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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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Association of PDIA5 (A) and BIRC6 (B) haplotypes with POAG.The graphs show the Fisher's P-values (Log(1/P); y-axis) with the haplotypes (x-axis) from 2 populations (San Diego (blue) and Salt Lake City (red). The PDIA5 haplotypes are composed of the following rsSNPs: rs11720822, rs2241962, rs2667465, rs3792361, rs3792390, rs4677994, rs702029, rs836833. The BIRC6 haplotypes are composed of the following rsSNPs: rs12612824, rs17820747, rs2069213, rs2254106, and rs2754511. Haplotypes with frequencies <0.03 were excluded from the analysis. Haplotypes significantly associated with POAG are indicated with an asterisk (Bonferroni adjusted P<0.004 for PDIA5; Bonferroni adjusted P<0.01 for BIRC6).
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pone-0020649-g002: Association of PDIA5 (A) and BIRC6 (B) haplotypes with POAG.The graphs show the Fisher's P-values (Log(1/P); y-axis) with the haplotypes (x-axis) from 2 populations (San Diego (blue) and Salt Lake City (red). The PDIA5 haplotypes are composed of the following rsSNPs: rs11720822, rs2241962, rs2667465, rs3792361, rs3792390, rs4677994, rs702029, rs836833. The BIRC6 haplotypes are composed of the following rsSNPs: rs12612824, rs17820747, rs2069213, rs2254106, and rs2754511. Haplotypes with frequencies <0.03 were excluded from the analysis. Haplotypes significantly associated with POAG are indicated with an asterisk (Bonferroni adjusted P<0.004 for PDIA5; Bonferroni adjusted P<0.01 for BIRC6).

Mentions: We next compared the distributions of the haplotypes composed of these PDIA5 and BIRC6 SNPs (Figure 2, Tables S7, S8, S9, S10). The frequency of the GTAAAGGG haplotype of PDIA5 was higher in POAG cases than controls in both the Salt Lake City and San Diego populations (odds ratio = 2.4 (95% CI 1.6–3.5) in the Salt Lake City population; odds ratio = 6.0 (95% CI 2.4–16.3) for the San Diego population; Tables S7 and S8), implicating it as a risk haplotype in both populations. In addition to SNPs in PDIA5, we identified one SNP in BIRC6, rs2754511, that was significantly associated with POAG in both the Salt Lake City (P = 1.6×10−8) and San Diego population (P = 7.5×10−4) (Figure 1 and Table S2). Haplotype analysis indicates that the GAAAT haplotype of BIRC6 appears to be protective in each population (Tables S9 and S10).


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 of PDIA5 (A) and BIRC6 (B) haplotypes with POAG.The graphs show the Fisher's P-values (Log(1/P); y-axis) with the haplotypes (x-axis) from 2 populations (San Diego (blue) and Salt Lake City (red). The PDIA5 haplotypes are composed of the following rsSNPs: rs11720822, rs2241962, rs2667465, rs3792361, rs3792390, rs4677994, rs702029, rs836833. The BIRC6 haplotypes are composed of the following rsSNPs: rs12612824, rs17820747, rs2069213, rs2254106, and rs2754511. Haplotypes with frequencies <0.03 were excluded from the analysis. Haplotypes significantly associated with POAG are indicated with an asterisk (Bonferroni adjusted P<0.004 for PDIA5; Bonferroni adjusted P<0.01 for BIRC6).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020649-g002: Association of PDIA5 (A) and BIRC6 (B) haplotypes with POAG.The graphs show the Fisher's P-values (Log(1/P); y-axis) with the haplotypes (x-axis) from 2 populations (San Diego (blue) and Salt Lake City (red). The PDIA5 haplotypes are composed of the following rsSNPs: rs11720822, rs2241962, rs2667465, rs3792361, rs3792390, rs4677994, rs702029, rs836833. The BIRC6 haplotypes are composed of the following rsSNPs: rs12612824, rs17820747, rs2069213, rs2254106, and rs2754511. Haplotypes with frequencies <0.03 were excluded from the analysis. Haplotypes significantly associated with POAG are indicated with an asterisk (Bonferroni adjusted P<0.004 for PDIA5; Bonferroni adjusted P<0.01 for BIRC6).
Mentions: We next compared the distributions of the haplotypes composed of these PDIA5 and BIRC6 SNPs (Figure 2, Tables S7, S8, S9, S10). The frequency of the GTAAAGGG haplotype of PDIA5 was higher in POAG cases than controls in both the Salt Lake City and San Diego populations (odds ratio = 2.4 (95% CI 1.6–3.5) in the Salt Lake City population; odds ratio = 6.0 (95% CI 2.4–16.3) for the San Diego population; Tables S7 and S8), implicating it as a risk haplotype in both populations. In addition to SNPs in PDIA5, we identified one SNP in BIRC6, rs2754511, that was significantly associated with POAG in both the Salt Lake City (P = 1.6×10−8) and San Diego population (P = 7.5×10−4) (Figure 1 and Table S2). Haplotype analysis indicates that the GAAAT haplotype of BIRC6 appears to be protective in each population (Tables S9 and S10).

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