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

Björn Hergen Laabs; Christine Klein; Jelena Pozojevic; Aloysius Domingo; Norbert Brüggemann; Karen Grütz; Raymond L. Rosales; Roland Dominic Jamora; Gerard Saranza; Cid C. Diesta; Michael Wittig; Susen Schaake; Marija Dulovic-Mahlow; Jana Quismundo; Pia Otto; Patrick Acuna; Criscely Go; Nutan Sharma; Trisha Multhaupt-Buell; Ulrich Müller; Henrike Hanssen; Fabian Kilpert; Andre Franke; Arndt Rolfs; Peter Bauer; Valerija Dobričić; Katja Lohmann; Laurie J. Ozelius; Frank J. Kaiser; Inke R. König; Ana Westenberger

doi:10.1038/s41467-021-23491-4

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

Björn Hergen Laabs, Christine Klein, Jelena Pozojevic, Aloysius Domingo, Norbert Brüggemann, Karen Grütz, Raymond L. Rosales, Roland Dominic Jamora, Gerard Saranza, Cid C. Diesta, Michael Wittig, Susen Schaake, Marija Dulovic-Mahlow, Jana Quismundo, Pia Otto, Patrick Acuna, Criscely Go, Nutan Sharma, Trisha Multhaupt-Buell, Ulrich MüllerHenrike Hanssen, Fabian Kilpert, Andre Franke, Arndt Rolfs, Peter Bauer, Valerija Dobričić, Katja Lohmann, Laurie J. Ozelius, Frank J. Kaiser, Inke R. König^*, Ana Westenberger

^*Corresponding author for this work

Abstract

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.

Original language	English
Article number	3216
Journal	Nature Communications
Volume	12
Issue number	1
Pages (from-to)	3216
ISSN	1751-8628
DOIs	https://doi.org/10.1038/s41467-021-23491-4
Publication status	Published - 28.05.2021

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Research Area: Medical Genetics

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Laabs, B. H., Klein, C., Pozojevic, J., Domingo, A., Brüggemann, N., Grütz, K., Rosales, R. L., Jamora, R. D., Saranza, G., Diesta, C. C., Wittig, M., Schaake, S., Dulovic-Mahlow, M., Quismundo, J., Otto, P., Acuna, P., Go, C., Sharma, N., Multhaupt-Buell, T., ... Westenberger, A. (2021). Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism. Nature Communications, 12(1), 3216. [3216]. https://doi.org/10.1038/s41467-021-23491-4

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title = "Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism",

abstract = "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{\textquoteright}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.",

author = "Laabs, {Bj{\"o}rn Hergen} and Christine Klein and Jelena Pozojevic and Aloysius Domingo and Norbert Br{\"u}ggemann and Karen Gr{\"u}tz and Rosales, {Raymond L.} and Jamora, {Roland Dominic} and Gerard Saranza and Diesta, {Cid C.} and Michael Wittig and Susen Schaake and Marija Dulovic-Mahlow and Jana Quismundo and Pia Otto and Patrick Acuna and Criscely Go and Nutan Sharma and Trisha Multhaupt-Buell and Ulrich M{\"u}ller and Henrike Hanssen and Fabian Kilpert and Andre Franke and Arndt Rolfs and Peter Bauer and Valerija Dobri{\v c}i{\'c} and Katja Lohmann and Ozelius, {Laurie J.} and Kaiser, {Frank J.} and K{\"o}nig, {Inke R.} and Ana Westenberger",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s).",

year = "2021",

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Laabs, BH , Klein, C , Pozojevic, J, Domingo, A, Brüggemann, N , Grütz, K, Rosales, RL, Jamora, RD, Saranza, G, Diesta, CC, Wittig, M, Schaake, S, Dulovic-Mahlow, M, Quismundo, J, Otto, P, Acuna, P, Go, C, Sharma, N, Multhaupt-Buell, T, Müller, U, Hanssen, H, Kilpert, F, Franke, A, Rolfs, A, Bauer, P, Dobričić, V , Lohmann, K, Ozelius, LJ, Kaiser, FJ, König, IR & Westenberger, A 2021, 'Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism', Nature Communications, vol. 12, no. 1, 3216, pp. 3216. https://doi.org/10.1038/s41467-021-23491-4

TY - JOUR

T1 - Identifying genetic modifiers of age-associated penetrance in X-linked dystonia-parkinsonism

AU - Laabs, Björn Hergen

AU - Klein, Christine

AU - Pozojevic, Jelena

AU - Domingo, Aloysius

AU - Brüggemann, Norbert

AU - Grütz, Karen

AU - Rosales, Raymond L.

AU - Jamora, Roland Dominic

AU - Saranza, Gerard

AU - Diesta, Cid C.

AU - Wittig, Michael

AU - Schaake, Susen

AU - Dulovic-Mahlow, Marija

AU - Quismundo, Jana

AU - Otto, Pia

AU - Acuna, Patrick

AU - Go, Criscely

AU - Sharma, Nutan

AU - Multhaupt-Buell, Trisha

AU - Müller, Ulrich

AU - Hanssen, Henrike

AU - Kilpert, Fabian

AU - Franke, Andre

AU - Rolfs, Arndt

AU - Bauer, Peter

AU - Dobričić, Valerija

AU - Lohmann, Katja

AU - Ozelius, Laurie J.

AU - Kaiser, Frank J.

AU - König, Inke R.

AU - Westenberger, Ana

PY - 2021/5/28

Y1 - 2021/5/28

N2 - 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.

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

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