iPSC modelling and multi-omics analysis to understand age-related macular degeneration

Lead Research Organisation: University of Manchester
Department Name: School of Biological Sciences

Abstract

Age-related macular degeneration (AMD) is a leading global cause of blindness that affects 8-12% of people over the age of 60 years. It is estimated that by the year 2040, 288 million people will be affected by AMD. As such, it represents one of the biggest economic burdens faced by healthcare services around the world. AMD is a complex condition, caused by a combination of non-modifiable (e.g. increasing age, ethnicity) and modifiable (e.g. obesity, smoking, dietary antioxidant intake) risk factors. Genetic variants also play a significant role in AMD risk, with rare and common polymorphisms in the Complement factor H (CFH) gene accountable for up to 50% increased risk of disease development. Animal and cellular models of AMD are not able to accurately replicate the biological complexities of the condition, thus precluding understanding of the contribution of genetic variants to disease pathogenesis. Consequently, there are very few treatment options available. Early-onset macular degeneration (EOMD) is an important cause of severe and progressive visual loss in young adults that shows very similar disease pathology to AMD. Unlike AMD, EOMD has a much weaker association with life-style related risk factors and is often present in more than one generation of a family suggesting a strong genetic component. Research has shown that rare, deleterious and common AMD-associated DNA changes in the CFH gene underlie EOMD in a proportion of cases. The aim of this project is to study the role of CFH impacting variants disease pathogenesis using induced pluripotent stem cells (iPSC) differentiated in to retinal pigment epithelium (RPE) from EOMD patients. This study will investigate the direct impact of genetic variation on protein function, before employing cutting-edge 'omics methodologies to measure the genome-wide effect of impaired protein function at multiple biological levels. Increased understanding of EOMD biology will shed light on the mechanisms driving AMD onset and progression, and will facilitate the development of treatment strategies. In addition, further insight into the the contribution of genetic variants to disease development will provide more patients and their families with specialised care, precise diagnosis, prognostic information and genetic counselling- crucial in the era of personalised genomic medicine.

Technical Summary

The use of monogenic sub-forms to unravel the complexities of common disease is a recognised strategy that has been used to further understanding of diabetes, cancer and autoimmune disease. Age-related macular degeneration (AMD) is the leading cause of severe visual loss in the Western world. AMD exemplifies common disorders but is atypical in its genetic contribution. However, a major limitation in AMD research is a lack of comprehension of the functional impact of genetic contributors to disease outcome thus restricting the clinical usefulness of genetic information. Further, animal and cellular models do not replicate the genetic and metabolic complexities of the condition, thus impeding understanding and limiting the development of treatments. Recent research has implicated rare and common AMD-associated risk alleles in the Complement Factor H (CFH) gene as the underlying cause of monogenic, early-onset macular degeneration (EOMD); a condition that is pathologically similar to AMD. This study aims to investigate the role of CFH impacting variants using induced pluripotent stem cells (iPSCs) derived from genetically defined EOMD patients. The retinal pigment epithelium (RPE) is considered to be the primary site of disease in EOMD/AMD, therefore this project aims to develop an iPSC-RPE model of EOMD. By employing a multi-level, holistic, systems biology approach, this work aims to measure the genome-wide impact of impaired Factor H (FH) function with the aim of identifying novel gene regulatory networks and disease pathways that will inform understanding of monogenic and complex forms of macular degeneration. Increased understanding of the contribution of genetic variants to EOMD/AMD pathology will facilitate the development of stratified medicine approaches to patient care. Further, identification of the molecular mechanisms underpinning macular degeneration will expedite the development of novel therapeutic modalities.
 
Description Postgraduate training/PhD student supervision
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Influenced training of practitioners or researchers
Impact Training postgraduate/PhD students in the analysis of genomic data and DNA variant interpretation. Training postgraduate students in stem cell derivation and the applications of stem cells in human disease modelling, clinical research and transnational medicine.
 
Description A comprehensive molecular analysis and iPSC model of early adult-onset macular degeneration (EOMD) to better understand AMD.
Amount £164,042 (GBP)
Organisation University of Manchester 
Sector Academic/University
Country United Kingdom
Start 10/2018 
End 04/2021
 
Title Early-onset macular degeneration gene panel 
Description I have designed and implemented an advanced DNA sequencing assay to measure the contribution of rare and common genetic variants in the development of early-onset macular degeneration/drusen. This assay encompasses the full transcribed region of 8 disease related genes; the coding regions of 35 genes previously associated with the disease and/or pathways known to be important in the disease pathology; and 77 common single nucleotide polymorphisms that have previously been associated with increased risk of age-related macular degeneration. It is anticipated that this assay will allow the development of a quantitative profile of the impact of genetic variants in their contribution to EOMD such that this information may be used to inform clinical decisions regarding disease risk, onset, progression and severity, and could be used to inform genetic counselling regarding anticipated visual outcomes and risk to family members. 
Type Of Material Technology assay or reagent 
Year Produced 2018 
Provided To Others? No  
Impact This assay has enabled the diagnosis ophthalmic disease in patients who did not receive a result from genetic testing available on the National Health Service. 
 
