The NEI/NCBI dbGAP database: Genotypes and haplotypes that may specifically predispose to risk of neovascular age-related macular degeneration

Zhang, Hong; Morrison, Margaux A.; DeWan, Andrew T.; Adams, S. M.; Andreoli, Michael T.; Huynh, Nancy; Regan, Meredith M.; Brown, Anna; Miller, Joan W.; Kim, Ivana K.; Hoh, Josephine; DeAngelis, Margaret M.

doi:10.1186/1471-2350-9-51

Cited by 57 publications

(70 citation statements)

References 37 publications

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“…This hypothesis predicts that suppression of IGF-1 has the potential to protect patients from developing NvAMD (64). These findings offer a complementary understanding of HtrA1's multiple functions, based on the catalogue of NvAMD-associated SNPs (2) and existing HtrA1 animal models (70,71). For instance, the fact that the most prevalent HTRA1 variant, rs11200638, harbors a SNP within the promoter region suggests that increased expression of HTRA1 may contribute to NvAMD (27,28).…”

Section: Discussionmentioning

confidence: 98%

“…ingle nucleotide polymorphisms (SNPs) that fall within the coding region have the potential to alter the amino acid sequence of a gene's product and therefore can serve as a Rosetta stone for understanding the pathogenesis of human disorders (1,2). A curiosity that emerged from human genome-wide association studies is that exonic SNPs that do not alter the amino acid sequence of the protein product (i.e., SNPs that are synonymous) are as common as SNPs that do (i.e., SNPs that are nonsynonymous) (3).…”

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confidence: 99%

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Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

Jacobo

DeAngelis

Kim

et al. 2013

Molecular and Cellular Biology

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Synonymous single nucleotide polymorphisms (SNPs) within a transcript's coding region produce no change in the amino acid sequence of the protein product and are therefore intuitively assumed to have a neutral effect on protein function. We report that two common variants of high-temperature requirement A1 (HTRA1) that increase the inherited risk of neovascular agerelated macular degeneration (NvAMD) harbor synonymous SNPs within exon 1 of HTRA1 that convert common codons for Ala34 and Gly36 to less frequently used codons. The frequent-to-rare codon conversion reduced the mRNA translation rate and appeared to compromise HtrA1's conformation and function. The protein product generated from the SNP-containing cDNA displayed enhanced susceptibility to proteolysis and a reduced affinity for an anti-HtrA1 antibody. The NvAMD-associated synonymous polymorphisms lie within HtrA1's putative insulin-like growth factor 1 (IGF-1) binding domain. They reduced HtrA1's abilities to associate with IGF-1 and to ameliorate IGF-1-stimulated signaling events and cellular responses. These observations highlight the relevance of synonymous codon usage to protein function and implicate homeostatic protein quality control mechanisms that may go awry in NvAMD. Single nucleotide polymorphisms (SNPs) that fall within the coding region have the potential to alter the amino acid sequence of a gene's product and therefore can serve as a Rosetta stone for understanding the pathogenesis of human disorders (1, 2). A curiosity that emerged from human genome-wide association studies is that exonic SNPs that do not alter the amino acid sequence of the protein product (i.e., SNPs that are synonymous) are as common as SNPs that do (i.e., SNPs that are nonsynonymous) (3). Furthermore, some of the disease-associated synonymous SNPs constitute the molecular underpinnings of pathology, meaning that they are enriched in affected human subjects and alter the gene product. For the majority (95%) of disease-associated synonymous SNPs, aberrant gene products were attributed to unstable mRNA transcripts with a reduced half-life or mutations in splice sites that resulted in exon skipping (4, 5). In other cases, synonymous SNPs caused translational defects independently of mRNA splicing errors (6-9).A parsimonious mechanism by which synonymous SNPs impact the integrity of protein products involves the alteration of codon usage. In vivo, folding of nascent proteins proceeds cotranslationally (10, 11) and is influenced by the rate of ribosome transit through the mRNA template. What distinguishes synonymous codons that encode a given degenerate amino acid is the abundance of their corresponding tRNA, which is lower for infrequently used codons than for frequently used codons (12, 13). Consequently, codon frequency can influence the rate of translation. Of note, codon bias has been widely described in prokaryotes and single-celled eukaryotes but less extensively in complex eukaryotes.In humans, correlations between optimum codon usage and either protein expression...

