Limits...
Genome-wide association analyses of genetic, phenotypic, and environmental risks in the age-related eye disease study.

Ryu E, Fridley BL, Tosakulwong N, Bailey KR, Edwards AO - Mol. Vis. (2010)

Bottom Line: An additional 26 novel SNPs potentially associated with AMD were identified, but none were definitely replicated in a second independent group of subjects.Smoking did not interact with known AMD loci, but was associated with late AMD.There continues to be evidence that the 10q26 (age-related maculopathy susceptibility 2 gene [ARMS2]) locus spanning PLEKHA1-LOC387715-HTRA1 and the C3 gene may contain multiple independent genetic risks contributing to AMD.

View Article: PubMed Central - PubMed

Affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.

ABSTRACT

Purpose: To present genome-wide association analyses of genotypic and environmental risks on age-related macular degeneration (AMD) using 593 subjects from the age-related eye disease study (AREDS), after adjusting for population stratification and including questionable controls.

Methods: Single nucleotide polymorphism (SNP) associations with AMD for the non-Hispanic white population were investigated using a log-additive model after adjusting for population stratification. Replication of possible SNP-disease association was performed by genotyping an independent group of 444 AMD case and 300 control subjects. Logistic regression models were used to assess interaction effects between smoking and SNPs associated with AMD. Independent genetic risk effects among the disease-associated SNPs were also investigated using multiple logistic regression models.

Results: Population stratification was observed among the individuals having a self-reported race of non-Hispanic white. Risk allele frequencies at established AMD loci demonstrated that questionable control subjects were similar to control subjects in the AREDS, suggesting that they could be used as true controls in the analyses. Genetic loci (complement factor H [CFH], complement factor B [CFB], the age-related maculopathy susceptibility 2 locus containing the hypothetical gene [LOC387715]/the high-temperature requirement A-1 [HTRA1], and complement component 3 [C3]) that were already known to be associated with AMD were identified. An additional 26 novel SNPs potentially associated with AMD were identified, but none were definitely replicated in a second independent group of subjects. Smoking did not interact with known AMD loci, but was associated with late AMD. Statistically independent genetic signals were observed within the Pleckstrin homology domain-containing family A member 1 (PLEKHA1) region near LOC387715/HTRA1 and within a haplotype spanning exon 19 of the C3 gene.

Conclusions: Population stratification among Caucasian subjects from the multicentered AREDS was observed, suggesting that it should be adjusted for in future studies. The AREDS questionable control subjects can be used as control subjects in the AREDS genome-wide association study (GWAS). Smoking was an independent risk factor for advanced AMD in the AREDS subjects. There continues to be evidence that the 10q26 (age-related maculopathy susceptibility 2 gene [ARMS2]) locus spanning PLEKHA1-LOC387715-HTRA1 and the C3 gene may contain multiple independent genetic risks contributing to AMD.

Show MeSH

Related in: MedlinePlus

Comparison of the frequency of the risk allele for four single nucleotide polymorphisms (SNPs) known to contribute to age-related macular degeneration (AMD) in the age-related eye disease study (AREDS) “control” and “questionable control” subjects. Each of these SNPs has been consistently associated with AMD in multiple studies. The figure shows that the questionable control category was similar to the control category in terms of the frequency of the risk allele. Questionable control subjects can be used as controls in analyses using the AREDS data set. Abbreviations: RCA is the regulation of complement activation locus containing the gene encoding CFH; please see introduction for other gene and locus names.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3008720&req=5

f1: Comparison of the frequency of the risk allele for four single nucleotide polymorphisms (SNPs) known to contribute to age-related macular degeneration (AMD) in the age-related eye disease study (AREDS) “control” and “questionable control” subjects. Each of these SNPs has been consistently associated with AMD in multiple studies. The figure shows that the questionable control category was similar to the control category in terms of the frequency of the risk allele. Questionable control subjects can be used as controls in analyses using the AREDS data set. Abbreviations: RCA is the regulation of complement activation locus containing the gene encoding CFH; please see introduction for other gene and locus names.

Mentions: The risk allele frequencies in the 27 questionable control subjects were compared to the other control and AMD subtypes using a two-sample test for equality of proportions (Figure 1). The risk allele frequencies in the questionable control group were very similar to those from the control group, but not from the cases. P values comparing questionable controls to control groups varied from 0.48 to 1, while those comparing them to cases varied from 1.04×10−5 to 0.06. Thus, the questionable controls could be combined with the controls for subsequent analyses.


