Progress in the genetic analysis of Parkinson’s disease
Abstract The pace of genetic discovery in complex disease has accelerated exponentially over the last decade. Our fund of knowledge of the foundational genetics in disease has never been as great. There is a clear path forward to the resolution of the genetic architecture toward a point at which we...
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Veröffentlicht in: | Human molecular genetics 2019-11, Vol.28 (R2), p.R215-R218 |
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The pace of genetic discovery in complex disease has accelerated exponentially over the last decade. Our fund of knowledge of the foundational genetics in disease has never been as great. There is a clear path forward to the resolution of the genetic architecture toward a point at which we will saturate the biological understanding of disease through genetics. This understanding continues to provide fundamental insights into disease biology and, with the advent of new data and methodologies, the path from gene to function is becoming clearer and cleaner. In this opinion piece, we discuss progress in the genetics of Parkinson disease. We explore what genetics has revealed thus far in the context of disease biology. We highlight mitophagy/autophagy, dopamine metabolism and the adaptive immune system. We try and link these findings together to give a holistic view of pathogenesis with the underlying theme that disease pathogenesis relates to a failure of damage response pathways. In the 1990s, Parkinson’s disease was regarded a non-genetic disorder. Since that time, however, a huge number of Mendelian loci and risk loci have been identified by positional cloning and by genome-wide association studies. In this review, it is not our intent to list each gene and locus and review their identification [Hernandez, D.G., Reed, X. and Singleton, A.B. (2016) Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. J. Neurochem., 139 Suppl 1, 59–74] but rather to outline the pathogenetic mechanisms that these analyses are revealing and then, given the large number of loci already identified, to lay out what we hope future analyses may help us understand, both in terms of disease mechanisms and for risk prediction for the syndrome. |
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The pace of genetic discovery in complex disease has accelerated exponentially over the last decade. Our fund of knowledge of the foundational genetics in disease has never been as great. There is a clear path forward to the resolution of the genetic architecture toward a point at which we will saturate the biological understanding of disease through genetics. This understanding continues to provide fundamental insights into disease biology and, with the advent of new data and methodologies, the path from gene to function is becoming clearer and cleaner. In this opinion piece, we discuss progress in the genetics of Parkinson disease. We explore what genetics has revealed thus far in the context of disease biology. We highlight mitophagy/autophagy, dopamine metabolism and the adaptive immune system. We try and link these findings together to give a holistic view of pathogenesis with the underlying theme that disease pathogenesis relates to a failure of damage response pathways. In the 1990s, Parkinson’s disease was regarded a non-genetic disorder. Since that time, however, a huge number of Mendelian loci and risk loci have been identified by positional cloning and by genome-wide association studies. In this review, it is not our intent to list each gene and locus and review their identification [Hernandez, D.G., Reed, X. and Singleton, A.B. (2016) Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. J. Neurochem., 139 Suppl 1, 59–74] but rather to outline the pathogenetic mechanisms that these analyses are revealing and then, given the large number of loci already identified, to lay out what we hope future analyses may help us understand, both in terms of disease mechanisms and for risk prediction for the syndrome.</description><identifier>ISSN: 0964-6906</identifier><identifier>EISSN: 1460-2083</identifier><identifier>DOI: 10.1093/hmg/ddz183</identifier><identifier>PMID: 31518392</identifier><language>eng</language><publisher>England: Oxford University Press</publisher><subject>Autophagy - genetics ; Dopamine - metabolism ; Endodeoxyribonucleases - genetics ; Genetic Predisposition to Disease ; Genome-Wide Association Study ; Genotype ; Humans ; Invited Review ; Mitophagy - genetics ; Oxidative Stress - genetics ; Parkinson Disease - genetics ; Phenotype ; Risk Factors ; Ubiquitin-Protein Ligases - genetics</subject><ispartof>Human molecular genetics, 2019-11, Vol.28 (R2), p.R215-R218</ispartof><rights>The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 2019</rights><rights>The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c474t-d361d08fd8d5f94bd76b439a893444c61f6dd2b459c494acbd67071adff5781a3</citedby><cites>FETCH-LOGICAL-c474t-d361d08fd8d5f94bd76b439a893444c61f6dd2b459c494acbd67071adff5781a3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>230,314,776,780,881,1578,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31518392$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Singleton, Andrew</creatorcontrib><creatorcontrib>Hardy, John</creatorcontrib><title>Progress in the genetic analysis of Parkinson’s disease</title><title>Human molecular genetics</title><addtitle>Hum Mol Genet</addtitle><description>Abstract