Title Patient derived iPSC-RPE model of early-onset macular drusen 
Description I have devised a method for the generation of iPSCs from genetically characterised patients with a rare form of early-onset macular drusen/degeneration (EOMD). I use these iPSC lines to generate retinal pigment epithelial (RPE) cells in order to create an accurate model of disease onset, progression and pathology in order to better understand the genetic and molecular mechanisms underpinning EOMD. This model is highly accurate and allows the study of disease pathology in a disease-relevant tissue whilst avoiding/replacing the use of animals. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2019 
Provided To Others? No  
Impact The development of this disease model fully replaces the use of animals, a major principle of the NC3Rs. 
 
Title Early-onset macular degeneration gene panel 
Description I have designed and implemented an advanced DNA sequencing assay to measure the contribution of rare and common genetic variants in the development of early-onset macular degeneration/drusen. This assay encompasses the full transcribed region of 8 disease related genes; the coding regions of 35 genes previously associated with the disease and/or pathways known to be important in the disease pathology; and 77 common single nucleotide polymorphisms that have previously been associated with increased risk of age-related macular degeneration. It is anticipated that this assay will allow the development of a quantitative profile of the impact of genetic variants in their contribution to EOMD such that this information may be used to inform clinical decisions regarding disease risk, onset, progression and severity, and could be used to inform genetic counselling regarding anticipated visual outcomes and risk to family members. 
Type Of Material Data analysis technique 
Year Produced 2018 
Provided To Others? No  
Impact This assay has enabled the diagnosis ophthalmic disease in patients who did not receive a result from genetic testing available on the National Health Service. 
 
Description Columbia Stem Cell Initiative: Cloumbia Stem Cell Core Facility 
Organisation Columbia University
Country United States 
Sector Academic/University 
PI Contribution Exchange of expertise in stem cell derivation and CRISPR-Cas9 genome editing.
Collaborator Contribution CUMC Stem Cell Core Facility provided me with training in induced pluripotent stem cell (iPSC) derivation, retinal pigment epithelium differentiation, and CRISPR-Cas9 genome editing. The core continues to share expertise in advancement in this area and helped me generate some iPSC lines that i have used in my research.
Impact Manuscript in preparation: Small molecules restore the expression and function of mutant proteins underpinning autosomal dominant and recessive disease (Liu and Taylor et al. (2019))
Start Year 2017
 
Description European Retinal Disease Consortium 
Organisation Columbia University
Country United States 
Sector Academic/University 
PI Contribution Collaboration for the identification of novel causes of macular degeneration and inherited retinal disease. I have contributed candidate genes and variant interpretation expertise. I represented Manchester Centre for Genomic Medicine at the European Retinal Disease Consortium (ERDC) Conference (2018, Les Diablerets, Switzerland) were i shared our research interests and expertise, and offered areas for collaboration.
Collaborator Contribution The ERDC continues to support my research by offering a network of expertise and big data sets for the identification of the genetic causes of macular degeneration.
Impact ERDC members meet twice a year to exchange genetic and clinical data of persons with IRDs. This collaboration has resulted in many joint papers to date. Research outputs:- PMID: 29320387;28918053;28794130;28575650;28285769;27814526;28795510;28159970;28412069;27302843;27070432;26910043;27063057;26766544;27460420;26891008;27339364;27208209;27063057;26908613;27486781;27339364;25802487;28173158;27588451;26691986;25882705;26167768;26350383;25883087;26720483;25616768;25972256;25629076;25346251;26056285;26574802;25983245;25541840;26263531;26306921;25859010;26029869;25227500;18452394;18179881;19074801;19578023;19615668;19896113;19409519;19200527;19268277;19854499;19375515;19006237;20673862;20375346;20549516;21151602;20340138;20159111;20081859;20398884;20705279;20506298;20232351;20398886;20835237;20079931;21069908;20538994;20519033;19683999;21179236;21882291;20881296;21835304;22136677;21295282;21267001;21267011;21549338;21825197;22004887;21234346;21344540;22901948;22177090;23143442;22325361;22917891;22264887;22355252;22661473;23251578;22940612;22009552;22842230;22234150;22446187;23304067;24290379;23940504;23725738;23946133;23499059;23716654;23993198;23308101;23746546;23356391;24043777;23350551;23246293;23486539;23307924;23755871;23788369;24959063;24144451;24940029;24737827;24697911;24876279;25018096;24992209;24780881;25404053;25352746;25342620;25082829;24916380;25030840;25859010;25227500;25168386;25616768;25802487;25629076;25346251;25541840;25749990;25883087;25574057;25574898;25882705;25375654;25356532;25385675;+29300381+;29232904;29706639;29276052;30105367;30080950;28749477.
Start Year 2008
 