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Section: Discussionmentioning

confidence: 98%

mentioning

confidence: 99%

Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

Jacobo

DeAngelis

Kim

et al. 2013

Molecular and Cellular Biology

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“…Some integrated applications are publicly available to bring together phenotypes, genotypes, and resulting associations. NCBI has launched dbGaP (Zhang et al 2008), a public database to archive genotype and clinical phenotype data from human studies. The Complex Trait Consortium has launched GeneNetwork (Wu (Groth et al 2007).…”

Section: Standards For Submissionmentioning

confidence: 99%

Uniform standards for genome databases in forest and fruit trees

Wegrzyn

Main

Figueroa

et al. 2012

Tree Genetics & Genomes

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TreeGenes and tree fruit Genome Database Resources serve the international forestry and fruit tree genomics research communities, respectively. These databases hold similar sequence data and provide resources for the submission and recovery of this information in order to enable comparative genomics research. Large-scale genotype and phenotype projects have recently spawned the development of independent tools and interfaces within these repositories to deliver information to both geneticists and breeders. The increase in next generation sequencing projects has increased the amount of data as well as the scale of analysis that can be performed. These two repositories are now working towards a similar goal of archiving the diverse, independent data sets generated from genotype/phenotype experiments. This is achieved through focused development on data input standards (templates), pipelines for the storage and automated curation, and consistent annotation efforts through the application of widely accepted ontologies to improve the extraction and exchange of the data for comparative analysis. Efforts towards standardization are not limited to genotype/phenotype experiments but are also being applied to other data types to improve gene prediction and annotation for de novo sequencing projects. The resources developed towards these goals represent the first large-scale coordinated effort in plant Communicated by T. Drudge A contribution to the special issue "The genomes of the giants: a walk through the forest of tree genomes".

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“…A c.1277T>C mutation encoding a p.Y402H amino acid substitution is strongly associated with age-related macular degeneration (AMD), a common form of visual impairment in the elderly. A study by Zhang et al (2008) analyzed data from 134 discordant sib pairs on rs1061170 along with other SNPs previously determined to be associated with AMD. Yan et al (2009) also used these data to illustrate several test statistics for assessing association in genetically related pairs.…”

Section: Macular Degeneration Examplementioning

confidence: 99%

Genotype‐Based Association Analysis Using Discordant Pairs: A Penetrance Odds Ratio Approach

Grover

Cole

Hamilton

2013

Annals of Human Genetics

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SummaryGenotypic counts of paired relatives discordant for a complex late-onset disease are often used to test for genetic association. The power of the various statistical test options, when data on covariates are unavailable, has been the focus of recent research. Comparison of the Cochran-Armitage, Bhapkar, and McNemar tests indicates that none is superior to the others in all cases. Using an alternative approach, we found that the theoretical genotypic frequencies of the discordant pairs depend only on the penetrance odds ratios, after conditioning. These odds ratios can be estimated by maximizing a product binomial likelihood and provide insight into the mode of inheritance. We identified cases where exact maximum likelihood (ML) estimates can be explicitly obtained. This approach led us to two tests for association which depend on likelihood ratio (LR) or score statistics. We quantified the power of these tests analytically and examined their performance through simulation. We explored the utility of these tests with an example from the literature-the association between complement factor H (CFH) polymorphisms and age-related macular degeneration. The LR and Score tests serve as simple and effective ways of interpreting paired case-control data sets.

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The NEI/NCBI dbGAP database: Genotypes and haplotypes that may specifically predispose to risk of neovascular age-related macular degeneration

Cited by 57 publications

References 37 publications

Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

Age-Related Macular Degeneration-Associated Silent Polymorphisms in HtrA1 Impair Its Ability To Antagonize Insulin-Like Growth Factor 1

Uniform standards for genome databases in forest and fruit trees

Genotype‐Based Association Analysis Using Discordant Pairs: A Penetrance Odds Ratio Approach

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