PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome

Schormair, Barbara; Kemlink, David; Roeske, D.; Eckstein, Gertrud; Xiong, Lan; Lichtner, Peter; Ripke, Stephan; Trenkwalder, Claudia; Zimprich, Alexander; Stiasny‐Kolster, Karin; Oertel, Wolfgang H.; Bachmann, Cornelius G.; Paulus, Walter; Högl, Birgit; Frauscher, Birgit; Gschliesser, Viola; Poewe, Werner; Peglau, Ines; Vodička, Pavel; Vávrová, Jana; Šonka, Karel; Nevšímalová, Soňa; Montplaisir, Jacques; Turecki, Gustavo; Rouleau, Guy A.; Gieger, Christian; Illig, Thomas; Wichmann, H‐Erich; Holsboer, Florian; Müller‐Myhsok, Bertram; Meitinger, Thomas; Winkelmann, Juliane

doi:10.1038/ng.190

Cited by 251 publications

(204 citation statements)

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“…33,34 Intriguingly, a recent genome-wide association study has implicated PTPRD as a locus for RLS. 35 Moreover, genetic variants of PTPRD associate with bronchial asthma, 36 which is reported to occur at higher rates in children with ADHD, 37 and RLS patients have been shown to have increased use of asthma medications. 38 Studies of the PTPRD gene in mice show high expression in the hippocampus, the only brain region reported to be enlarged in ADHD, 39 along with involvement in spatial learning, long-term potentiation and axonal guidance of motor neurons.…”

Section: Resultsmentioning

confidence: 99%

Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes

et al. 2009

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Attention-deficit/hyperactivity disorder (ADHD) is a common and highly heritable disorder, but specific genetic factors underlying risk remain elusive. To assess the role of structural variation in ADHD, we identified 222 inherited copy number variations (CNVs) within 335 ADHD patients and their parents that were not detected in 2026 unrelated healthy individuals. Although no excess CNVs, either deletions or duplications, were found in the ADHD cohort relative to controls, the inherited rare CNV-associated gene set was significantly enriched for genes reported as candidates in studies of autism, schizophrenia and Tourette syndrome, including A2BP1, AUTS2, CNTNAP2 and IMMP2L. The ADHD CNV gene set was also significantly enriched for genes known to be important for psychological and neurological functions, including learning, behavior, synaptic transmission and central nervous system development. Four independent deletions were located within the protein tyrosine phosphatase gene, PTPRD, recently implicated as a candidate gene for restless legs syndrome, which frequently presents with ADHD. A deletion within the glutamate receptor gene, GRM5, was found in an affected parent and all three affected offspring whose ADHD phenotypes closely resembled those of the GRM5 null mouse. Together, these results suggest that rare inherited structural variations play an important role in ADHD development and indicate a set of putative candidate genes for further study in the etiology of ADHD.

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Section: Resultsmentioning

confidence: 99%

Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes

et al. 2009

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“…4 RLS also has a considerable heritability and is associated with multiple genetic risk factors. Genome-wide association studies [5][6][7][8][9][10] identified variants in six loci encompassing the genes MEIS1, BTBD9, MAP2K5/SKOR1, PTPRD, and TOX3/non-coding RNA.…”

Section: Introductionmentioning

confidence: 99%

Dilution of candidates: the case of iron-related genes in restless legs syndrome

et al. 2012

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Restless legs syndrome (RLS) is a common multifactorial disease. Some genetic risk factors have been identified. RLS susceptibility also has been related to iron. We therefore asked whether known iron-related genes are candidates for association with RLS and, vice versa, whether known RLS-associated loci influence iron parameters in serum. RLS/control samples (n ¼ 954/1814 in the discovery step, 735/736 in replication 1, and 736/735 in replication 2) were tested for association with SNPs located within 4 Mb intervals surrounding each gene from a list of 111 iron-related genes using a discovery threshold of P ¼ 5 Â 10 À4 . Two population cohorts (KORA F3 and F4 with together n ¼ 3447) were tested for association of six known RLS loci with iron, ferritin, transferrin, transferrin-saturation, and soluble transferrin receptor. Results were negative. None of the candidate SNPs at the iron-related gene loci was confirmed significantly. An intronic SNP, rs2576036, of KATNAL2 at 18q21.1 was significant in the first (P ¼ 0.00085) but not in the second replication step (joint nominal P-value ¼ 0.044). Especially, rs1800652 (C282Y) in the HFE gene did not associate with RLS. Moreover, SNPs at the known RLS loci did not significantly affect serum iron parameters in the KORA cohorts. In conclusion, the correlation between RLS and iron parameters in serum may be weaker than assumed. Moreover, in a general power analysis, we show that genetic effects are diluted if they are transmitted via an intermediate trait to an end-phenotype. Sample size formulas are provided for small effect sizes. Keywords: restless legs syndrome; iron parameters; MEIS1 haplotype; power calculation; linear regression; logistic regression INTRODUCTIONRestless legs syndrome (RLS) 1 is a sensory-motor disorder characterized by an urge to move and unpleasant sensations in the lower limbs at rest. In Caucasians, RLS is present in up to 10% of the population. 2,3 Pregnancy, uremia, celiac disease, and iron deficiency are considered to be risk factors. 4 RLS also has a considerable heritability and is associated with multiple genetic risk factors. Genome-wide association studies 5-10 identified variants in six loci encompassing the genes MEIS1, BTBD9, MAP2K5/SKOR1, PTPRD, and TOX3/non-coding RNA.Aiming for the identification of further genetic risk factors of RLS, we addressed the apparent relation of RLS susceptibility to iron metabolism and iron availability 11 that has been explained by cerebral iron being crucial in the etiology of RLS. 12 We therefore tested the SNPs at the loci of a candidate set of genes known to be involved in iron metabolism for association with RLS. Vice versa, we asked whether RLS genes are involved in iron metabolism because the RLSassociated SNP rs3923809 at the BTBD9 locus has previously been reported to be associated with the serum level of ferritin in a study on RLS subjects and their relatives. 6

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“…Additional risk variants have been identifi ed recently, consisting of two single nucleotide polymorphisms (SNPs) expressed in the pro tein tyrosine phosphatase, receptor type, D ( PTPRD ) gene, a gene involved with neuronal development that may also provide a possible functional association. 27 The importance of these studies is that they point toward a molecular mechanism for this condition. Little is known at this time about the exact function of most of these genes and how they play a role in the development of RLS/PLMS.…”

Section: Restless Legs Syndrome and Periodic Limb Movements In Sleepmentioning

confidence: 99%

Genetic and Immunologic Aspects of Sleep and Sleep Disorders

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2013

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PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome

Cited by 251 publications

References 15 publications

Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes

Rare structural variants found in attention-deficit hyperactivity disorder are preferentially associated with neurodevelopmental genes

Dilution of candidates: the case of iron-related genes in restless legs syndrome

Genetic and Immunologic Aspects of Sleep and Sleep Disorders

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