Description European Retinal Disease Consortium 
Organisation Ghent University Hospital
Country Belgium 
Sector Hospitals 
PI Contribution Collaboration for the identification of novel causes of macular degeneration and inherited retinal disease. I have contributed candidate genes and variant interpretation expertise. I represented Manchester Centre for Genomic Medicine at the European Retinal Disease Consortium (ERDC) Conference (2018, Les Diablerets, Switzerland) were i shared our research interests and expertise, and offered areas for collaboration.
Collaborator Contribution The ERDC continues to support my research by offering a network of expertise and big data sets for the identification of the genetic causes of macular degeneration.
Impact ERDC members meet twice a year to exchange genetic and clinical data of persons with IRDs. This collaboration has resulted in many joint papers to date. Research outputs:- PMID: 29320387;28918053;28794130;28575650;28285769;27814526;28795510;28159970;28412069;27302843;27070432;26910043;27063057;26766544;27460420;26891008;27339364;27208209;27063057;26908613;27486781;27339364;25802487;28173158;27588451;26691986;25882705;26167768;26350383;25883087;26720483;25616768;25972256;25629076;25346251;26056285;26574802;25983245;25541840;26263531;26306921;25859010;26029869;25227500;18452394;18179881;19074801;19578023;19615668;19896113;19409519;19200527;19268277;19854499;19375515;19006237;20673862;20375346;20549516;21151602;20340138;20159111;20081859;20398884;20705279;20506298;20232351;20398886;20835237;20079931;21069908;20538994;20519033;19683999;21179236;21882291;20881296;21835304;22136677;21295282;21267001;21267011;21549338;21825197;22004887;21234346;21344540;22901948;22177090;23143442;22325361;22917891;22264887;22355252;22661473;23251578;22940612;22009552;22842230;22234150;22446187;23304067;24290379;23940504;23725738;23946133;23499059;23716654;23993198;23308101;23746546;23356391;24043777;23350551;23246293;23486539;23307924;23755871;23788369;24959063;24144451;24940029;24737827;24697911;24876279;25018096;24992209;24780881;25404053;25352746;25342620;25082829;24916380;25030840;25859010;25227500;25168386;25616768;25802487;25629076;25346251;25541840;25749990;25883087;25574057;25574898;25882705;25375654;25356532;25385675;+29300381+;29232904;29706639;29276052;30105367;30080950;28749477.
Start Year 2008
 
Description European Retinal Disease Consortium 
Organisation Hebrew University of Jerusalem
Country Israel 
Sector Academic/University 
PI Contribution Collaboration for the identification of novel causes of macular degeneration and inherited retinal disease. I have contributed candidate genes and variant interpretation expertise. I represented Manchester Centre for Genomic Medicine at the European Retinal Disease Consortium (ERDC) Conference (2018, Les Diablerets, Switzerland) were i shared our research interests and expertise, and offered areas for collaboration.
Collaborator Contribution The ERDC continues to support my research by offering a network of expertise and big data sets for the identification of the genetic causes of macular degeneration.
Impact ERDC members meet twice a year to exchange genetic and clinical data of persons with IRDs. This collaboration has resulted in many joint papers to date. Research outputs:- PMID: 29320387;28918053;28794130;28575650;28285769;27814526;28795510;28159970;28412069;27302843;27070432;26910043;27063057;26766544;27460420;26891008;27339364;27208209;27063057;26908613;27486781;27339364;25802487;28173158;27588451;26691986;25882705;26167768;26350383;25883087;26720483;25616768;25972256;25629076;25346251;26056285;26574802;25983245;25541840;26263531;26306921;25859010;26029869;25227500;18452394;18179881;19074801;19578023;19615668;19896113;19409519;19200527;19268277;19854499;19375515;19006237;20673862;20375346;20549516;21151602;20340138;20159111;20081859;20398884;20705279;20506298;20232351;20398886;20835237;20079931;21069908;20538994;20519033;19683999;21179236;21882291;20881296;21835304;22136677;21295282;21267001;21267011;21549338;21825197;22004887;21234346;21344540;22901948;22177090;23143442;22325361;22917891;22264887;22355252;22661473;23251578;22940612;22009552;22842230;22234150;22446187;23304067;24290379;23940504;23725738;23946133;23499059;23716654;23993198;23308101;23746546;23356391;24043777;23350551;23246293;23486539;23307924;23755871;23788369;24959063;24144451;24940029;24737827;24697911;24876279;25018096;24992209;24780881;25404053;25352746;25342620;25082829;24916380;25030840;25859010;25227500;25168386;25616768;25802487;25629076;25346251;25541840;25749990;25883087;25574057;25574898;25882705;25375654;25356532;25385675;+29300381+;29232904;29706639;29276052;30105367;30080950;28749477.
Start Year 2008
 
