Applanation Tonometry local	drug
Hampshire cohort (UK) local	cohort
High tension glaucoma local	phenotype
HTG local	phenotype
HTG group local	cohort
intraocular pressure local	phenotype
Intraocular Pressure local	phenotype
IOP local	phenotype
KASPar chemistry local	drug
KHDRBS3	gene
LOC100129322 local	gene
MTAP	gene
MYOC local	gene
National Blood Service local	cohort
NEDD9 local	gene
new cases local	cohort
Normal tension glaucoma local	phenotype
NTF4 local	gene
NTG local	phenotype
NTG group local	cohort
ocular traits (sub-phenotypes) local	phenotype
optic disc area local	phenotype
optic disc size local	phenotype
optic neuropathy local	phenotype
OPTN local	gene
POAG local	phenotype
POAG risk local	phenotype
primary open-angle glaucoma local	phenotype
Primary open angle glaucoma local	phenotype
Primary open-angle glaucoma local	phenotype
Pseudoexfoliation glaucoma local	phenotype
quantitative ocular traits local	phenotype
rare variant	cohort
Replication POAG cohort local	cohort
replication sample	cohort
risk	phenotype
rs11884064 local	variant
rs11961171 local	variant
rs1657855 local	variant
rs16871186 local	variant
rs16871188 local	variant
rs16871204 local	variant
rs41463745 local	variant
rs4713332 local	variant
rs4713335 local	variant
rs924463 local	variant
single nucleotide polymorphisms	variant
SIX1 local	gene
SIX2 local	gene
SIX3	gene
SNP	cohort
SNP_KHDRBS3 local	variant
SNP_UBR7 local	variant
Southampton controls local	cohort
Southampton Controls local	cohort
SRBD1 local	gene
study cohort	cohort
TGFBR3 local	gene
TMCO1 local	gene
TMEM170B local	gene
Tomey Pachymeter SP-3000 local	drug
trait	phenotype
UBR7 local	gene
Ultrasound Pachymetry local	drug
variant near CAV1/CAV2 local	variant
vertical cup disc ratio local	phenotype
visual field loss local	phenotype
WDR36 local	gene
Wellcome Trust Case Controls Consortium 2 local	cohort
WTCCC2	cohort
ZNF469 local	gene

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