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Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism

X-linked dystonia-parkinsonism is a neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset variability. Employing a genome-wide association study to identify additional factors modifying age at onset, w...

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Autores principales: Laabs, Björn-Hergen, Klein, Christine, Pozojevic, Jelena, Domingo, Aloysius, Brüggemann, Norbert, Grütz, Karen, Rosales, Raymond L., Jamora, Roland Dominic, Saranza, Gerard, Diesta, Cid Czarina E., Wittig, Michael, Schaake, Susen, Dulovic-Mahlow, Marija, Quismundo, Jana, Otto, Pia, Acuna, Patrick, Go, Criscely, Sharma, Nutan, Multhaupt-Buell, Trisha, Müller, Ulrich, Hanssen, Henrike, Kilpert, Fabian, Franke, Andre, Rolfs, Arndt, Bauer, Peter, Dobričić, Valerija, Lohmann, Katja, Ozelius, Laurie J., Kaiser, Frank J., König, Inke R., Westenberger, Ana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163740/
https://www.ncbi.nlm.nih.gov/pubmed/34050153
http://dx.doi.org/10.1038/s41467-021-23491-4
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author Laabs, Björn-Hergen
Klein, Christine
Pozojevic, Jelena
Domingo, Aloysius
Brüggemann, Norbert
Grütz, Karen
Rosales, Raymond L.
Jamora, Roland Dominic
Saranza, Gerard
Diesta, Cid Czarina E.
Wittig, Michael
Schaake, Susen
Dulovic-Mahlow, Marija
Quismundo, Jana
Otto, Pia
Acuna, Patrick
Go, Criscely
Sharma, Nutan
Multhaupt-Buell, Trisha
Müller, Ulrich
Hanssen, Henrike
Kilpert, Fabian
Franke, Andre
Rolfs, Arndt
Bauer, Peter
Dobričić, Valerija
Lohmann, Katja
Ozelius, Laurie J.
Kaiser, Frank J.
König, Inke R.
Westenberger, Ana
author_facet Laabs, Björn-Hergen
Klein, Christine
Pozojevic, Jelena
Domingo, Aloysius
Brüggemann, Norbert
Grütz, Karen
Rosales, Raymond L.
Jamora, Roland Dominic
Saranza, Gerard
Diesta, Cid Czarina E.
Wittig, Michael
Schaake, Susen
Dulovic-Mahlow, Marija
Quismundo, Jana
Otto, Pia
Acuna, Patrick
Go, Criscely
Sharma, Nutan
Multhaupt-Buell, Trisha
Müller, Ulrich
Hanssen, Henrike
Kilpert, Fabian
Franke, Andre
Rolfs, Arndt
Bauer, Peter
Dobričić, Valerija
Lohmann, Katja
Ozelius, Laurie J.
Kaiser, Frank J.
König, Inke R.
Westenberger, Ana
author_sort Laabs, Björn-Hergen
collection PubMed
description X-linked dystonia-parkinsonism is a neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset variability. Employing a genome-wide association study to identify additional factors modifying age at onset, we establish that three independent loci are significantly associated with age at onset (p < 5 × 10(−8)). The lead single nucleotide polymorphisms collectively account for 25.6% of the remaining variance not explained by the hexanucleotide repeat and 13.0% of the overall variance in age at onset in X-linked dystonia-parkinsonism with the protective alleles delaying disease onset by seven years. These regions harbor or lie adjacent to MSH3 and PMS2, the genes that were recently implicated in modifying age at onset in Huntington’s disease, likely through a common pathway influencing repeat instability. Our work indicates the existence of three modifiers of age at onset in X-linked dystonia-parkinsonism that likely affect the DNA mismatch repair pathway.
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spelling pubmed-81637402021-06-11 Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism Laabs, Björn-Hergen Klein, Christine Pozojevic, Jelena Domingo, Aloysius Brüggemann, Norbert Grütz, Karen Rosales, Raymond L. Jamora, Roland Dominic Saranza, Gerard Diesta, Cid Czarina E. Wittig, Michael Schaake, Susen Dulovic-Mahlow, Marija Quismundo, Jana Otto, Pia Acuna, Patrick Go, Criscely Sharma, Nutan Multhaupt-Buell, Trisha Müller, Ulrich Hanssen, Henrike Kilpert, Fabian Franke, Andre Rolfs, Arndt Bauer, Peter Dobričić, Valerija Lohmann, Katja Ozelius, Laurie J. Kaiser, Frank J. König, Inke R. Westenberger, Ana Nat Commun Article X-linked dystonia-parkinsonism is a neurodegenerative disorder caused by a founder retrotransposon insertion, in which a polymorphic hexanucleotide repeat accounts for ~50% of age at onset variability. Employing a genome-wide association study to identify additional factors modifying age at onset, we establish that three independent loci are significantly associated with age at onset (p < 5 × 10(−8)). The lead single nucleotide polymorphisms collectively account for 25.6% of the remaining variance not explained by the hexanucleotide repeat and 13.0% of the overall variance in age at onset in X-linked dystonia-parkinsonism with the protective alleles delaying disease onset by seven years. These regions harbor or lie adjacent to MSH3 and PMS2, the genes that were recently implicated in modifying age at onset in Huntington’s disease, likely through a common pathway influencing repeat instability. Our work indicates the existence of three modifiers of age at onset in X-linked dystonia-parkinsonism that likely affect the DNA mismatch repair pathway. Nature Publishing Group UK 2021-05-28 /pmc/articles/PMC8163740/ /pubmed/34050153 http://dx.doi.org/10.1038/s41467-021-23491-4 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Laabs, Björn-Hergen
Klein, Christine
Pozojevic, Jelena
Domingo, Aloysius
Brüggemann, Norbert
Grütz, Karen
Rosales, Raymond L.
Jamora, Roland Dominic
Saranza, Gerard
Diesta, Cid Czarina E.
Wittig, Michael
Schaake, Susen
Dulovic-Mahlow, Marija
Quismundo, Jana
Otto, Pia
Acuna, Patrick
Go, Criscely
Sharma, Nutan
Multhaupt-Buell, Trisha
Müller, Ulrich
Hanssen, Henrike
Kilpert, Fabian
Franke, Andre
Rolfs, Arndt
Bauer, Peter
Dobričić, Valerija
Lohmann, Katja
Ozelius, Laurie J.
Kaiser, Frank J.
König, Inke R.
Westenberger, Ana
Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism
title Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism
title_full Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism
title_fullStr Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism
title_full_unstemmed Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism
title_short Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism
title_sort identifying genetic modifiers of age-associated penetrance in x-linked dystonia-parkinsonism
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163740/
https://www.ncbi.nlm.nih.gov/pubmed/34050153
http://dx.doi.org/10.1038/s41467-021-23491-4
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