Genome-wide association analyses of genetic, phenotypic, and environmental risks in the age-related eye disease study.

Ryu E, Fridley BL, Tosakulwong N, Bailey KR, Edwards AO - Mol. Vis. (2010)

Comparison of the frequency of the risk allele for four single nucleotide polymorphisms (SNPs) known to contribute to age-related macular degeneration (AMD) in the age-related eye disease study (AREDS) “control” and “questionable control” subjects. Each of these SNPs has been consistently associated with AMD in multiple studies. The figure shows that the questionable control category was similar to the control category in terms of the frequency of the risk allele. Questionable control subjects can be used as controls in analyses using the AREDS data set. Abbreviations: RCA is the regulation of complement activation locus containing the gene encoding CFH; please see introduction for other gene and locus names.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3008720&req=5

f1: Comparison of the frequency of the risk allele for four single nucleotide polymorphisms (SNPs) known to contribute to age-related macular degeneration (AMD) in the age-related eye disease study (AREDS) “control” and “questionable control” subjects. Each of these SNPs has been consistently associated with AMD in multiple studies. The figure shows that the questionable control category was similar to the control category in terms of the frequency of the risk allele. Questionable control subjects can be used as controls in analyses using the AREDS data set. Abbreviations: RCA is the regulation of complement activation locus containing the gene encoding CFH; please see introduction for other gene and locus names.
Mentions: The risk allele frequencies in the 27 questionable control subjects were compared to the other control and AMD subtypes using a two-sample test for equality of proportions (Figure 1). The risk allele frequencies in the questionable control group were very similar to those from the control group, but not from the cases. P values comparing questionable controls to control groups varied from 0.48 to 1, while those comparing them to cases varied from 1.04×10−5 to 0.06. Thus, the questionable controls could be combined with the controls for subsequent analyses.

Bottom Line: An additional 26 novel SNPs potentially associated with AMD were identified, but none were definitely replicated in a second independent group of subjects.Smoking did not interact with known AMD loci, but was associated with late AMD.There continues to be evidence that the 10q26 (age-related maculopathy susceptibility 2 gene [ARMS2]) locus spanning PLEKHA1-LOC387715-HTRA1 and the C3 gene may contain multiple independent genetic risks contributing to AMD.

View Article: PubMed Central - PubMed

Affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.

ABSTRACT

Purpose: To present genome-wide association analyses of genotypic and environmental risks on age-related macular degeneration (AMD) using 593 subjects from the age-related eye disease study (AREDS), after adjusting for population stratification and including questionable controls.

Methods: Single nucleotide polymorphism (SNP) associations with AMD for the non-Hispanic white population were investigated using a log-additive model after adjusting for population stratification. Replication of possible SNP-disease association was performed by genotyping an independent group of 444 AMD case and 300 control subjects. Logistic regression models were used to assess interaction effects between smoking and SNPs associated with AMD. Independent genetic risk effects among the disease-associated SNPs were also investigated using multiple logistic regression models.

Results: Population stratification was observed among the individuals having a self-reported race of non-Hispanic white. Risk allele frequencies at established AMD loci demonstrated that questionable control subjects were similar to control subjects in the AREDS, suggesting that they could be used as true controls in the analyses. Genetic loci (complement factor H [CFH], complement factor B [CFB], the age-related maculopathy susceptibility 2 locus containing the hypothetical gene [LOC387715]/the high-temperature requirement A-1 [HTRA1], and complement component 3 [C3]) that were already known to be associated with AMD were identified. An additional 26 novel SNPs potentially associated with AMD were identified, but none were definitely replicated in a second independent group of subjects. Smoking did not interact with known AMD loci, but was associated with late AMD. Statistically independent genetic signals were observed within the Pleckstrin homology domain-containing family A member 1 (PLEKHA1) region near LOC387715/HTRA1 and within a haplotype spanning exon 19 of the C3 gene.

Conclusions: Population stratification among Caucasian subjects from the multicentered AREDS was observed, suggesting that it should be adjusted for in future studies. The AREDS questionable control subjects can be used as control subjects in the AREDS genome-wide association study (GWAS). Smoking was an independent risk factor for advanced AMD in the AREDS subjects. There continues to be evidence that the 10q26 (age-related maculopathy susceptibility 2 gene [ARMS2]) locus spanning PLEKHA1-LOC387715-HTRA1 and the C3 gene may contain multiple independent genetic risks contributing to AMD.

Show MeSH
Related in: MedlinePlus