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Family-based and population-based association studies validate PTPRD as a risk factor for restless legs syndrome

Authors

  • Qinbo Yang MS,

    1. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, People's Republic of China
    2. Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
    3. Department of Molecular Medicine, CCLCM of Case Western Reserve University, Cleveland, Ohio, USA
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  • Lin Li PhD,

    1. Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
    2. Department of Molecular Medicine, CCLCM of Case Western Reserve University, Cleveland, Ohio, USA
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  • Rong Yang BS,

    1. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, People's Republic of China
    2. Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
    3. Department of Molecular Medicine, CCLCM of Case Western Reserve University, Cleveland, Ohio, USA
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  • Gong-Qing Shen MD, PhD,

    1. Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
    2. Department of Molecular Medicine, CCLCM of Case Western Reserve University, Cleveland, Ohio, USA
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  • Qiuyun Chen PhD,

    1. Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
    2. Department of Molecular Medicine, CCLCM of Case Western Reserve University, Cleveland, Ohio, USA
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  • Nancy Foldvary-Schaefer DO,

    1. Department of Molecular Medicine, CCLCM of Case Western Reserve University, Cleveland, Ohio, USA
    2. Center for Sleep Medicine, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA
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  • William G. Ondo MD,

    Corresponding author
    1. Department of Neurology, Baylor College of Medicine, Houston, Texas, USA
    • Department of Neurology, Baylor College of Medicine, Houston, TX
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  • Qing Kenneth Wang PhD, MBA

    Corresponding author
    1. Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Center for Human Genome Research, Huazhong University of Science and Technology, Wuhan, People's Republic of China
    2. Department of Molecular Cardiology, Center for Cardiovascular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA
    3. Department of Molecular Medicine, CCLCM of Case Western Reserve University, Cleveland, Ohio, USA
    4. Center for Sleep Medicine, Neurological Institute, Cleveland Clinic, Cleveland, Ohio, USA
    • Center for Cardiovascular Genetics/NE40, Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH 44195
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  • Relevant conflicts of interest/financial disclosures: Dr. N. Foldvary receives research support from Glaxo Smith Kline, Inc., and Dr. W.G. Ondo is a speaker and consultant for Glaxo Smith Kline, Inc., Allergan, Ipsen, TEVA, Lundbeck, and Novartis. Other authors report no disclosures. Full financial disclosures and author roles may be found in the online version of this article.

Abstract

Objective:

We previously mapped a genetic locus for restless legs syndrome (RLS) to chromosome 9p22-24 (RLS3) and a later genome-wide association study (GWAS) implicated the PTPRD gene at the RLS3 locus as a susceptibility gene for RLS. However, from the standpoint of genetics, the GWAS association needs to be validated by independent studies. In this study, we used both family-based and population-based association studies to assess the association between PTPRD and RLS in an American Caucasian population.

Methods:

We genotyped two intronic SNPs rs1975197 and rs4626664 in PTPRD in 144 family members from 15 families and a case control cohort of 189 patients and 560 controls. Direct DNA sequence analysis was used to screen coding exons and exon-intron boundaries of PTPRD for rare mutations.

Results:

A family-based sibling transmission disequilibrium test showed association of RLS with SNP rs1975197 (P = 0.015), but not with rs4626664 (P = 0.622). The association with rs1975197 was significantly replicated by a population-based case control association study (allelic P = 0.0004, odds ratio = 1.68; genotypic P = 0.0013 and 0.0003 for an additive and dominant model, respectively). One rare p.E1639D variant was identified in exon 39 in kindred RLS40005. The rare D1639 allele did not co-segregate with RLS in the family, suggesting that p.E1639D variant is not a causative mutation.

Conclusions:

This represents the first independent study to validate the association between PTPRD variants and RLS. Both family-based and population-based association studies suggest that PTPRD variant rs1975197 confers risk of RLS. © 2011 Movement Disorder Society

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