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  Identification of Restless Legs Syndrome Genes by Mutational Load Analysis

Tilch, E., Schormair, B., Zhao, C., Salminen V, A., Nikolic, A. A., Holzknecht, E., et al. (2020). Identification of Restless Legs Syndrome Genes by Mutational Load Analysis. Annals of Neurology, 87(2), 184-193. doi:10.1002/ana.25658.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0006-442D-C Version Permalink: http://hdl.handle.net/21.11116/0000-0006-442E-B
Genre: Journal Article

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 Creators:
Tilch, Erik, Author
Schormair, Barbara, Author
Zhao, Chen, Author
Salminen V, Aaro, Author
Nikolic, Ana Antic, Author
Holzknecht, Evi, Author
Hoegl, Birgit, Author
Poewe, Werner, Author
Bachmann, Cornelius G., Author
Paulus, Walter, Author
Trenkwalder, Claudia, Author
Oertel, Wolfgang H., Author
Hornyak, Magdolna, Author
Fietze, Ingo, Author
Berger, Klaus, Author
Lichtner, Peter, Author
Gieger, Christian, Author
Peters, Annette, Author
Mueller-Myhsok, Bertram1, Author
Hoischen, Alexander, Author
Winkelmann, Juliane, AuthorOexle, Konrad, Author more..
Affiliations:
1Max Planck Institute of Psychiatry, Max Planck Society, Kraepelinstr. 2-10, 80804 Munich, DE, ou_1607137              

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 Abstract: Objective Restless legs syndrome is a frequent neurological disorder with substantial burden on individual well-being and public health. Genetic risk loci have been identified, but the causatives genes at these loci are largely unknown, so that functional investigation and clinical translation of molecular research data are still inhibited. To identify putatively causative genes, we searched for highly significant mutational burden in candidate genes. Methods We analyzed 84 candidate genes in 4,649 patients and 4,982 controls by next generation sequencing using molecular inversion probes that targeted mainly coding regions. The burden of low-frequency and rare variants was assessed, and in addition, an algorithm (binomial performance deviation analysis) was established to estimate independently the sequence variation in the probe binding regions from the variation in sequencing depth. Results Highly significant results (considering the number of genes in the genome) of the conventional burden test and the binomial performance deviation analysis overlapped significantly. Fourteen genes were highly significant by one method and confirmed with Bonferroni-corrected significance by the other to show a differential burden of low-frequency and rare variants in restless legs syndrome. Nine of them (AAGAB, ATP2C1, CNTN4, COL6A6, CRBN, GLO1, NTNG1, STEAP4, VAV3) resided in the vicinity of known restless legs syndrome loci, whereas 5 (BBS7, CADM1, CREB5, NRG3, SUN1) have not previously been associated with restless legs syndrome. Burden test and binomial performance deviation analysis also converged significantly in fine-mapping potentially causative domains within these genes. Interpretation Differential burden with intragenic low-frequency variants reveals putatively causative genes in restless legs syndrome. ANN NEUROL 2019

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Language(s): eng - English
 Dates: 2019-12-012020
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Type: -
 Identifiers: ISI: 000503367600001
DOI: 10.1002/ana.25658
 Degree: -

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Title: Annals of Neurology
Source Genre: Journal
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Publ. Info: Boston : American Neurological Association
Pages: - Volume / Issue: 87 (2) Sequence Number: - Start / End Page: 184 - 193 Identifier: ISSN: 0364-5134
CoNE: https://pure.mpg.de/cone/journals/resource/954925523748