The NEI/NCBI dbGAP Database: Genotypes and Haplotypes That May Specifically Predispose to Risk of Neovascular Age-related Macular Degeneration

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The NEI/NCBI dbGAP Database: Genotypes and Haplotypes That May Specifically Predispose to Risk of Neovascular Age-related Macular Degeneration

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dc.contributor.author Morrison, Margaux A
dc.contributor.author DeWan, Andy
dc.contributor.author Adams, Scott
dc.contributor.author Andreoli, Michael
dc.contributor.author Regan, Maureen
dc.contributor.author Brown, Alison
dc.contributor.author Hoh, Josephine
dc.contributor.author DeAngelis, Margaret
dc.contributor.author Zhang, Hong
dc.contributor.author Huynh, Nancy
dc.contributor.author Miller, Joan Whitten
dc.contributor.author Kim, Ivana Kyung
dc.date.accessioned 2011-02-07T17:34:48Z
dc.date.issued 2008
dc.identifier.citation Zhang, Hong, Margaux A Morrison, Andy DeWan, Scott Adams, Michael Andreoli, Nancy Huynh, Maureen Regan, et al. 2008. The NEI/NCBI dbGAP database: Genotypes and haplotypes that may specifically predispose to risk of neovascular age-related macular degeneration. BMC Medical Genetics 9: 51. en_US
dc.identifier.issn 1471-2350 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:4706592
dc.description.abstract Background: To examine if the significantly associated SNPs derived from the genome wide allelic association study on the AREDS cohort at the NEI (dbGAP) specifically confer risk for neovascular age-related macular degeneration (AMD). We ascertained 134 unrelated patients with AMD who had one sibling with an AREDS classification 1 or less and was past the age at which the affected sibling was diagnosed (268 subjects). Genotyping was performed by both direct sequencing and Sequenom iPLEX system technology. Single SNP analyses were conducted with McNemar's Test (both 2 × 2 and 3 × 3 tests) and likelihood ratio tests (LRT). Conditional logistic regression was used to determine significant gene-gene interactions. LRT was used to determine the best fit for each genotypic model tested (additive, dominant or recessive). Results: Before release of individual data, p-value information was obtained directly from the AREDS dbGAP website. Of the 35 variants with P < 10^-6 examined, 23 significantly modified risk of neovascular AMD. Many variants located in tandem on 1q32-q22 including those in CFH, CFHR4, CFHR2, CFHR5, F13B, ASPM and ZBTB were significantly associated with AMD risk. Of these variants, single SNP analysis revealed that CFH rs572515 was the most significantly associated with AMD risk (P < 10^-6). Haplotype analysis supported our findings of single SNP association, demonstrating that the most significant haplotype, GATAGTTCTC, spanning CFH, CFHR4, and CFHR2 was associated with the greatest risk of developing neovascular AMD (P < 10^-6). Other than variants on 1q32-q22, only two SNPs, rs9288410 (MAP2) on 2q34-q35 and rs2014307 (PLEKHA1/HTRA1) on 10q26 were significantly associated with AMD status (P = .03 and P < 10^-6 respectively). After controlling for smoking history, gender and age, the most significant gene-gene interaction appears to be between rs10801575 (CFH) and rs2014307 (PLEKHA1/HTRA1) (P < 10^-11). The best genotypic fit for rs10801575 and rs2014307 was an additive model based on LRT. After applying a Bonferonni correction, no other significant interactions were identified between any other SNPs. Conclusion: This is the first replication study on the NEI dbGAP SNPs, demonstrating that alleles on 1q, 2q and 10q may predispose an individual to AMD. en_US
dc.language.iso en_US en_US
dc.publisher BioMed Central en_US
dc.relation.isversionof doi://10.1186/1471-2350-9-51 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2441616/pdf/ en_US
dash.license LAA
dc.title The NEI/NCBI dbGAP Database: Genotypes and Haplotypes That May Specifically Predispose to Risk of Neovascular Age-related Macular Degeneration en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal BMC Medical Genetics en_US
dash.depositing.author Huynh, Nancy
dc.date.available 2011-02-07T17:34:48Z
dash.affiliation.other HMS^Ophthalmology en_US
dash.affiliation.other HMS^Ophthalmology en_US
dash.affiliation.other HMS^Ophthalmology en_US
dash.affiliation.other HMS^Ophthalmology en_US

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