Abstract
Background Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. Methods In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10−8) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. Findings We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85–1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). Interpretation Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. Funding Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München–Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 898-907 |
| Number of pages | 10 |
| Journal | The Lancet Neurology |
| Volume | 16 |
| Issue number | 11 |
| DOIs | |
| State | Published - Nov 1 2017 |
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ASJC Scopus subject areas
- Clinical Neurology
Cite this
Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry : a meta-analysis. / 23andMe Research Team.
In: The Lancet Neurology, Vol. 16, No. 11, 01.11.2017, p. 898-907.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Identification of novel risk loci for restless legs syndrome in genome-wide association studies in individuals of European ancestry
T2 - a meta-analysis
AU - 23andMe Research Team
AU - Schormair, Barbara
AU - Zhao, Chen
AU - Bell, Steven
AU - Tilch, Erik
AU - Salminen, Aaro V.
AU - Pütz, Benno
AU - Dauvilliers, Yves
AU - Stefani, Ambra
AU - Högl, Birgit
AU - Poewe, Werner
AU - Kemlink, David
AU - Sonka, Karel
AU - Bachmann, Cornelius G.
AU - Paulus, Walter
AU - Trenkwalder, Claudia
AU - Oertel, Wolfgang H.
AU - Hornyak, Magdolna
AU - Teder-Laving, Maris
AU - Metspalu, Andres
AU - Hadjigeorgiou, Georgios M.
AU - Polo, Olli
AU - Fietze, Ingo
AU - Ross, Owen A
AU - Wszolek, Zbigniew K
AU - Butterworth, Adam S.
AU - Soranzo, Nicole
AU - Ouwehand, Willem H.
AU - Roberts, David J.
AU - Danesh, John
AU - Allen, Richard P.
AU - Earley, Christopher J.
AU - Ondo, William G.
AU - Xiong, Lan
AU - Montplaisir, Jacques
AU - Gan-Or, Ziv
AU - Perola, Markus
AU - Vodicka, Pavel
AU - Dina, Christian
AU - Franke, Andre
AU - Tittmann, Lukas
AU - Stewart, Alexandre F.R.
AU - Shah, Svati H.
AU - Gieger, Christian
AU - Peters, Annette
AU - Rouleau, Guy A.
AU - Berger, Klaus
AU - Oexle, Konrad
AU - Di Angelantonio, Emanuele
AU - Hinds, David A.
AU - Müller-Myhsok, Bertram
PY - 2017/11/1
Y1 - 2017/11/1
N2 - Background Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. Methods In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10−8) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. Findings We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85–1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). Interpretation Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. Funding Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München–Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.
AB - Background Restless legs syndrome is a prevalent chronic neurological disorder with potentially severe mental and physical health consequences. Clearer understanding of the underlying pathophysiology is needed to improve treatment options. We did a meta-analysis of genome-wide association studies (GWASs) to identify potential molecular targets. Methods In the discovery stage, we combined three GWAS datasets (EU-RLS GENE, INTERVAL, and 23andMe) with diagnosis data collected from 2003 to 2017, in face-to-face interviews or via questionnaires, and involving 15 126 cases and 95 725 controls of European ancestry. We identified common variants by fixed-effect inverse-variance meta-analysis. Significant genome-wide signals (p≤5 × 10−8) were tested for replication in an independent GWAS of 30 770 cases and 286 913 controls, followed by a joint analysis of the discovery and replication stages. We did gene annotation, pathway, and gene-set-enrichment analyses and studied the genetic correlations between restless legs syndrome and traits of interest. Findings We identified and replicated 13 new risk loci for restless legs syndrome and confirmed the previously identified six risk loci. MEIS1 was confirmed as the strongest genetic risk factor for restless legs syndrome (odds ratio 1·92, 95% CI 1·85–1·99). Gene prioritisation, enrichment, and genetic correlation analyses showed that identified pathways were related to neurodevelopment and highlighted genes linked to axon guidance (associated with SEMA6D), synapse formation (NTNG1), and neuronal specification (HOXB cluster family and MYT1). Interpretation Identification of new candidate genes and associated pathways will inform future functional research. Advances in understanding of the molecular mechanisms that underlie restless legs syndrome could lead to new treatment options. We focused on common variants; thus, additional studies are needed to dissect the roles of rare and structural variations. Funding Deutsche Forschungsgemeinschaft, Helmholtz Zentrum München–Deutsches Forschungszentrum für Gesundheit und Umwelt, National Research Institutions, NHS Blood and Transplant, National Institute for Health Research, British Heart Foundation, European Commission, European Research Council, National Institutes of Health, National Institute of Neurological Disorders and Stroke, NIH Research Cambridge Biomedical Research Centre, and UK Medical Research Council.
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UR - http://www.scopus.com/inward/citedby.url?scp=85031737266&partnerID=8YFLogxK
U2 - 10.1016/S1474-4422(17)30327-7
DO - 10.1016/S1474-4422(17)30327-7
M3 - Article
C2 - 29029846
AN - SCOPUS:85031737266
VL - 16
SP - 898
EP - 907
JO - The Lancet Neurology
JF - The Lancet Neurology
SN - 1474-4422
IS - 11
ER -