Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene
Identifieur interne : 000958 ( Main/Exploration ); précédent : 000957; suivant : 000959Single‐cell expression profiling of dopaminergic neurons combined with association analysis identifies pyridoxal kinase as Parkinson's disease gene
Auteurs : Matthias Elstner [Allemagne] ; Christopher M. Morris [Royaume-Uni] ; Katharina Heim [Allemagne] ; Peter Lichtner [Allemagne] ; Andreas Bender [Allemagne] ; Divya Mehta [Allemagne] ; Claudia Schulte [Allemagne] ; Manu Sharma [Allemagne] ; Gavin Hudson [Royaume-Uni] ; Stefano Goldwurm [Italie] ; Alessandro Giovanetti [Italie] ; Massimo Zeviani [Italie] ; David J. Burn [Royaume-Uni] ; Ian G. Mckeith [Royaume-Uni] ; Robert H. Perry [Royaume-Uni] ; E. Jaros [Royaume-Uni] ; Rejko Krüger [Allemagne] ; H. Rich Wichmann [Allemagne] ; Stefan Schreiber [Allemagne] ; Harry Campbell [Royaume-Uni] ; James F. Wilson [Royaume-Uni] ; Alan F. Wright [Royaume-Uni] ; Malcolm Dunlop [Royaume-Uni] ; Giorgio Pistis [Italie] ; Daniela Toniolo [Italie] ; Patrick F. Chinnery [Royaume-Uni] ; Thomas Gasser [Allemagne] ; Thomas Klopstock [Allemagne] ; Thomas Meitinger [Allemagne] ; Holger Prokisch [Allemagne] ; Douglass M. Turnbull [Royaume-Uni]Source :
- Annals of Neurology [ 0364-5134 ] ; 2009-12.
Abstract
Objective: The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined. Methods: We carried out whole‐genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single‐nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts. Results: We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 × 10−7), PDXK (vitamin B6/dopamine metabolism, p = 3.27 × 10−6), SRGAP3 (axon guidance, p = 5.65 × 10−6), and TRAPPC4 (vesicle transport, p = 5.81 × 10−6). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 × 10−7 (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18–1.44). Interpretation: We provide an example of how microgenomic genome‐wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD. Ann Neurol 2009;66:792–798
Url:
DOI: 10.1002/ana.21780
Affiliations:
- Allemagne, Italie, Royaume-Uni
- Bade-Wurtemberg, Bavière, District de Haute-Bavière, District de Tübingen, Lombardie, Schleswig-Holstein, Écosse
- Kiel, Milan, Munich, Tübingen, Édimbourg
- Université d'Édimbourg
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Besta,” Milan</wicri:regionArea><wicri:noRegion>” Milan</wicri:noRegion></affiliation></author><author><name sortKey="Zeviani, Massimo" sort="Zeviani, Massimo" uniqKey="Zeviani M" first="Massimo" last="Zeviani">Massimo Zeviani</name><affiliation wicri:level="1"><country xml:lang="fr">Italie</country><wicri:regionArea>Unit of Molecular Neurogenetics, IRCCS Foundation Neurological Institute “C. Besta,” Milan</wicri:regionArea><wicri:noRegion>” Milan</wicri:noRegion></affiliation></author><author><name sortKey="Burn, David J" sort="Burn, David J" uniqKey="Burn D" first="David J." last="Burn">David J. Burn</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne</wicri:regionArea><wicri:noRegion>Newcastle upon Tyne</wicri:noRegion></affiliation></author><author><name sortKey="Mckeith, Ian G" sort="Mckeith, Ian G" uniqKey="Mckeith I" first="Ian G." last="Mckeith">Ian G. Mckeith</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne</wicri:regionArea><wicri:noRegion>Newcastle upon Tyne</wicri:noRegion></affiliation></author><author><name sortKey="Perry, Robert H" sort="Perry, Robert H" uniqKey="Perry R" first="Robert H." last="Perry">Robert H. Perry</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne</wicri:regionArea><wicri:noRegion>Newcastle upon Tyne</wicri:noRegion></affiliation></author><author><name sortKey="Jaros, E" sort="Jaros, E" uniqKey="Jaros