Description European Retinal Disease Consortium 
Organisation McGill University Health Centre
Country Canada 
Sector Academic/University 
PI Contribution Collaboration for the identification of novel causes of macular degeneration and inherited retinal disease. I have contributed candidate genes and variant interpretation expertise. I represented Manchester Centre for Genomic Medicine at the European Retinal Disease Consortium (ERDC) Conference (2018, Les Diablerets, Switzerland) were i shared our research interests and expertise, and offered areas for collaboration.
Collaborator Contribution The ERDC continues to support my research by offering a network of expertise and big data sets for the identification of the genetic causes of macular degeneration.
Impact ERDC members meet twice a year to exchange genetic and clinical data of persons with IRDs. This collaboration has resulted in many joint papers to date. Research outputs:- PMID: 29320387;28918053;28794130;28575650;28285769;27814526;28795510;28159970;28412069;27302843;27070432;26910043;27063057;26766544;27460420;26891008;27339364;27208209;27063057;26908613;27486781;27339364;25802487;28173158;27588451;26691986;25882705;26167768;26350383;25883087;26720483;25616768;25972256;25629076;25346251;26056285;26574802;25983245;25541840;26263531;26306921;25859010;26029869;25227500;18452394;18179881;19074801;19578023;19615668;19896113;19409519;19200527;19268277;19854499;19375515;19006237;20673862;20375346;20549516;21151602;20340138;20159111;20081859;20398884;20705279;20506298;20232351;20398886;20835237;20079931;21069908;20538994;20519033;19683999;21179236;21882291;20881296;21835304;22136677;21295282;21267001;21267011;21549338;21825197;22004887;21234346;21344540;22901948;22177090;23143442;22325361;22917891;22264887;22355252;22661473;23251578;22940612;22009552;22842230;22234150;22446187;23304067;24290379;23940504;23725738;23946133;23499059;23716654;23993198;23308101;23746546;23356391;24043777;23350551;23246293;23486539;23307924;23755871;23788369;24959063;24144451;24940029;24737827;24697911;24876279;25018096;24992209;24780881;25404053;25352746;25342620;25082829;24916380;25030840;25859010;25227500;25168386;25616768;25802487;25629076;25346251;25541840;25749990;25883087;25574057;25574898;25882705;25375654;25356532;25385675;+29300381+;29232904;29706639;29276052;30105367;30080950;28749477.
Start Year 2008
 
Description European Retinal Disease Consortium 
Organisation National Institute of Health and Medical Research (INSERM)
Department Institute of Neuroscience Montpellier
Country France 
Sector Academic/University 
PI Contribution Collaboration for the identification of novel causes of macular degeneration and inherited retinal disease. I have contributed candidate genes and variant interpretation expertise. I represented Manchester Centre for Genomic Medicine at the European Retinal Disease Consortium (ERDC) Conference (2018, Les Diablerets, Switzerland) were i shared our research interests and expertise, and offered areas for collaboration.
Collaborator Contribution The ERDC continues to support my research by offering a network of expertise and big data sets for the identification of the genetic causes of macular degeneration.
Impact ERDC members meet twice a year to exchange genetic and clinical data of persons with IRDs. This collaboration has resulted in many joint papers to date. Research outputs:- PMID: 29320387;28918053;28794130;28575650;28285769;27814526;28795510;28159970;28412069;27302843;27070432;26910043;27063057;26766544;27460420;26891008;27339364;27208209;27063057;26908613;27486781;27339364;25802487;28173158;27588451;26691986;25882705;26167768;26350383;25883087;26720483;25616768;25972256;25629076;25346251;26056285;26574802;25983245;25541840;26263531;26306921;25859010;26029869;25227500;18452394;18179881;19074801;19578023;19615668;19896113;19409519;19200527;19268277;19854499;19375515;19006237;20673862;20375346;20549516;21151602;20340138;20159111;20081859;20398884;20705279;20506298;20232351;20398886;20835237;20079931;21069908;20538994;20519033;19683999;21179236;21882291;20881296;21835304;22136677;21295282;21267001;21267011;21549338;21825197;22004887;21234346;21344540;22901948;22177090;23143442;22325361;22917891;22264887;22355252;22661473;23251578;22940612;22009552;22842230;22234150;22446187;23304067;24290379;23940504;23725738;23946133;23499059;23716654;23993198;23308101;23746546;23356391;24043777;23350551;23246293;23486539;23307924;23755871;23788369;24959063;24144451;24940029;24737827;24697911;24876279;25018096;24992209;24780881;25404053;25352746;25342620;25082829;24916380;25030840;25859010;25227500;25168386;25616768;25802487;25629076;25346251;25541840;25749990;25883087;25574057;25574898;25882705;25375654;25356532;25385675;+29300381+;29232904;29706639;29276052;30105367;30080950;28749477.
Start Year 2008
 
