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Age-related macular degeneration: genome-wide association studies to translation.

ABSTRACT: In recent years, genome-wide association studies (GWAS), which are able to analyze the contribution to disease of genetic variations that are common within a population, have attracted considerable investment. Despite identifying genetic variants for many conditions, they have been criticized for yielding data with minimal clinical utility. However, in this regard, age-related macular degeneration (AMD), the most common form of blindness in the Western world, is a striking exception. Through GWAS, common genetic variants at a number of loci have been discovered. Two loci in particular, including genes of the complement cascade on chromosome 1 and the ARMS2/HTRA1 genes on chromosome 10, have been shown to convey significantly increased susceptibility to developing AMD. Today, although it is possible to screen individuals for a genetic predisposition to the disease, effective interventional strategies for those at risk of developing AMD are scarce. Ongoing research in this area is nonetheless promising. After providing brief overviews of AMD and common disease genetics, we outline the main recent advances in the understanding of AMD, particularly those made through GWAS. Finally, the true merit of these findings and their current and potential translational value is examined.Genet Med 18 4, 283-289.

SUBMITTER: Black JR

PROVIDER: S-EPMC4823638 | biostudies-literature | 2016 Apr

REPOSITORIES: biostudies-literature

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Age-related macular degeneration: genome-wide association studies to translation.

Black James R M JR Clark Simon J SJ

Genetics in medicine : official journal of the American College of Medical Genetics 20150528 4

In recent years, genome-wide association studies (GWAS), which are able to analyze the contribution to disease of genetic variations that are common within a population, have attracted considerable investment. Despite identifying genetic variants for many conditions, they have been criticized for yielding data with minimal clinical utility. However, in this regard, age-related macular degeneration (AMD), the most common form of blindness in the Western world, is a striking exception. Through GWA ...[more]

PMID: 26020418

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Project description:PurposeTo determine if plasma metabolic profiles can detect differences between patients with neovascular age-related macular degeneration (NVAMD) and similarly-aged controls.MethodsMetabolomic analysis using liquid chromatography with Fourier-transform mass spectrometry (LC-FTMS) was performed on plasma samples from 26 NVAMD patients and 19 controls. Data were collected from mass/charge ratio (m/z) 85 to 850 on a Thermo LTQ-FT mass spectrometer, and metabolic features were extracted using an adaptive processing software package. Both non-transformed and log2 transformed data were corrected using Benjamini and Hochberg False Discovery Rate (FDR) to account for multiple testing. Orthogonal Partial Least Squares-Discriminant Analysis was performed to determine metabolic features that distinguished NVAMD patients from controls. Individual m/z features were matched to the Kyoto Encyclopedia of Genes and Genomes database and the Metlin metabolomics database, and metabolic pathways associated with NVAMD were identified using MetScape.ResultsOf the 1680 total m/z features detected by LC-FTMS, 94 unique m/z features were significantly different between NVAMD patients and controls using FDR (q = 0.05). A comparison of these features to those found with log2 transformed data (n = 132, q = 0.2) revealed 40 features in common, reaffirming the involvement of certain metabolites. Such metabolites included di- and tripeptides, covalently modified amino acids, bile acids, and vitamin D-related metabolites. Correlation analysis revealed associations among certain significant features, and pathway analysis demonstrated broader changes in tyrosine metabolism, sulfur amino acid metabolism, and amino acids related to urea metabolism.ConclusionsThese data suggest that metabolomic analysis can identify a panel of individual metabolites that differ between NVAMD cases and controls. Pathway analysis can assess the involvement of certain metabolic pathways, such as tyrosine and urea metabolism, and can provide further insight into the pathophysiology of AMD.

Project description:Genome-wide association studies provide important insights to the genetic component of disease risks. However, an existing challenge is how to incorporate collective effects of interactions beyond the level of independent single nucleotide polymorphism (SNP) tests. While methods considering each SNP pair separately have provided insights, a large portion of expected heritability may reside in higher-order interaction effects.We describe an inference approach (discrete discriminant analysis; DDA) designed to probe collective interactions while treating both genotypes and phenotypes as random variables. The genotype distributions in case and control groups are modeled separately based on empirical allele frequency and covariance data, whose differences yield disease risk parameters. We compared pairwise tests and collective inference methods, the latter based both on DDA and logistic regression. Analyses using simulated data demonstrated that significantly higher sensitivity and specificity can be achieved with collective inference in comparison to pairwise tests, and with DDA in comparison to logistic regression. Using age-related macular degeneration (AMD) data, we demonstrated two possible applications of DDA. In the first application, a genome-wide SNP set is reduced into a small number (?100) of variants via filtering and SNP pairs with significant interactions are identified. We found that interactions between SNPs with highest AMD association were epigenetically active in the liver, adipocytes, and mesenchymal stem cells. In the other application, multiple groups of SNPs were formed from the genome-wide data and their relative strengths of association were compared using cross-validation. This analysis allowed us to discover novel collections of loci for which interactions between SNPs play significant roles in their disease association. In particular, we considered pathway-based groups of SNPs containing up to ?10, 000 variants in each group. In addition to pathways related to complement activation, our collective inference pointed to pathway groups involved in phospholipid synthesis, oxidative stress, and apoptosis, consistent with the AMD pathogenesis mechanism where the dysfunction of retinal pigment epithelium cells plays central roles.The simultaneous inference of collective interaction effects within a set of SNPs has the potential to reveal novel aspects of disease association.

Project description:PurposeTo investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to identify which genetic variants are associated with these 2 subtypes.DesignSibling correlation study and genome-wide association study (GWAS).ParticipantsFor the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls.MethodsParticipants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts.Main outcome measuresConcordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes.ResultsThe difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 × 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio [OR], 1.47; P = 4.3 × 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 × 10(-14) for combined discovery and replication analysis).ConclusionsWhether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies.

Dataset Information

Age-related macular degeneration: genome-wide association studies to translation.

Publications

Age-related macular degeneration: genome-wide association studies to translation.

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