E" first="E." last="Jaros">E. Jaros</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne</wicri:regionArea><wicri:noRegion>Newcastle upon Tyne</wicri:noRegion></affiliation></author><author><name sortKey="Kruger, Rejko" sort="Kruger, Rejko" uniqKey="Kruger R" first="Rejko" last="Krüger">Rejko Krüger</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation></author><author><name sortKey="Wichmann, H Rich" sort="Wichmann, H Rich" uniqKey="Wichmann H" first="H. Rich" last="Wichmann">H. Rich Wichmann</name><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg</wicri:regionArea><wicri:noRegion>Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation></author><author><name sortKey="Schreiber, Stefan" sort="Schreiber, Stefan" uniqKey="Schreiber S" first="Stefan" last="Schreiber">Stefan Schreiber</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Clinical Molecular Biology, Christian‐Albrechts University, Kiel</wicri:regionArea><placeName><region type="land" nuts="2">Schleswig-Holstein</region><settlement type="city">Kiel</settlement></placeName></affiliation></author><author><name sortKey="Campbell, Harry" sort="Campbell, Harry" uniqKey="Campbell H" first="Harry" last="Campbell">Harry Campbell</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Community Health Sciences and Institute for Genetics and Molecular Medicine, University of Edinburgh Medical School, Edinburgh</wicri:regionArea><placeName><settlement type="city">Édimbourg</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Wilson, James F" sort="Wilson, James F" uniqKey="Wilson J" first="James F." last="Wilson">James F. Wilson</name><affiliation wicri:level="4"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Centre for Population Health Sciences, University of Edinburgh, Edinburgh</wicri:regionArea><placeName><settlement type="city">Édimbourg</settlement><region type="country">Écosse</region></placeName><orgName type="university">Université d'Édimbourg</orgName></affiliation></author><author><name sortKey="Wright, Alan F" sort="Wright, Alan F" uniqKey="Wright A" first="Alan F." last="Wright">Alan F. Wright</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Genetics and Molecular Medicine, MRC Human Genetics Unit, Edinburgh</wicri:regionArea><placeName><settlement type="city">Édimbourg</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Dunlop, Malcolm" sort="Dunlop, Malcolm" uniqKey="Dunlop M" first="Malcolm" last="Dunlop">Malcolm Dunlop</name><affiliation wicri:level="3"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute of Genetics and Molecular Medicine, Colon Cancer Genetics Group, University of Edinburgh and MRC Human Genetics Unit, Edinburgh</wicri:regionArea><placeName><settlement type="city">Édimbourg</settlement><region type="country">Écosse</region></placeName></affiliation></author><author><name sortKey="Pistis, Giorgio" sort="Pistis, Giorgio" uniqKey="Pistis G" first="Giorgio" last="Pistis">Giorgio Pistis</name><affiliation wicri:level="3"><country xml:lang="fr">Italie</country><wicri:regionArea>San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milan</wicri:regionArea><placeName><settlement type="city">Milan</settlement><region nuts="2">Lombardie</region></placeName></affiliation></author><author><name sortKey="Toniolo, Daniela" sort="Toniolo, Daniela" uniqKey="Toniolo D" first="Daniela" last="Toniolo">Daniela Toniolo</name><affiliation wicri:level="3"><country xml:lang="fr">Italie</country><wicri:regionArea>San Raffaele Scientific Institute, Division of Genetics and Cell Biology, Milan</wicri:regionArea><placeName><settlement type="city">Milan</settlement><region