Description European Retinal Disease Consortium 
Organisation Radboud University Nijmegen
Department Ophthalmology Nijmegen
Country Netherlands 
Sector Academic/University 
PI Contribution Collaboration for the identification of novel causes of macular degeneration and inherited retinal disease. I have contributed candidate genes and variant interpretation expertise. I represented Manchester Centre for Genomic Medicine at the European Retinal Disease Consortium (ERDC) Conference (2018, Les Diablerets, Switzerland) were i shared our research interests and expertise, and offered areas for collaboration.
Collaborator Contribution The ERDC continues to support my research by offering a network of expertise and big data sets for the identification of the genetic causes of macular degeneration.
Impact ERDC members meet twice a year to exchange genetic and clinical data of persons with IRDs. This collaboration has resulted in many joint papers to date. Research outputs:- PMID: 29320387;28918053;28794130;28575650;28285769;27814526;28795510;28159970;28412069;27302843;27070432;26910043;27063057;26766544;27460420;26891008;27339364;27208209;27063057;26908613;27486781;27339364;25802487;28173158;27588451;26691986;25882705;26167768;26350383;25883087;26720483;25616768;25972256;25629076;25346251;26056285;26574802;25983245;25541840;26263531;26306921;25859010;26029869;25227500;18452394;18179881;19074801;19578023;19615668;19896113;19409519;19200527;19268277;19854499;19375515;19006237;20673862;20375346;20549516;21151602;20340138;20159111;20081859;20398884;20705279;20506298;20232351;20398886;20835237;20079931;21069908;20538994;20519033;19683999;21179236;21882291;20881296;21835304;22136677;21295282;21267001;21267011;21549338;21825197;22004887;21234346;21344540;22901948;22177090;23143442;22325361;22917891;22264887;22355252;22661473;23251578;22940612;22009552;22842230;22234150;22446187;23304067;24290379;23940504;23725738;23946133;23499059;23716654;23993198;23308101;23746546;23356391;24043777;23350551;23246293;23486539;23307924;23755871;23788369;24959063;24144451;24940029;24737827;24697911;24876279;25018096;24992209;24780881;25404053;25352746;25342620;25082829;24916380;25030840;25859010;25227500;25168386;25616768;25802487;25629076;25346251;25541840;25749990;25883087;25574057;25574898;25882705;25375654;25356532;25385675;+29300381+;29232904;29706639;29276052;30105367;30080950;28749477.
Start Year 2008
 
Description European Retinal Disease Consortium 
Organisation Technion - Israel Institute of Technology
Country Israel 
Sector Academic/University 
PI Contribution Collaboration for the identification of novel causes of macular degeneration and inherited retinal disease. I have contributed candidate genes and variant interpretation expertise. I represented Manchester Centre for Genomic Medicine at the European Retinal Disease Consortium (ERDC) Conference (2018, Les Diablerets, Switzerland) were i shared our research interests and expertise, and offered areas for collaboration.
Collaborator Contribution The ERDC continues to support my research by offering a network of expertise and big data sets for the identification of the genetic causes of macular degeneration.
Impact ERDC members meet twice a year to exchange genetic and clinical data of persons with IRDs. This collaboration has resulted in many joint papers to date. Research outputs:- PMID: 29320387;28918053;28794130;28575650;28285769;27814526;28795510;28159970;28412069;27302843;27070432;26910043;27063057;26766544;27460420;26891008;27339364;27208209;27063057;26908613;27486781;27339364;25802487;28173158;27588451;26691986;25882705;26167768;26350383;25883087;26720483;25616768;25972256;25629076;25346251;26056285;26574802;25983245;25541840;26263531;26306921;25859010;26029869;25227500;18452394;18179881;19074801;19578023;19615668;19896113;19409519;19200527;19268277;19854499;19375515;19006237;20673862;20375346;20549516;21151602;20340138;20159111;20081859;20398884;20705279;20506298;20232351;20398886;20835237;20079931;21069908;20538994;20519033;19683999;21179236;21882291;20881296;21835304;22136677;21295282;21267001;21267011;21549338;21825197;22004887;21234346;21344540;22901948;22177090;23143442;22325361;22917891;22264887;22355252;22661473;23251578;22940612;22009552;22842230;22234150;22446187;23304067;24290379;23940504;23725738;23946133;23499059;23716654;23993198;23308101;23746546;23356391;24043777;23350551;23246293;23486539;23307924;23755871;23788369;24959063;24144451;24940029;24737827;24697911;24876279;25018096;24992209;24780881;25404053;25352746;25342620;25082829;24916380;25030840;25859010;25227500;25168386;25616768;25802487;25629076;25346251;25541840;25749990;25883087;25574057;25574898;25882705;25375654;25356532;25385675;+29300381+;29232904;29706639;29276052;30105367;30080950;28749477.
Start Year 2008
 
