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Genes of the unfolded protein response pathway harbor risk alleles for primary open angle glaucoma.

Carbone MA, Chen Y, Hughes GA, Weinreb RN, Zabriskie NA, Zhang K, Anholt RR - PLoS ONE (2011)

Bottom Line: This multiple testing problem can be surmounted with very large population sizes when common alleles of large effects give rise to disease status.Previous genome-wide analysis in a Drosophila ocular hypertension model identified transcripts with altered regulation and showed induction of the unfolded protein response (UPR) upon overexpression of transgenic human glaucoma-associated myocilin (MYOC).Thus, effectiveness of the UPR in response to accumulation of misfolded or aggregated proteins may contribute to the pathogenesis of POAG and provide targets for early therapeutic intervention.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, North Carolina State University, Raleigh, North Carolina, United States of America.

ABSTRACT
The statistical power of genome-wide association (GWA) studies to detect risk alleles for human diseases is limited by the unfavorable ratio of SNPs to study subjects. This multiple testing problem can be surmounted with very large population sizes when common alleles of large effects give rise to disease status. However, GWA approaches fall short when many rare alleles may give rise to a common disease, or when the number of subjects that can be recruited is limited. Here, we demonstrate that this multiple testing problem can be overcome by a comparative genomics approach in which an initial genome-wide screen in a genetically amenable model organism is used to identify human orthologues that may harbor risk alleles for adult-onset primary open angle glaucoma (POAG). Glaucoma is a major cause of blindness, which affects over 60 million people worldwide. Several genes have been associated with juvenile onset glaucoma, but genetic factors that predispose to adult onset primary open angle glaucoma (POAG) remain largely unknown. Previous genome-wide analysis in a Drosophila ocular hypertension model identified transcripts with altered regulation and showed induction of the unfolded protein response (UPR) upon overexpression of transgenic human glaucoma-associated myocilin (MYOC). We selected 16 orthologous genes with 62 polymorphic markers and identified in two independent human populations two genes of the UPR that harbor POAG risk alleles, BIRC6 and PDIA5. Thus, effectiveness of the UPR in response to accumulation of misfolded or aggregated proteins may contribute to the pathogenesis of POAG and provide targets for early therapeutic intervention.

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Related in: MedlinePlus

Association between POAG and candidate gene tagging rsSNPs.The graph shows the genotypic P-values (Log(1/P); y-axis) from likelihood ratio Chi-squared tests of associations with candidate gene SNPs (x-axis) from 2 populations (San Diego (blue) and Salt Lake City (red)). The black arrows indicate SNPs that were significant in both the San Diego and Salt Lake City cohorts. The black horizontal line indicates the Bonferroni adjusted P-value (P = 0.0008).
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pone-0020649-g001: Association between POAG and candidate gene tagging rsSNPs.The graph shows the genotypic P-values (Log(1/P); y-axis) from likelihood ratio Chi-squared tests of associations with candidate gene SNPs (x-axis) from 2 populations (San Diego (blue) and Salt Lake City (red)). The black arrows indicate SNPs that were significant in both the San Diego and Salt Lake City cohorts. The black horizontal line indicates the Bonferroni adjusted P-value (P = 0.0008).

Mentions: Mutations in MYOC have been associated with juvenile onset glaucoma, and with some cases of POAG [17], [19]. OPTN has also been associated with various forms of glaucoma, including POAG and normal tension glaucoma [20]. We did not detect associations between MYOC with POAG in either the Salt Lake City or San Diego population. This is perhaps not surprising as MYOC mutations have been associated with only ∼3–4% of POAG cases [7]. We did, however, find an association between OPTN and POAG in the Salt Lake City population (rs10906308, P = 5.84×10–9; Figure 1 and Table S2). The same SNP in the San Diego population, however, does not reach statistical significance (P = 0.04). Similarly, SNPs in CYP1B1 and PSMB7, which encodes proteasome subunit beta 7, are significantly associated with POAG in the Salt Lake City population only (Figure 1 and Table S2). Thus, previously reported associations with POAG of at least some candidate genes were replicated in at least one of our populations.