The pace of genetic discovery in complex disease has accelerated exponentially over the last decade. Our fund of knowledge of the foundational genetics in disease has never been as great. There is a clear path forward to the resolution of the genetic architecture toward a point at which we will saturate the biological understanding of disease through genetics. This understanding continues to provide fundamental insights into disease biology and, with the advent of new data and methodologies, the path from gene to function is becoming clearer and cleaner. In this opinion piece, we discuss progress in the genetics of Parkinson disease. We explore what genetics has revealed thus far in the context of disease biology. We highlight mitophagy/autophagy, dopamine metabolism and the adaptive immune system. We try and link these findings together to give a holistic view of pathogenesis with the underlying theme that disease pathogenesis relates to a failure of damage response pathways. In the 1990s, Parkinson’s disease was regarded a non-genetic disorder. Since that time, however, a huge number of Mendelian loci and risk loci have been identified by positional cloning and by genome-wide association studies. In this review, it is not our intent to list each gene and locus and review their identification [Hernandez, D.G., Reed, X. and Singleton, A.B. (2016) Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. J. Neurochem., 139 Suppl 1, 59–74] but rather to outline the pathogenetic mechanisms that these analyses are revealing and then, given the large number of loci already identified, to lay out what we hope future analyses may help us understand, both in terms of disease mechanisms and for risk prediction for the syndrome.</description><subject>Autophagy - genetics</subject><subject>Dopamine - metabolism</subject><subject>Endodeoxyribonucleases - genetics</subject><subject>Genetic Predisposition to Disease</subject><subject>Genome-Wide Association Study</subject><subject>Genotype</subject><subject>Humans</subject><subject>Invited Review</subject><subject>Mitophagy - genetics</subject><subject>Oxidative Stress - genetics</subject><subject>Parkinson Disease - genetics</subject><subject>Phenotype</subject><subject>Risk Factors</subject><subject>Ubiquitin-Protein Ligases - genetics</subject><issn>0964-6906</issn><issn>1460-2083</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMtKxDAUQIMozji68QOkG0GEatKkabIRZPAFA85C1yFN0k60bcakFcaVv-Hv-SVWOg66cXUX93Du5QBwiOAZghyfL-ryXOs3xPAWGCNCYZxAhrfBGHJKYsohHYG9EJ4gRJTgbBeMMEp7midjwOfeld6EENkmahcmKk1jWqsi2chqFWyIXBHNpX-2TXDN5_tHiLQNRgazD3YKWQVzsJ4T8Hh99TC9jWf3N3fTy1msSEbaWGOKNGSFZjotOMl1RnOCuWQcE0IURQXVOslJyhXhRKpc0wxmSOqiSDOGJJ6Ai8G77PLaaGWa1stKLL2tpV8JJ634u2nsQpTuVVCWJQTjXnCyFnj30pnQitoGZapKNsZ1QSQJh4xTmNIePR1Q5V0I3hSbMwiK79aiby2G1j189PuxDfoTtweOB8B1y_9EX4TniZg</recordid><startdate>20191121</startdate><enddate>20191121</enddate><creator>Singleton, Andrew</creator><creator>Hardy, John</creator><general>Oxford University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>20191121</creationdate><title>Progress in the genetic analysis of Parkinson’s disease</title><author>Singleton, Andrew ; Hardy, John</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c474t-d361d08fd8d5f94bd76b439a893444c61f6dd2b459c494acbd67071adff5781a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Autophagy - genetics</topic><topic>Dopamine - metabolism</topic><topic>Endodeoxyribonucleases - genetics</topic><topic>Genetic Predisposition to Disease</topic><topic>Genome-Wide Association Study</topic><topic>Genotype</topic><topic>Humans</topic><topic>Invited Review</topic><topic>Mitophagy - genetics</topic><topic>Oxidative Stress - genetics</topic><topic>Parkinson Disease - genetics</topic><topic>Phenotype</topic><topic>Risk Factors</topic><topic>Ubiquitin-Protein Ligases - genetics</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Singleton, Andrew</creatorcontrib><creatorcontrib>Hardy, John</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Human molecular genetics</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Singleton, Andrew</au><au>Hardy, John</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Progress in the genetic analysis of Parkinson’s disease</atitle><jtitle>Human molecular genetics</jtitle><addtitle>Hum Mol Genet</addtitle><date>2019-11-21</date><risdate>2019</risdate><volume>28</volume><issue>R2</issue><spage>R215</spage><epage>R218</epage><pages>R215-R218</pages><issn>0964-6906</issn><eissn>1460-2083</eissn><abstract>Abstract
The pace of genetic discovery in complex disease has accelerated exponentially over the last decade. Our fund of knowledge of the foundational genetics in disease has never been as great. There is a clear path forward to the resolution of the genetic architecture toward a point at which we will saturate the biological understanding of disease through genetics. This understanding continues to provide fundamental insights into disease biology and, with the advent of new data and methodologies, the path from gene to function is becoming clearer and cleaner. In this opinion piece, we discuss progress in the genetics of Parkinson disease. We explore what genetics has revealed thus far in the context of disease biology. We highlight mitophagy/autophagy, dopamine metabolism and the adaptive immune system. We try and link these findings together to give a holistic view of pathogenesis with the underlying theme that disease pathogenesis relates to a failure of damage response pathways. In the 1990s, Parkinson’s disease was regarded a non-genetic disorder. Since that time, however, a huge number of Mendelian loci and risk loci have been identified by positional cloning and by genome-wide association studies. In this review, it is not our intent to list each gene and locus and review their identification [Hernandez, D.G., Reed, X. and Singleton, A.B. (2016) Genetics in Parkinson disease: Mendelian versus non-Mendelian inheritance. J. Neurochem., 139 Suppl 1, 59–74] but rather to outline the pathogenetic mechanisms that these analyses are revealing and then, given the large number of loci already identified, to lay out what we hope future analyses may help us understand, both in terms of disease mechanisms and for risk prediction for the syndrome.</abstract><cop>England</cop><pub>Oxford University Press</pub><pmid>31518392</pmid><doi>10.1093/hmg/ddz183</doi><oa>free_for_read</oa></addata></record> |
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subjects | Autophagy - genetics Dopamine - metabolism Endodeoxyribonucleases - genetics Genetic Predisposition to Disease Genome-Wide Association Study Genotype Humans Invited Review Mitophagy - genetics Oxidative Stress - genetics Parkinson Disease - genetics Phenotype Risk Factors Ubiquitin-Protein Ligases - genetics |
title | Progress in the genetic analysis of Parkinson’s disease |
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