Description European Retinal Disease Consortium 
Organisation Telethon Foundation
Department Telethon Institute of Genetics and Medicine (TIGEM)
Country Italy 
Sector Charity/Non Profit 
PI Contribution Collaboration for the identification of novel causes of macular degeneration and inherited retinal disease. I have contributed candidate genes and variant interpretation expertise. I represented Manchester Centre for Genomic Medicine at the European Retinal Disease Consortium (ERDC) Conference (2018, Les Diablerets, Switzerland) were i shared our research interests and expertise, and offered areas for collaboration.
Collaborator Contribution The ERDC continues to support my research by offering a network of expertise and big data sets for the identification of the genetic causes of macular degeneration.
Impact ERDC members meet twice a year to exchange genetic and clinical data of persons with IRDs. This collaboration has resulted in many joint papers to date. Research outputs:- PMID: 29320387;28918053;28794130;28575650;28285769;27814526;28795510;28159970;28412069;27302843;27070432;26910043;27063057;26766544;27460420;26891008;27339364;27208209;27063057;26908613;27486781;27339364;25802487;28173158;27588451;26691986;25882705;26167768;26350383;25883087;26720483;25616768;25972256;25629076;25346251;26056285;26574802;25983245;25541840;26263531;26306921;25859010;26029869;25227500;18452394;18179881;19074801;19578023;19615668;19896113;19409519;19200527;19268277;19854499;19375515;19006237;20673862;20375346;20549516;21151602;20340138;20159111;20081859;20398884;20705279;20506298;20232351;20398886;20835237;20079931;21069908;20538994;20519033;19683999;21179236;21882291;20881296;21835304;22136677;21295282;21267001;21267011;21549338;21825197;22004887;21234346;21344540;22901948;22177090;23143442;22325361;22917891;22264887;22355252;22661473;23251578;22940612;22009552;22842230;22234150;22446187;23304067;24290379;23940504;23725738;23946133;23499059;23716654;23993198;23308101;23746546;23356391;24043777;23350551;23246293;23486539;23307924;23755871;23788369;24959063;24144451;24940029;24737827;24697911;24876279;25018096;24992209;24780881;25404053;25352746;25342620;25082829;24916380;25030840;25859010;25227500;25168386;25616768;25802487;25629076;25346251;25541840;25749990;25883087;25574057;25574898;25882705;25375654;25356532;25385675;+29300381+;29232904;29706639;29276052;30105367;30080950;28749477.
Start Year 2008
 
Description European Retinal Disease Consortium 
Organisation University of Lausanne
Department Department of Medical Genetics
Country Switzerland 
Sector Academic/University 
PI Contribution Collaboration for the identification of novel causes of macular degeneration and inherited retinal disease. I have contributed candidate genes and variant interpretation expertise. I represented Manchester Centre for Genomic Medicine at the European Retinal Disease Consortium (ERDC) Conference (2018, Les Diablerets, Switzerland) were i shared our research interests and expertise, and offered areas for collaboration.
Collaborator Contribution The ERDC continues to support my research by offering a network of expertise and big data sets for the identification of the genetic causes of macular degeneration.
Impact ERDC members meet twice a year to exchange genetic and clinical data of persons with IRDs. This collaboration has resulted in many joint papers to date. Research outputs:- PMID: 29320387;28918053;28794130;28575650;28285769;27814526;28795510;28159970;28412069;27302843;27070432;26910043;27063057;26766544;27460420;26891008;27339364;27208209;27063057;26908613;27486781;27339364;25802487;28173158;27588451;26691986;25882705;26167768;26350383;25883087;26720483;25616768;25972256;25629076;25346251;26056285;26574802;25983245;25541840;26263531;26306921;25859010;26029869;25227500;18452394;18179881;19074801;19578023;19615668;19896113;19409519;19200527;19268277;19854499;19375515;19006237;20673862;20375346;20549516;21151602;20340138;20159111;20081859;20398884;20705279;20506298;20232351;20398886;20835237;20079931;21069908;20538994;20519033;19683999;21179236;21882291;20881296;21835304;22136677;21295282;21267001;21267011;21549338;21825197;22004887;21234346;21344540;22901948;22177090;23143442;22325361;22917891;22264887;22355252;22661473;23251578;22940612;22009552;22842230;22234150;22446187;23304067;24290379;23940504;23725738;23946133;23499059;23716654;23993198;23308101;23746546;23356391;24043777;23350551;23246293;23486539;23307924;23755871;23788369;24959063;24144451;24940029;24737827;24697911;24876279;25018096;24992209;24780881;25404053;25352746;25342620;25082829;24916380;25030840;25859010;25227500;25168386;25616768;25802487;25629076;25346251;25541840;25749990;25883087;25574057;25574898;25882705;25375654;25356532;25385675;+29300381+;29232904;29706639;29276052;30105367;30080950;28749477.
Start Year 2008
 
