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Tilch, E. ; Schormair, B. ; Zhao, C. ; Salminen, A.V. ; Antic Nikolic, A. ; Holzknecht, E.* ; Högl, B.* ; Poewe, W.* ; Bachmann, C.G.* ; Paulus, W.* ; Trenkwalder, C.* ; Oertel, W.H. ; Hornyak, M.* ; Fietze, I.* ; Berger, K.* ; Lichtner, P. ; Gieger, C. ; Peters, A. ; Müller-Myhsok, B.* ; Hoischen, A.* ; Winkelmann, J. ; Oexle, K.

Identification of restless legs syndrome genes by mutational load analysis.

Ann. Neurol. 87, 184-193 (2020)
Publ. Version/Full Text Postprint DOI PMC
Open Access Hybrid
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Gene Identification ; Rare Variants ; Restless Legs Syndrome; Genome-wide Association; Risk; Spectrum; Epidemiology; Framework; Complex
Language english
Publication Year 2020
Prepublished in Year 2019
HGF-reported in Year 2019
ISSN (print) / ISBN 0364-5134
e-ISSN 1531-8249
Journal Annals of Neurology
Quellenangaben Volume: 87, Issue: 2, Pages: 184-193 Article Number: , Supplement: ,
Publisher Wiley
Publishing Place 111 River St, Hoboken 07030-5774, Nj Usa
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Institute of Human Genetics (IHG)
Institute of Epidemiology (EPI)
POF-Topic(s) 30205 - Bioengineering and Digital Health
30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30202 - Environmental Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-503200-001
G-500700-001
G-504091-004
G-504000-001
DOI 10.1002/ana.25658
WOS ID WOS:000503367600001
Scopus ID 85076747618
PubMed ID 31788832
Erfassungsdatum 2019-12-06
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