nuts="2">Lombardie</region></placeName></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Italie</country><wicri:regionArea>Istituto di Genetica Molecolare ‐ Consiglio Nazionale delle Ricerche, Pavia</wicri:regionArea><wicri:noRegion>Pavia</wicri:noRegion></affiliation></author><author><name sortKey="Chinnery, Patrick F" sort="Chinnery, Patrick F" uniqKey="Chinnery P" first="Patrick F." last="Chinnery">Patrick F. Chinnery</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne</wicri:regionArea><wicri:noRegion>Newcastle upon Tyne</wicri:noRegion></affiliation><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne</wicri:regionArea><wicri:noRegion>Newcastle upon Tyne</wicri:noRegion></affiliation></author><author><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Section for Neurodegenerative Diseases, Hertie‐Institute for Clinical Brain Research, University of Tübingen, Tübingen</wicri:regionArea><placeName><region type="land" nuts="1">Bade-Wurtemberg</region><region type="district" nuts="2">District de Tübingen</region><settlement type="city">Tübingen</settlement></placeName></affiliation></author><author><name sortKey="Klopstock, Thomas" sort="Klopstock, Thomas" uniqKey="Klopstock T" first="Thomas" last="Klopstock">Thomas Klopstock</name><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Department of Neurology, Ludwig‐Maximilians‐University, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Meitinger, Thomas" sort="Meitinger, Thomas" uniqKey="Meitinger T" first="Thomas" last="Meitinger">Thomas Meitinger</name><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg</wicri:regionArea><wicri:noRegion>Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Human Genetics, Technical University Munich, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Prokisch, Holger" sort="Prokisch, Holger" uniqKey="Prokisch H" first="Holger" last="Prokisch">Holger Prokisch</name><affiliation wicri:level="1"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg</wicri:regionArea><wicri:noRegion>Neuherberg</wicri:noRegion><wicri:noRegion>Neuherberg</wicri:noRegion></affiliation><affiliation wicri:level="3"><country xml:lang="fr">Allemagne</country><wicri:regionArea>Institute of Human Genetics, Technical University Munich, Munich</wicri:regionArea><placeName><region type="land" nuts="1">Bavière</region><region type="district" nuts="2">District de Haute-Bavière</region><settlement type="city">Munich</settlement></placeName></affiliation></author><author><name sortKey="Turnbull, Douglass M" sort="Turnbull, Douglass M" uniqKey="Turnbull D" first="Douglass M." last="Turnbull">Douglass M. Turnbull</name><affiliation wicri:level="1"><country xml:lang="fr">Royaume-Uni</country><wicri:regionArea>Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne</wicri:regionArea><wicri:noRegion>Newcastle upon Tyne</wicri:noRegion></affiliation></author></analytic><monogr></monogr><series><title level="j">Annals of Neurology</title><title level="j" type="sub">Official Journal of the American Neurological Association and the Child Neurology Society</title><title level="j" type="abbrev">Ann Neurol.</title><idno type="ISSN">0364-5134</idno><idno type="eISSN">1531-8249</idno><imprint><publisher>Wiley Subscription Services, Inc., A Wiley Company</publisher><pubPlace>Hoboken</pubPlace><date type="published" when="2009-12">2009-12</date><biblScope unit="volume">66</biblScope><biblScope unit="issue">6</biblScope><biblScope unit="page" from="792">792</biblScope><biblScope unit="page" to="798">798</biblScope></imprint><idno type="ISSN">0364-5134</idno></series><idno type="istex">2BC3F834E82888B9EB2A98E42CFBDD319BDDB254</idno><idno type="DOI">10.1002/ana.21780</idno><idno