Description European Retinal Disease Consortium 
Organisation University of Leeds
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration for the identification of novel causes of macular degeneration and inherited retinal disease. I have contributed candidate genes and variant interpretation expertise. I represented Manchester Centre for Genomic Medicine at the European Retinal Disease Consortium (ERDC) Conference (2018, Les Diablerets, Switzerland) were i shared our research interests and expertise, and offered areas for collaboration.
Collaborator Contribution The ERDC continues to support my research by offering a network of expertise and big data sets for the identification of the genetic causes of macular degeneration.
Impact ERDC members meet twice a year to exchange genetic and clinical data of persons with IRDs. This collaboration has resulted in many joint papers to date. Research outputs:- PMID: 29320387;28918053;28794130;28575650;28285769;27814526;28795510;28159970;28412069;27302843;27070432;26910043;27063057;26766544;27460420;26891008;27339364;27208209;27063057;26908613;27486781;27339364;25802487;28173158;27588451;26691986;25882705;26167768;26350383;25883087;26720483;25616768;25972256;25629076;25346251;26056285;26574802;25983245;25541840;26263531;26306921;25859010;26029869;25227500;18452394;18179881;19074801;19578023;19615668;19896113;19409519;19200527;19268277;19854499;19375515;19006237;20673862;20375346;20549516;21151602;20340138;20159111;20081859;20398884;20705279;20506298;20232351;20398886;20835237;20079931;21069908;20538994;20519033;19683999;21179236;21882291;20881296;21835304;22136677;21295282;21267001;21267011;21549338;21825197;22004887;21234346;21344540;22901948;22177090;23143442;22325361;22917891;22264887;22355252;22661473;23251578;22940612;22009552;22842230;22234150;22446187;23304067;24290379;23940504;23725738;23946133;23499059;23716654;23993198;23308101;23746546;23356391;24043777;23350551;23246293;23486539;23307924;23755871;23788369;24959063;24144451;24940029;24737827;24697911;24876279;25018096;24992209;24780881;25404053;25352746;25342620;25082829;24916380;25030840;25859010;25227500;25168386;25616768;25802487;25629076;25346251;25541840;25749990;25883087;25574057;25574898;25882705;25375654;25356532;25385675;+29300381+;29232904;29706639;29276052;30105367;30080950;28749477.
Start Year 2008
 
Description UK Inherited Retinal Disease Consortium 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution I have provided time and expertise in the analysis of whole exome and genome data from patients with as yet undiagnosed forms of macular degeneration and retinal degeneration. I have also provided expertise in the interpretation of genetic variants arising from these large data sets. I have identified novel retinal disease genes and forged further international collaborations in the identification of additional families affected by mutations in these novel genes to work towards joint publications.
Collaborator Contribution Collaborators within the UK Inherited Retinal Disease Consortium have provided patient data, and corresponding clinical and phenotypic data for inclusion in my research. The consortium has also provided advice and expertise in the analysis and interpretation of data/results generated by my research. The consortium has also provided expertise and advice during manuscript preparation.
Impact Data acquisition and analysis: To date, the Consortium has sent 375 DNA samples for exome and 40 samples for genome analysis, and continues to analyse data from patients that have not yet received a diagnosis for their retinal problems. Our team has significantly increased available capacity for storing, sharing and analysing data (specifically whole genome data) by investing in the IT infrastructure required. This is vital for a project that is so heavily focused on the collection and analysis of data and collaboration between multiple sites. Novel Gene Identification: Five new disease causing genes have been identified (PMID: 28285769, 28253385, 27889058, 27281386, 25983245), with more candidates under investigation. Diagnostic Yield: This team has been able to find the genetic basis for disease in more than 230 cases providing diagnoses for many patients and their families. Patient/public engagement: Regular 'Strategic and Advisory Committee meetings' are held. The committee includes several patient representatives, who are supporting the development of the project. The work of the committee aims to ensure patients can monitor progress, disseminate information, hold the consortium to account, and exert influence where appropriate. Research Outputs: Seventeen papers have been published by the consortium to date. The consortium works continuously to communicate research findings to the wider scientific community in order to share the latest developments, avoid duplication of work and drive progress forward. A further thirteen publications are in the proposal stages. Collaborations: The consortium has joined the Genetics England Clinical Interpretation Partnership (GECIP), associated with the UK 100,000 Genome Project. Their position as part of the GECIP will keep inherited retinal disease (IRD) on the national agenda at a crucial time for IRD research. Importantly, their work has also led to discoveries that would not have been possible without this project; advancing our knowledge of IRD and informing the development of future treatments for those facing visual impairment.
Start Year 2015
 
