Family-based and population-based association studies validate PTPRD as a risk factor for restless legs syndrome.
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.
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.
Qinbo
Q
Yang
Lin
L
Li
Rong
R
Yang
Gong-Qing
GQ
Shen
Qiuyun
Q
Chen
Nancy
N
Foldvary-Schaefer
William G
WG
Ondo
Qing Kenneth
QK
Wang
D016009:Chi-Square Distribution; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D015331:Cohort Studies; D018672:Community Health Planning; D005192:Family Health; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2 / Q000235:genetics*; D012148:Restless Legs Syndrome / Q000453:epidemiology* / Q000235:genetics*; D012307:Risk Factors
C090899:PTPRD protein, human; D054623:Receptor-Like Protein Tyrosine Phosphatases, Class 2
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