type="ArticleID">ANA21780</idno></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0364-5134</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass><langUsage><language ident="en">en</language></langUsage></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">Objective: The etiology of Parkinson disease (PD) is complex and multifactorial, with hereditary and environmental factors contributing. Monogenic forms have provided molecular clues to disease mechanisms but genetic modifiers of idiopathic PD are still to be determined. Methods: We carried out whole‐genome expression profiling of isolated human substantia nigra (SN) neurons from patients with PD vs. controls followed by association analysis of tagging single‐nucleotide polymorphisms (SNPs) in differentially regulated genes. Association was investigated in a German PD sample and confirmed in Italian and British cohorts. Results: We identified four differentially expressed genes located in PD candidate pathways, ie, MTND2 (mitochondrial, p = 7.14 × 10−7), PDXK (vitamin B6/dopamine metabolism, p = 3.27 × 10−6), SRGAP3 (axon guidance, p = 5.65 × 10−6), and TRAPPC4 (vesicle transport, p = 5.81 × 10−6). We identified a DNA variant (rs2010795) in PDXK associated with an increased risk of PD in the German cohort (p = 0.00032). This association was confirmed in the British (p = 0.028) and Italian (p = 0.0025) cohorts individually and reached a combined value of p = 1.2 × 10−7 (odds ratio [OR], 1.3; 95% confidence interval [CI], 1.18–1.44). Interpretation: We provide an example of how microgenomic genome‐wide expression studies in combination with association analysis can aid to identify genetic modifiers in neurodegenerative disorders. The detection of a genetic variant in PDXK, together with evidence accumulating from clinical studies, emphasize the impact of vitamin B6 status and metabolism on disease risk and therapy in PD. Ann Neurol 2009;66:792–798</div></front></TEI><affiliations><list><country><li>Allemagne</li><li>Italie</li><li>Royaume-Uni</li></country><region><li>Bade-Wurtemberg</li><li>Bavière</li><li>District de Haute-Bavière</li><li>District de Tübingen</li><li>Lombardie</li><li>Schleswig-Holstein</li><li>Écosse</li></region><settlement><li>Kiel</li><li>Milan</li><li>Munich</li><li>Tübingen</li><li>Édimbourg</li></settlement><orgName><li>Université d'Édimbourg</li></orgName></list><tree><country name="Allemagne"><noRegion><name sortKey="Elstner, Matthias" sort="Elstner, Matthias" uniqKey="Elstner M" first="Matthias" last="Elstner">Matthias Elstner</name></noRegion><name sortKey="Bender, Andreas" sort="Bender, Andreas" uniqKey="Bender A" first="Andreas" last="Bender">Andreas Bender</name><name sortKey="Elstner, Matthias" sort="Elstner, Matthias" uniqKey="Elstner M" first="Matthias" last="Elstner">Matthias Elstner</name><name sortKey="Gasser, Thomas" sort="Gasser, Thomas" uniqKey="Gasser T" first="Thomas" last="Gasser">Thomas Gasser</name><name sortKey="Heim, Katharina" sort="Heim, Katharina" uniqKey="Heim K" first="Katharina" last="Heim">Katharina Heim</name><name sortKey="Klopstock, Thomas" sort="Klopstock, Thomas" uniqKey="Klopstock T" first="Thomas" last="Klopstock">Thomas Klopstock</name><name sortKey="Kruger, Rejko" sort="Kruger, Rejko" uniqKey="Kruger R" first="Rejko" last="Krüger">Rejko Krüger</name><name sortKey="Lichtner, Peter" sort="Lichtner, Peter" uniqKey="Lichtner P" first="Peter" last="Lichtner">Peter Lichtner</name><name sortKey="Mehta, Divya" sort="Mehta, Divya" uniqKey="Mehta D" first="Divya" last="Mehta">Divya Mehta</name><name sortKey="Meitinger, Thomas" sort="Meitinger, Thomas" uniqKey="Meitinger T" first="Thomas" last="Meitinger">Thomas Meitinger</name><name