Exome Sequencing Reveals Signal Transduction Genes Involved in Impulse Control Disorders in Parkinson's Disease
Introduction: Impulse control disorders (ICDs) frequently complicate dopamine agonist (DA) therapy in Parkinson's disease (PD). There is growing evidence of a high heritability for ICDs in the general population and in PD. Variants on genes belonging to the reward pathway have been shown to acc...
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Frontiers Media S.A.
2020-07-01
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Online Access: | https://www.frontiersin.org/article/10.3389/fneur.2020.00641/full |
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Article |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sabine Prud'hon Sabine Prud'hon Samir Bekadar Samir Bekadar Agnès Rastetter Justine Guégan Florence Cormier-Dequaire Florence Cormier-Dequaire Lucette Lacomblez Lucette Lacomblez Graziella Mangone Graziella Mangone Hana You Hana You Mailys Daniau Yannick Marie Hélène Bertrand Suzanne Lesage Sophie Tezenas Du Montcel Mathieu Anheim Mathieu Anheim Mathieu Anheim Alexis Brice Alexis Brice Fabrice Danjou Jean-Christophe Corvol Jean-Christophe Corvol |
spellingShingle |
Sabine Prud'hon Sabine Prud'hon Samir Bekadar Samir Bekadar Agnès Rastetter Justine Guégan Florence Cormier-Dequaire Florence Cormier-Dequaire Lucette Lacomblez Lucette Lacomblez Graziella Mangone Graziella Mangone Hana You Hana You Mailys Daniau Yannick Marie Hélène Bertrand Suzanne Lesage Sophie Tezenas Du Montcel Mathieu Anheim Mathieu Anheim Mathieu Anheim Alexis Brice Alexis Brice Fabrice Danjou Jean-Christophe Corvol Jean-Christophe Corvol Exome Sequencing Reveals Signal Transduction Genes Involved in Impulse Control Disorders in Parkinson's Disease Frontiers in Neurology Parkinson's disease (PD) dopamine agonists (DA) impulse control disorders (ICD) pharmacogenetics exome sequencing |
author_facet |
Sabine Prud'hon Sabine Prud'hon Samir Bekadar Samir Bekadar Agnès Rastetter Justine Guégan Florence Cormier-Dequaire Florence Cormier-Dequaire Lucette Lacomblez Lucette Lacomblez Graziella Mangone Graziella Mangone Hana You Hana You Mailys Daniau Yannick Marie Hélène Bertrand Suzanne Lesage Sophie Tezenas Du Montcel Mathieu Anheim Mathieu Anheim Mathieu Anheim Alexis Brice Alexis Brice Fabrice Danjou Jean-Christophe Corvol Jean-Christophe Corvol |
author_sort |
Sabine Prud'hon |
title |
Exome Sequencing Reveals Signal Transduction Genes Involved in Impulse Control Disorders in Parkinson's Disease |
title_short |
Exome Sequencing Reveals Signal Transduction Genes Involved in Impulse Control Disorders in Parkinson's Disease |
title_full |
Exome Sequencing Reveals Signal Transduction Genes Involved in Impulse Control Disorders in Parkinson's Disease |
title_fullStr |
Exome Sequencing Reveals Signal Transduction Genes Involved in Impulse Control Disorders in Parkinson's Disease |
title_full_unstemmed |
Exome Sequencing Reveals Signal Transduction Genes Involved in Impulse Control Disorders in Parkinson's Disease |
title_sort |
exome sequencing reveals signal transduction genes involved in impulse control disorders in parkinson's disease |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Neurology |
issn |
1664-2295 |
publishDate |
2020-07-01 |
description |
Introduction: Impulse control disorders (ICDs) frequently complicate dopamine agonist (DA) therapy in Parkinson's disease (PD). There is growing evidence of a high heritability for ICDs in the general population and in PD. Variants on genes belonging to the reward pathway have been shown to account for part of this heritability. We aimed to identify new pathways associated with ICDs in PD.Methods: Thirty-six Parkinsonian patients on DA therapy with (n = 18) and without ICDs (n = 18) matched on age at PD's onset, and gender was selected to represent the most extreme phenotypes of their category. Exome sequencing was performed, and variants with a strong functional impact in brain-expressed genes were selected. Allele frequencies and their distribution in genes and pathways were analyzed with single variant and SKAT-O tests. The 10 most associated variants, genes, and pathways were retained for replication in the Parkinson's progression markers initiative (PPMI) cohort.Results: None of markers tested passed the significance threshold adjusted for multiple comparisons. However, the “Adenylate cyclase activating” pathway, one of the top associated pathways in the discovery data set (p = 1.6 × 10−3) was replicated in the PPMI cohort and was significantly associated with ICDs in a post hoc pooled analysis (combined p-value 3.3 × 10−5). Two of the 10 most associated variants belonged to genes implicated in cAMP and ERK signaling (rs34193571 in RasGRF2, p = 5 × 10−4; rs1877652 in PDE2A, p = 8 × 10−4) although non-significant after Bonferroni correction.Conclusion: Our results suggest that genes implicated in the signaling pathways linked to G protein-coupled receptors participate to genetic susceptibility to ICDs in PD. |
topic |
Parkinson's disease (PD) dopamine agonists (DA) impulse control disorders (ICD) pharmacogenetics exome sequencing |
url |
https://www.frontiersin.org/article/10.3389/fneur.2020.00641/full |
