A Genome-Wide Association Study Identifies  UTRN  Gene Polymorphism for Restless Legs Syndrome in a Korean Population

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Abstract

Objective

Restless legs syndrome (RLS) is a highly heritable and common neurological sensorimotor disease disturbing sleep. The objective of study was to investigate significant gene for RLS by performing GWA and replication study in a Korean population.

Methods

We performed a GWA study for RLS symptom group (n=325) and non-RLS group (n=2,603) from the Korea Genome Epidemiology Study. We subsequently performed a replication study in RLS and normal controls (227 RLS and 229 controls) to confirm the present GWA study findings as well as previous GWA study results.

Results

In the initial GWA study of RLS, we observed an association of rs11645604 (OR=1.531, p=1.18×10 ⁻⁶) in MPHOSPH6 on chromosome 16q23.3, rs1918752 (OR=0.6582, p=1.93×10 ⁻⁶) and rs9390170 (OR=0.6778, p=7.67×10 ⁻⁶) in UTRN on chromosome 6q24. From the replication samples, we found rs9390170 in UTRN (p=0.036) and rs3923809 and rs9296249 in BTBD9 (p=0.045, p=0.046, respectively) were significantly associated with RLS. Moreover, we found the haplotype polymorphisms of rs9357271, rs3923809, and rs9296249 (overall p=5.69×10 ⁻¹⁸) in BTBD9 was associated with RLS.

Conclusion

From our sequential GWA and replication study, we could hypothesize rs9390170 polymorphism in UTRN is a novel genetic marker for susceptibility to RLS. Regarding with utrophin, which is encoded by UTRN, is preferentially expressed in the neuromuscular synapse and myotendinous junctions, we speculate that utrophin is involved in RLS, particularly related to the neuromuscular aspects.

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Most cited references 22

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Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health.

Richard Allen, Daniel Picchietti, Wayne Hening … (2003)

Restless legs syndrome is a common yet frequently undiagnosed sensorimotor disorder. In 1995, the International Restless Legs Syndrome Study Group developed standardized criteria for the diagnosis of restless legs syndrome. Since that time, additional scientific scrutiny and clinical experience have led to a better understanding of the condition. Modification of the criteria is now necessary to better reflect that increased body of knowledge, as well as to clarify slight confusion with the wording of the original criteria. The restless legs syndrome diagnostic criteria and epidemiology workshop at the National Institutes of Health. Members of the International Restless Legs Syndrome Study Group and authorities on epidemiology and the design of questionnaires and scales. To modify the current criteria for the diagnosis of restless legs syndrome, to develop new criteria for the diagnosis of restless legs syndrome in the cognitively impaired elderly and in children, to create standardized criteria for the identification of augmentation, and to establish consistent questions for use in epidemiology studies. The essential diagnostic criteria for restless legs syndrome were developed and approved by workshop participants and the executive committee of the International Restless Legs Syndrome Study Group. Criteria were also developed and approved for the additional aforementioned groups.

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Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions.

Florian Holsboer, Claudia Trenkwalder, Bertram Müller-Myhsok … (2007)

Restless legs syndrome (RLS) is a frequent neurological disorder characterized by an imperative urge to move the legs during night, unpleasant sensation in the lower limbs, disturbed sleep and increased cardiovascular morbidity. In a genome-wide association study we found highly significant associations between RLS and intronic variants in the homeobox gene MEIS1, the BTBD9 gene encoding a BTB(POZ) domain as well as variants in a third locus containing the genes encoding mitogen-activated protein kinase MAP2K5 and the transcription factor LBXCOR1 on chromosomes 2p, 6p and 15q, respectively. Two independent replications confirmed these association signals. Each genetic variant was associated with a more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk. MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder.

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A genetic risk factor for periodic limb movements in sleep.

Hreinn Stefansson, David B. Rye, Andrew Hicks … (2007)

The restless legs syndrome (RLS) is a common neurologic disorder characterized by an irresistible urge to move the legs. It is a major cause of sleep disruption. Periodic limb movements in sleep are detectable in most patients with RLS and represent an objective physiological metric. To search for sequence variants contributing to RLS, we performed a genomewide association study and two replication studies. To minimize phenotypic heterogeneity, we focused on patients with RLS who had objectively documented periodic limb movements in sleep. We measured serum ferritin levels, since iron depletion has been associated with the pathogenesis of RLS. In an Icelandic discovery sample of patients with RLS and periodic limb movements in sleep, we observed a genomewide significant association with a common variant in an intron of BTBD9 on chromosome 6p21.2 (odds ratio, 1.8; P=2x10(-9)). This association was replicated in a second Icelandic sample (odds ratio, 1.8; P=4x10(-4)) and a U.S. sample (odds ratio, 1.5; P=4x10(-3)). With this variant, the population attributable risk of RLS with periodic limb movements was approximately 50%. An association between the variant and periodic limb movements in sleep without RLS (and the absence of such an association for RLS without periodic limb movements) suggests that we have identified a genetic determinant of periodic limb movements in sleep (odds ratio, 1.9; P=1x10(-17)). Serum ferritin levels were decreased by 13% per allele of the at-risk variant (95% confidence interval, 5 to 20; P=0.002). We have discovered a variant associated with susceptibility to periodic limb movements in sleep. The inverse correlation of the variant with iron stores is consistent with the suspected involvement of iron depletion in the pathogenesis of the disease. Copyright 2007 Massachusetts Medical Society.

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Author and article information

Journal

Journal ID (nlm-ta): Psychiatry Investig

Journal ID (iso-abbrev): Psychiatry Investig

Journal ID (publisher-id): PI

Title: Psychiatry Investigation

Publisher: Korean Neuropsychiatric Association

ISSN (Print): 1738-3684

ISSN (Electronic): 1976-3026

Publication date (Print): November 2017

Publication date (Electronic): 07 November 2017

Volume: 14

Issue: 6

Pages: 830-838

Affiliations

[1 ]Department of Psychiatry, Korea University College of Medicine, Seoul, Republic of Korea.

[2 ]Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea.

[3 ]Department of Psychiatry, School of Medicine, Gachon University, Incheon, Republic of Korea.

[4 ]Department of Psychiatry, Inje University, Ilsan Paik Hospital, Goyang, Republic of Korea.

[5 ]Department of Neurology, Seoul University College of Medicine, Seoul, Republic of Korea.

[6 ]Seoul Sleep Center, Seoul, Republic of Korea.

[7 ]Kosleep Clinic, Seoul, Republic of Korea.

[8 ]Broad Institute of MIT and Harvard, Cambridge, MA, USA.

[9 ]Department of Neurology, Korea University College of Medicine, Seoul, Republic of Korea.

Author notes

Correspondence: Hyun Goo Woo, MD, PhD. Department of Physiology, Ajou University School of Medicine, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Republic of Korea. Tel: +82-31-219-5045, Fax: +82-31-219-5049, hg@ 123456ajou.ac.kr

Correspondence: Heon-Jeong Lee, MD, PhD. Department of Psychiatry, Anam Hospital, