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

43 Citations (Scopus)

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

Funding

The study was supported by the Deutsche Forschungsgemeinschaft (DFG; FOR 2488 to C.K., N.B., K.L., F.J.K., I.R.K., and A.W.; SFB 936 [project C5] to C.K.), the Collaborative Center for X-linked Dystonia-Parkinsonism at Massachusetts General Hospital (to N.B., C.K., L.J.O., N.S., T.M.-B., and C.G.), the Else Kröner Fresenius Foundation (to N.B.), intramural funds from the University of Lübeck (to C.K. and M.D.-M.), and a career development award from the Hermann and Lilly Schilling Foundation (to C.K.). Furthermore, this work received infrastructure support by the DFG Cluster of Excellence “Precision Medicine in Chronic Inflammation” (PMI, EXC2167 to A.F.). We thank the XDP patients and their relatives for their participation in this study; the Sunshine Care Foundation and members of their staff (including genetic councilors N.G.M. Ganza and B.B. Lagarde) for the infrastructure they have established and for their devoted and hard work; Dr. L.V. Lee, Dr. R. Kaji, and Dr. T. Kawarai for referral of DNA samples and clinical information; Dr. L. Bertram who was involved in early scientific discussions of the study, acquisition of funding, and supervision of the collection of the GSA-based genotyping data; and H. Pawlack for technical assistance, including genotyping of DNA samples.

Research Areas and Centers

Research Area: Medical Genetics

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-021-23491-4

Cite this

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. Article 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 \textasciitilde{}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.",

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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

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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

Abstract

Funding

Research Areas and Centers

UN SDGs

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Perfood Research Award 2022 (Medicine)

Cite this

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

Abstract

Funding

Research Areas and Centers

UN SDGs

Access to Document

Other files and links

Fingerprint

Prizes

Perfood Research Award 2022 (Medicine)

Cite this