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doaj-a8e44937a63d407785ed3f69bf40cd442020-11-25T03:26:23ZengFrontiers Media S.A.Frontiers in Neurology1664-22952020-07-011110.3389/fneur.2020.00641527887Exome Sequencing Reveals Signal Transduction Genes Involved in Impulse Control Disorders in Parkinson's DiseaseSabine Prud'hon0Sabine Prud'hon1Samir Bekadar2Samir Bekadar3Agnès Rastetter4Justine Guégan5Florence Cormier-Dequaire6Florence Cormier-Dequaire7Lucette Lacomblez8Lucette Lacomblez9Graziella Mangone10Graziella Mangone11Hana You12Hana You13Mailys Daniau14Yannick Marie15Hélène Bertrand16Suzanne Lesage17Sophie Tezenas Du Montcel18Mathieu Anheim19Mathieu Anheim20Mathieu Anheim21Alexis Brice22Alexis Brice23Fabrice Danjou24Jean-Christophe Corvol25Jean-Christophe Corvol26Sorbonne Université, INSERM UMRS 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle, ICM, Paris, FranceAssistance Publique Hôpitaux de Paris, Centre d'Investigation Clinique neurosciences, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, FranceSorbonne Université, INSERM UMRS 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle, ICM, Paris, FranceAssistance Publique Hôpitaux de Paris, Centre d'Investigation Clinique neurosciences, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, FranceSorbonne Université, INSERM UMRS 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle, ICM, Paris, FranceSorbonne Université, INSERM UMRS 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle, ICM, Paris, FranceSorbonne Université, INSERM UMRS 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle, ICM, Paris, FranceAssistance Publique Hôpitaux de Paris, Centre d'Investigation Clinique neurosciences, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, FranceAssistance Publique Hôpitaux de Paris, Centre d'Investigation Clinique neurosciences, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, FranceAssistance Publique Hôpitaux de Paris, Department of Pharmacology, Hôpital Pitié-Salpêtrière, Paris, FranceSorbonne Université, INSERM UMRS 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle, ICM, Paris, FranceAssistance Publique Hôpitaux de Paris, Centre d'Investigation Clinique neurosciences, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, FranceSorbonne Université, INSERM UMRS 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle, ICM, Paris, FranceAssistance Publique Hôpitaux de Paris, Centre d'Investigation Clinique neurosciences, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, FranceSorbonne Université, INSERM UMRS 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle, ICM, Paris, FranceSorbonne Université, INSERM UMRS 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle, ICM, Paris, FranceSorbonne Université, INSERM UMRS 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle, ICM, Paris, FranceSorbonne Université, INSERM UMRS 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle, ICM, Paris, FranceAssistance Publique Hôpitaux de Paris, Sorbonne Université, INSERM, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Hôpital Pitié-Salpêtrière, Paris, FranceHôpitaux Universitaires de Strasbourg, Department of Neurology, Strasbourg, FranceInstitut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), UMR 7104 CNRS/Unistra, Inserm U1258, Illkirch, FranceFédération de Médecine Translationnelle de Strasbourg, Université de Strasbourg, Strasbourg, FranceSorbonne Université, INSERM UMRS 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle, ICM, Paris, FranceAssistance Publique Hôpitaux de Paris, Department of Genetics, Hôpital Pitié-Salpêtrière, Paris, FranceSorbonne Université, INSERM UMRS 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle, ICM, Paris, FranceSorbonne Université, INSERM UMRS 1127, CNRS UMR 7225, Institut du Cerveau et de la Moelle, ICM, Paris, FranceAssistance Publique Hôpitaux de Paris, Centre d'Investigation Clinique neurosciences, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, FranceIntroduction: Impulse control disorders (ICDs) frequently complicate dopamine agonist (DA) therapy in Parkinson's disease (PD). There is growing evidence of a high heritability for ICDs in the general population and in PD. Variants on genes belonging to the reward pathway have been shown to account for part of this heritability. We aimed to identify new pathways associated with ICDs in PD.Methods: Thirty-six Parkinsonian patients on DA therapy with (n = 18) and without ICDs (n = 18) matched on age at PD's onset, and gender was selected to represent the most extreme phenotypes of their category. Exome sequencing was performed, and variants with a strong functional impact in brain-expressed genes were selected. Allele frequencies and their distribution in genes and pathways were analyzed with single variant and SKAT-O tests. The 10 most associated variants, genes, and pathways were retained for replication in the Parkinson's progression markers initiative (PPMI) cohort.Results: None of markers tested passed the significance threshold adjusted for multiple comparisons. However, the “Adenylate cyclase activating” pathway, one of the top associated pathways in the discovery data set (p = 1.6 × 10−3) was replicated in the PPMI cohort and was significantly associated with ICDs in a post hoc pooled analysis (combined p-value 3.3 × 10−5). Two of the 10 most associated variants belonged to genes implicated in cAMP and ERK signaling (rs34193571 in RasGRF2, p = 5 × 10−4; rs1877652 in PDE2A, p = 8 × 10−4) although non-significant after Bonferroni correction.Conclusion: Our results suggest that genes implicated in the signaling pathways linked to G protein-coupled receptors participate to genetic susceptibility to ICDs in PD.https://www.frontiersin.org/article/10.3389/fneur.2020.00641/fullParkinson's disease (PD)dopamine agonists (DA)impulse control disorders (ICD)pharmacogeneticsexome sequencing |