Dataset Information

Age related Macular Degeneration (AMD)-- Michigan, Mayo, AREDS, Pennsylvania (MMAP) Cohort Study: A Joint Genome Wide Association Study

ABSTRACT:

Age-related Macular Degeneration (AMD) is a leading cause of incurable blindness in people over the age of 65. AMD is a late-onset multi-factorial neurodegenerative disease and its pathogenesis involves interaction of genetic and environmental factors. Several chromosomal regions have been associated with AMD susceptibility through linkage analysis (Swaroop et al., 2009). More recent studies provide strong evidence that variants within the CFH gene cluster on chromosome 1 and at/near LOC387715/ARMS2 on chromosome 10 are strongly associated with disease. Variants at other genes including C2/BF, C3, CFI and APOE4, also contribute to AMD susceptibility.

Our primary goals are to identify genetic variants and haplotypes that are associated with AMD. The underlying hypothesis is that DNA variation(s) in multiple genetic susceptibility loci will predispose individuals to AMD pathogenesis, and comparison of DNA of cases and controls should identify these susceptibility variants. Our studies are focused on the genetic analysis of advanced AMD and should provide novel insights into disease diagnosis, progression and pathology.

We have assembled a collaborative group of researchers from the University of Michigan, Mayo Clinic, University of Pennsylvania, and the AREDS group including National Eye Institute intramural investigators, who collected clinical data and DNA from a large number of patients affected with AMD and from unaffected controls. The primary source of funding was National Eye Institute. Through this collaborative effort, we submitted and obtained usable genotyping data on 2184 patients and 1155 controls from the Center for Inherited Disease Research (CIDR).

PROVIDER: phs000182.v2.p1 | EGA |

REPOSITORIES: EGA

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Publications

Toll-like receptor polymorphisms and age-related macular degeneration.

Edwards Albert O AO Chen Dequan D Fridley Brooke L BL James Katherine M KM Wu Yanhong Y Abecasis Goncalo G Swaroop Anand A Othman Mohammad M Branham Kari K Iyengar Sudha K SK Sivakumaran Theru A TA Klein Ronald R Klein Barbara E K BE Tosakulwong Nirubol N

Investigative ophthalmology & visual science 20080401 4

<h4>Purpose</h4>Evidence from genetic-association studies in conjunction with the demonstration of complement deposition in the retina and choroid implicates noncellular pathways of innate immunity in the pathogenesis of age-related macular degeneration (AMD). The purpose of this study was to determine whether common variation in the 10 human toll-like receptors (TLRs) alters the risk of AMD.<h4>Methods</h4>Sixty-eight SNPs were iteratively genotyped across the TLR genes in a cohort of 577 subje ...[more]

PMID: 18385087

Publication: 1/17

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Project description:Age-related Macular Degeneration (AMD) is a leading cause of incurable blindness in people over the age of 65. AMD is a late-onset multi-factorial neurodegenerative disease and its pathogenesis involves interaction of genetic and environmental factors. Several chromosomal regions have been associated with AMD susceptibility through linkage analysis (<a href="http://www.ncbi.nlm.nih.gov/pubmed/19405847">Swaroop et al., 2009</a>). More recent studies provide strong evidence that variants within the CFH gene cluster on chromosome 1 and at/near LOC387715/ARMS2 on chromosome 10 are strongly associated with the disease. Variants at other genes including C2/BF, C3, CFI and APOE4, also contribute to AMD susceptibility. Our primary goals are to identify genetic variants and haplotypes that are associated with AMD. The underlying hypothesis is that DNA variation(s) in multiple genetic susceptibility loci will predispose individuals to AMD pathogenesis, and comparison of DNA of cases and controls should identify these susceptibility variants. Our studies are focused on the genetic analysis of advanced AMD and should provide novel insights into disease diagnosis, progression and pathology. We have assembled a collaborative group of researchers from the University of Michigan, Mayo Clinic, University of Pennsylvania, and the AREDS group including National Eye Institute intramural investigators, who collected clinical data and DNA from a large number of patients affected with AMD and from unaffected controls. The primary source of funding was National Eye Institute. Study 1: To identify genetic variants and haplotypes that are associated with AMD, we submitted and obtained usable genotyping data on 2185 patients and 1155 controls from the Center for Inherited Disease Research (CIDR). Study 2: To identify rare coding variants associated with a large increase in risk of AMD, 10 candidate loci spanning 57 genes were sequenced in 2,335 cases and 789 controls. Probes were designed to capture 96.5% of the coding sequence and 35% of total locus sequence, generating an average 123Mb of on-target sequence per individual at 127x average depth. Substudies: <li><a href="./study.cgi?study_id=phs000182">phs000182</a> AMD-MMAP Cohort Study: A Joint Genome-Wide Asscociation Study</li> <li><a href="./study.cgi?study_id=phs000246">phs000246</a> Fuchs' Corneal Dystrophy GWAS</li> <li><a href="./study.cgi?study_id=phs000457">phs000457</a> MMAP Methylation in AMD</li> <li><a href="./study.cgi?study_id=phs000685">phs000685</a> Age-Related Macular Degeneration Targeted Sequencing Study</li>

Project description:Cloutier2012 - Feedback motif for Parkinson's disease This model is described in the article: Feedback motif for the pathogenesis of Parkinson's disease. Cloutier M, Middleton R, Wellstead P. IET Syst Biol 2012 Jun; 6(3): 86-93 Abstract: Previous article on the integrative modelling of Parkinson's disease (PD) described a mathematical model with properties suggesting that PD pathogenesis is associated with a feedback-induced biochemical bistability. In this article, the authors show that the dynamics of the mathematical model can be extracted and distilled into an equivalent two-state feedback motif whose stability properties are controlled by multi-factorial combinations of risk factors and genetic mutations associated with PD. Based on this finding, the authors propose a principle for PD pathogenesis in the form of the switch-like transition of a bistable feedback process from 'healthy' homeostatic levels of reactive oxygen species and the protein ?-synuclein, to an alternative 'disease' state in which concentrations of both molecules are stable at the damagingly high-levels associated with PD. The bistability is analysed using the rate curves and steady-state response characteristics of the feedback motif. In particular, the authors show how a bifurcation in the feedback motif marks the pathogenic moment at which the 'healthy' state is lost and the 'disease' state is initiated. Further analysis shows how known risks (such as: age, toxins and genetic predisposition) modify the stability characteristics of the feedback motif in a way that is compatible with known features of PD, and which explain properties such as: multi-factorial causality, variability in susceptibility and severity, multi-timescale progression and the special cases of familial Parkinson's and Parkinsonian symptoms induced purely by toxic stress. Stress of 2.6 obtained by optimization (parameter S1) was imposed between days 10 and 150 in order to reproduce the Figure. This model is hosted on BioModels Database and identified by: BIOMD0000000558. To cite BioModels Database, please use: BioModels Database: An enhanced, curated and annotated resource for published quantitative kinetic models. To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Dataset Information

Age related Macular Degeneration (AMD)-- Michigan, Mayo, AREDS, Pennsylvania (MMAP) Cohort Study: A Joint Genome Wide Association Study

Publications

Toll-like receptor polymorphisms and age-related macular degeneration.

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