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

Gibson J, Griffiths H, De Salvo G, Cole M, Jacob A, Macleod A, Yang Y, Menon G, Cree A, Ennis S, Lotery A - Mol. Vis. (2012)

Bottom Line: 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.We found 4 nominally significant results in the replication cohort, but none passed correction for multiple testing.We found evidence for 3 known genes (TMCO1, CDKN2B, and S1 RNA binding domain 1 [SRBD1]) in this study.

View Article: PubMed Central - PubMed

Affiliation: Genetic Epidemiology and Genomic Informatics Group, Human Genetics, Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, UK.

ABSTRACT

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.

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Related in: MedlinePlus

A plot of the most significant region in the discovery sample GWAS. This plot shows the region around the most significant result in the discovery sample GWAS. SNPs are plotted as the -log10 of the p-value. The plot was produced using LocusZoom.
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f1: A plot of the most significant region in the discovery sample GWAS. This plot shows the region around the most significant result in the discovery sample GWAS. SNPs are plotted as the -log10 of the p-value. The plot was produced using LocusZoom.

Mentions: There were two SNPs with GWAS significance (p<1×10−8) in the risk analysis, the most significant was on chromosome 6 (rs11961171, p=8.55±10−13) and had 6 SNPs (rs41463745, rs4713332, rs16871186, rs16871188, rs4713335, and rs16871204) in the clump (p≤0.0002) and four other independent SNPs in the surrounding region (Figure 1). The genes nearest to the signal are neural precursor cell expressed, developmentally down-regulated 9 (NEDD9), LOC100129322, and transmembrane protein 170B (TMEM170B). We chose three independent SNPs to genotype in this region in the replication sample. The second GWAS significant SNP was on chromosome 16 (rs924463) with no supporting evidence from the surrounding region suggesting a likely false positive. Figure 2 shows a Manhattan plot of the risk GWAS.


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

Gibson J, Griffiths H, De Salvo G, Cole M, Jacob A, Macleod A, Yang Y, Menon G, Cree A, Ennis S, Lotery A - Mol. Vis. (2012)

A plot of the most significant region in the discovery sample GWAS. This plot shows the region around the most significant result in the discovery sample GWAS. SNPs are plotted as the -log10 of the p-value. The plot was produced using LocusZoom.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3351427&req=5

f1: A plot of the most significant region in the discovery sample GWAS. This plot shows the region around the most significant result in the discovery sample GWAS. SNPs are plotted as the -log10 of the p-value. The plot was produced using LocusZoom.
Mentions: There were two SNPs with GWAS significance (p<1×10−8) in the risk analysis, the most significant was on chromosome 6 (rs11961171, p=8.55±10−13) and had 6 SNPs (rs41463745, rs4713332, rs16871186, rs16871188, rs4713335, and rs16871204) in the clump (p≤0.0002) and four other independent SNPs in the surrounding region (Figure 1). The genes nearest to the signal are neural precursor cell expressed, developmentally down-regulated 9 (NEDD9), LOC100129322, and transmembrane protein 170B (TMEM170B). We chose three independent SNPs to genotype in this region in the replication sample. The second GWAS significant SNP was on chromosome 16 (rs924463) with no supporting evidence from the surrounding region suggesting a likely false positive. Figure 2 shows a Manhattan plot of the risk GWAS.

Bottom Line: 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.We found 4 nominally significant results in the replication cohort, but none passed correction for multiple testing.We found evidence for 3 known genes (TMCO1, CDKN2B, and S1 RNA binding domain 1 [SRBD1]) in this study.

View Article: PubMed Central - PubMed

Affiliation: Genetic Epidemiology and Genomic Informatics Group, Human Genetics, Faculty of Medicine, University of Southampton, Southampton General Hospital, Tremona Road, Southampton, UK.

ABSTRACT

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.

Show MeSH
Related in: MedlinePlus