Description UK Inherited Retinal Disease Consortium 
Organisation University of Leeds
Department Faculty of Medicine and Health
Country United Kingdom 
Sector Academic/University 
PI Contribution I have provided time and expertise in the analysis of whole exome and genome data from patients with as yet undiagnosed forms of macular degeneration and retinal degeneration. I have also provided expertise in the interpretation of genetic variants arising from these large data sets. I have identified novel retinal disease genes and forged further international collaborations in the identification of additional families affected by mutations in these novel genes to work towards joint publications.
Collaborator Contribution Collaborators within the UK Inherited Retinal Disease Consortium have provided patient data, and corresponding clinical and phenotypic data for inclusion in my research. The consortium has also provided advice and expertise in the analysis and interpretation of data/results generated by my research. The consortium has also provided expertise and advice during manuscript preparation.
Impact Data acquisition and analysis: To date, the Consortium has sent 375 DNA samples for exome and 40 samples for genome analysis, and continues to analyse data from patients that have not yet received a diagnosis for their retinal problems. Our team has significantly increased available capacity for storing, sharing and analysing data (specifically whole genome data) by investing in the IT infrastructure required. This is vital for a project that is so heavily focused on the collection and analysis of data and collaboration between multiple sites. Novel Gene Identification: Five new disease causing genes have been identified (PMID: 28285769, 28253385, 27889058, 27281386, 25983245), with more candidates under investigation. Diagnostic Yield: This team has been able to find the genetic basis for disease in more than 230 cases providing diagnoses for many patients and their families. Patient/public engagement: Regular 'Strategic and Advisory Committee meetings' are held. The committee includes several patient representatives, who are supporting the development of the project. The work of the committee aims to ensure patients can monitor progress, disseminate information, hold the consortium to account, and exert influence where appropriate. Research Outputs: Seventeen papers have been published by the consortium to date. The consortium works continuously to communicate research findings to the wider scientific community in order to share the latest developments, avoid duplication of work and drive progress forward. A further thirteen publications are in the proposal stages. Collaborations: The consortium has joined the Genetics England Clinical Interpretation Partnership (GECIP), associated with the UK 100,000 Genome Project. Their position as part of the GECIP will keep inherited retinal disease (IRD) on the national agenda at a crucial time for IRD research. Importantly, their work has also led to discoveries that would not have been possible without this project; advancing our knowledge of IRD and informing the development of future treatments for those facing visual impairment.
Start Year 2015
 
Description UK Inherited Retinal Disease Consortium 
Organisation University of Oxford
Department Nuffield Department of Clinical Neurosciences
Country United Kingdom 
Sector Academic/University 
PI Contribution I have provided time and expertise in the analysis of whole exome and genome data from patients with as yet undiagnosed forms of macular degeneration and retinal degeneration. I have also provided expertise in the interpretation of genetic variants arising from these large data sets. I have identified novel retinal disease genes and forged further international collaborations in the identification of additional families affected by mutations in these novel genes to work towards joint publications.
Collaborator Contribution Collaborators within the UK Inherited Retinal Disease Consortium have provided patient data, and corresponding clinical and phenotypic data for inclusion in my research. The consortium has also provided advice and expertise in the analysis and interpretation of data/results generated by my research. The consortium has also provided expertise and advice during manuscript preparation.
Impact Data acquisition and analysis: To date, the Consortium has sent 375 DNA samples for exome and 40 samples for genome analysis, and continues to analyse data from patients that have not yet received a diagnosis for their retinal problems. Our team has significantly increased available capacity for storing, sharing and analysing data (specifically whole genome data) by investing in the IT infrastructure required. This is vital for a project that is so heavily focused on the collection and analysis of data and collaboration between multiple sites. Novel Gene Identification: Five new disease causing genes have been identified (PMID: 28285769, 28253385, 27889058, 27281386, 25983245), with more candidates under investigation. Diagnostic Yield: This team has been able to find the genetic basis for disease in more than 230 cases providing diagnoses for many patients and their families. Patient/public engagement: Regular 'Strategic and Advisory Committee meetings' are held. The committee includes several patient representatives, who are supporting the development of the project. The work of the committee aims to ensure patients can monitor progress, disseminate information, hold the consortium to account, and exert influence where appropriate. Research Outputs: Seventeen papers have been published by the consortium to date. The consortium works continuously to communicate research findings to the wider scientific community in order to share the latest developments, avoid duplication of work and drive progress forward. A further thirteen publications are in the proposal stages. Collaborations: The consortium has joined the Genetics England Clinical Interpretation Partnership (GECIP), associated with the UK 100,000 Genome Project. Their position as part of the GECIP will keep inherited retinal disease (IRD) on the national agenda at a crucial time for IRD research. Importantly, their work has also led to discoveries that would not have been possible without this project; advancing our knowledge of IRD and informing the development of future treatments for those facing visual impairment.
Start Year 2015
 
Title Early-onset macular degeneration 
Description I am currently developing and validating an advanced sequencing assay for the diagnosis of early-onset macular degeneration and to measure the impact of rare and common genetic variants in disease pathogenesis. 
Type Diagnostic Tool - Non-Imaging
Year Development Stage Completed 2018
Development Status Under active development/distribution
Impact This assay has enabled the diagnosis ophthalmic disease in patients who did not receive a result from genetic testing available on the National Health Service and it is hoped that it will be made available nationally/internationally once fully validated.