Genes of the unfolded protein response pathway harbor risk alleles for primary open angle glaucoma.

Carbone MA, Chen Y, Hughes GA, Weinreb RN, Zabriskie NA, Zhang K, Anholt RR - PLoS ONE (2011)

Association between POAG and candidate gene tagging rsSNPs.The graph shows the genotypic P-values (Log(1/P); y-axis) from likelihood ratio Chi-squared tests of associations with candidate gene SNPs (x-axis) from 2 populations (San Diego (blue) and Salt Lake City (red)). The black arrows indicate SNPs that were significant in both the San Diego and Salt Lake City cohorts. The black horizontal line indicates the Bonferroni adjusted P-value (P = 0.0008).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3105107&req=5

pone-0020649-g001: Association between POAG and candidate gene tagging rsSNPs.The graph shows the genotypic P-values (Log(1/P); y-axis) from likelihood ratio Chi-squared tests of associations with candidate gene SNPs (x-axis) from 2 populations (San Diego (blue) and Salt Lake City (red)). The black arrows indicate SNPs that were significant in both the San Diego and Salt Lake City cohorts. The black horizontal line indicates the Bonferroni adjusted P-value (P = 0.0008).
Mentions: Mutations in MYOC have been associated with juvenile onset glaucoma, and with some cases of POAG [17], [19]. OPTN has also been associated with various forms of glaucoma, including POAG and normal tension glaucoma [20]. We did not detect associations between MYOC with POAG in either the Salt Lake City or San Diego population. This is perhaps not surprising as MYOC mutations have been associated with only ∼3–4% of POAG cases [7]. We did, however, find an association between OPTN and POAG in the Salt Lake City population (rs10906308, P = 5.84×10–9; Figure 1 and Table S2). The same SNP in the San Diego population, however, does not reach statistical significance (P = 0.04). Similarly, SNPs in CYP1B1 and PSMB7, which encodes proteasome subunit beta 7, are significantly associated with POAG in the Salt Lake City population only (Figure 1 and Table S2). Thus, previously reported associations with POAG of at least some candidate genes were replicated in at least one of our populations.

Bottom Line: This multiple testing problem can be surmounted with very large population sizes when common alleles of large effects give rise to disease status.Previous genome-wide analysis in a Drosophila ocular hypertension model identified transcripts with altered regulation and showed induction of the unfolded protein response (UPR) upon overexpression of transgenic human glaucoma-associated myocilin (MYOC).Thus, effectiveness of the UPR in response to accumulation of misfolded or aggregated proteins may contribute to the pathogenesis of POAG and provide targets for early therapeutic intervention.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, North Carolina State University, Raleigh, North Carolina, United States of America.

ABSTRACT
The statistical power of genome-wide association (GWA) studies to detect risk alleles for human diseases is limited by the unfavorable ratio of SNPs to study subjects. This multiple testing problem can be surmounted with very large population sizes when common alleles of large effects give rise to disease status. However, GWA approaches fall short when many rare alleles may give rise to a common disease, or when the number of subjects that can be recruited is limited. Here, we demonstrate that this multiple testing problem can be overcome by a comparative genomics approach in which an initial genome-wide screen in a genetically amenable model organism is used to identify human orthologues that may harbor risk alleles for adult-onset primary open angle glaucoma (POAG). Glaucoma is a major cause of blindness, which affects over 60 million people worldwide. Several genes have been associated with juvenile onset glaucoma, but genetic factors that predispose to adult onset primary open angle glaucoma (POAG) remain largely unknown. Previous genome-wide analysis in a Drosophila ocular hypertension model identified transcripts with altered regulation and showed induction of the unfolded protein response (UPR) upon overexpression of transgenic human glaucoma-associated myocilin (MYOC). We selected 16 orthologous genes with 62 polymorphic markers and identified in two independent human populations two genes of the UPR that harbor POAG risk alleles, BIRC6 and PDIA5. Thus, effectiveness of the UPR in response to accumulation of misfolded or aggregated proteins may contribute to the pathogenesis of POAG and provide targets for early therapeutic intervention.

Show MeSH
Related in: MedlinePlus