Barbara Schormair1,2, Chen Zhao1, Aaro V Salminen1, Konrad Oexle1,2, Juliane Winkelmann1,2,3,4. 1. Institute of Neurogenomics, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany. 2. Institute of Human Genetics, School of Medicine, Technical University of Munich, Munich, Germany. 3. Chair of Neurogenetics, School of Medicine, Technical University of Munich, Munich, Germany. 4. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Abstract
STUDY OBJECTIVES: Several candidate gene studies have been published for idiopathic restless legs syndrome (RLS) in populations of European ancestry, but the reported associations have not been confirmed in independent samples. Our aim was to reassess these findings in a large case-control dataset in order to evaluate their validity. METHODS: We screened PubMed for RLS candidate gene studies. We used the genome-wide association study (GWAS) dataset of the International EU-RLS-GENE Consortium as our replication sample, which provided genome-wide single-variant association data based on at most 17 220 individuals of European ancestry. We performed additional gene-based tests using the software MAGMA and assessed the power of our study using the genpwr R package. RESULTS: We identified 14 studies conducted in European samples which assessed 45 variants in 27 genes of which 5 variants had been reported as significantly associated. None of these individual variants were replicated in our GWAS-based reassessment (nominal p > 0.05) and gene-based tests for the respective five genes ADH1B, GABRR3, HMOX1, MAOA, and VDR, were also nonsignificant (nominal p > 0.05). Our replication dataset was well powered to detect the reported effects, even when adjusting for effect size overestimation due to winner's curse. Power estimates were close to 100% for all variants. CONCLUSION: In summary, none of the significant single-variant associations from candidate gene studies were confirmed in our GWAS dataset. Therefore, these associations were likely false positive. Our observations emphasize the need for large sample sizes and stringent significance thresholds in future association studies for RLS.
STUDY OBJECTIVES: Several candidate gene studies have been published for idiopathic restless legs syndrome (RLS) in populations of European ancestry, but the reported associations have not been confirmed in independent samples. Our aim was to reassess these findings in a large case-control dataset in order to evaluate their validity. METHODS: We screened PubMed for RLS candidate gene studies. We used the genome-wide association study (GWAS) dataset of the International EU-RLS-GENE Consortium as our replication sample, which provided genome-wide single-variant association data based on at most 17 220 individuals of European ancestry. We performed additional gene-based tests using the software MAGMA and assessed the power of our study using the genpwr R package. RESULTS: We identified 14 studies conducted in European samples which assessed 45 variants in 27 genes of which 5 variants had been reported as significantly associated. None of these individual variants were replicated in our GWAS-based reassessment (nominal p > 0.05) and gene-based tests for the respective five genes ADH1B, GABRR3, HMOX1, MAOA, and VDR, were also nonsignificant (nominal p > 0.05). Our replication dataset was well powered to detect the reported effects, even when adjusting for effect size overestimation due to winner's curse. Power estimates were close to 100% for all variants. CONCLUSION: In summary, none of the significant single-variant associations from candidate gene studies were confirmed in our GWAS dataset. Therefore, these associations were likely false positive. Our observations emphasize the need for large sample sizes and stringent significance thresholds in future association studies for RLS.
Authors: Félix J Jiménez-Jiménez; Hortensia Alonso-Navarro; Elena García-Martín; José A G Agúndez Journal: Sleep Med Rev Date: 2017-08-31 Impact factor: 11.609
Authors: Angela Roco; Félix Javier Jiménez-Jiménez; Hortensia Alonso-Navarro; Carmen Martínez; Martín Zurdo; Laura Turpín-Fenoll; Jorge Millán; Teresa Adeva-Bartolomé; Esther Cubo; Francisco Navacerrada; Ana Rojo-Sebastián; Lluisa Rubio; Marisol Calleja; José Francisco Plaza-Nieto; Belén Pilo-de-la-Fuente; Margarita Arroyo-Solera; Elena García-Martín; José A G Agúndez Journal: J Neural Transm (Vienna) Date: 2012-09-22 Impact factor: 3.575
Authors: Félix Javier Jiménez-Jiménez; Hortensia Alonso-Navarro; Carmen Martínez; Martín Zurdo; Laura Turpín-Fenoll; Jorge Millán-Pascual; Teresa Adeva-Bartolomé; Esther Cubo; Francisco Navacerrada; Ana Rojo-Sebastián; Lluisa Rubio; Marisol Calleja; José Francisco Plaza-Nieto; Belén Pilo-de-la-Fuente; Margarita Arroyo-Solera; Esteban García-Albea; Elena García-Martín; José A G Agúndez Journal: J Neural Transm (Vienna) Date: 2014-10-10 Impact factor: 3.575
Authors: Félix Javier Jiménez-Jiménez; Elena García-Martín; Hortensia Alonso-Navarro; Carmen Martínez; Martín Zurdo; Laura Turpín-Fenoll; Jorge Millán-Pascual; Teresa Adeva-Bartolomé; Esther Cubo; Francisco Navacerrada; Ana Rojo-Sebastián; Lluisa Rubio; Sara Ortega-Cubero; Pau Pastor; Marisol Calleja; José Francisco Plaza-Nieto; Belén Pilo-De-La-Fuente; Margarita Arroyo-Solera; Esteban García-Albea; José A G Agúndez Journal: Medicine (Baltimore) Date: 2015-11 Impact factor: 1.817