sortKey="Meitinger, Thomas" sort="Meitinger, Thomas" uniqKey="Meitinger T" first="Thomas" last="Meitinger">Thomas Meitinger</name><name sortKey="Prokisch, Holger" sort="Prokisch, Holger" uniqKey="Prokisch H" first="Holger" last="Prokisch">Holger Prokisch</name><name sortKey="Prokisch, Holger" sort="Prokisch, Holger" uniqKey="Prokisch H" first="Holger" last="Prokisch">Holger Prokisch</name><name sortKey="Schreiber, Stefan" sort="Schreiber, Stefan" uniqKey="Schreiber S" first="Stefan" last="Schreiber">Stefan Schreiber</name><name sortKey="Schulte, Claudia" sort="Schulte, Claudia" uniqKey="Schulte C" first="Claudia" last="Schulte">Claudia Schulte</name><name sortKey="Sharma, Manu" sort="Sharma, Manu" uniqKey="Sharma M" first="Manu" last="Sharma">Manu Sharma</name><name sortKey="Wichmann, H Rich" sort="Wichmann, H Rich" uniqKey="Wichmann H" first="H. Rich" last="Wichmann">H. Rich Wichmann</name></country><country name="Royaume-Uni"><noRegion><name sortKey="Morris, Christopher M" sort="Morris, Christopher M" uniqKey="Morris C" first="Christopher M." last="Morris">Christopher M. Morris</name></noRegion><name sortKey="Burn, David J" sort="Burn, David J" uniqKey="Burn D" first="David J." last="Burn">David J. Burn</name><name sortKey="Campbell, Harry" sort="Campbell, Harry" uniqKey="Campbell H" first="Harry" last="Campbell">Harry Campbell</name><name sortKey="Chinnery, Patrick F" sort="Chinnery, Patrick F" uniqKey="Chinnery P" first="Patrick F." last="Chinnery">Patrick F. Chinnery</name><name sortKey="Chinnery, Patrick F" sort="Chinnery, Patrick F" uniqKey="Chinnery P" first="Patrick F." last="Chinnery">Patrick F. Chinnery</name><name sortKey="Dunlop, Malcolm" sort="Dunlop, Malcolm" uniqKey="Dunlop M" first="Malcolm" last="Dunlop">Malcolm Dunlop</name><name sortKey="Hudson, Gavin" sort="Hudson, Gavin" uniqKey="Hudson G" first="Gavin" last="Hudson">Gavin Hudson</name><name sortKey="Hudson, Gavin" sort="Hudson, Gavin" uniqKey="Hudson G" first="Gavin" last="Hudson">Gavin Hudson</name><name sortKey="Jaros, E" sort="Jaros, E" uniqKey="Jaros E" first="E." last="Jaros">E. Jaros</name><name sortKey="Mckeith, Ian G" sort="Mckeith, Ian G" uniqKey="Mckeith I" first="Ian G." last="Mckeith">Ian G. Mckeith</name><name sortKey="Perry, Robert H" sort="Perry, Robert H" uniqKey="Perry R" first="Robert H." last="Perry">Robert H. Perry</name><name sortKey="Turnbull, Douglass M" sort="Turnbull, Douglass M" uniqKey="Turnbull D" first="Douglass M." last="Turnbull">Douglass M. Turnbull</name><name sortKey="Wilson, James F" sort="Wilson, James F" uniqKey="Wilson J" first="James F." last="Wilson">James F. Wilson</name><name sortKey="Wright, Alan F" sort="Wright, Alan F" uniqKey="Wright A" first="Alan F." last="Wright">Alan F. Wright</name></country><country name="Italie"><region name="Lombardie"><name sortKey="Goldwurm, Stefano" sort="Goldwurm, Stefano" uniqKey="Goldwurm S" first="Stefano" last="Goldwurm">Stefano Goldwurm</name></region><name sortKey="Giovanetti, Alessandro" sort="Giovanetti, Alessandro" uniqKey="Giovanetti A" first="Alessandro" last="Giovanetti">Alessandro Giovanetti</name><name sortKey="Pistis, Giorgio" sort="Pistis, Giorgio" uniqKey="Pistis G" first="Giorgio" last="Pistis">Giorgio Pistis</name><name sortKey="Toniolo, Daniela" sort="Toniolo, Daniela" uniqKey="Toniolo D" first="Daniela" last="Toniolo">Daniela Toniolo</name><name sortKey="Toniolo, Daniela" sort="Toniolo, Daniela" uniqKey="Toniolo D" first="Daniela" last="Toniolo">Daniela Toniolo</name><name sortKey="Zeviani, Massimo" sort="Zeviani, Massimo" uniqKey="Zeviani M" first="Massimo" last="Zeviani">Massimo Zeviani</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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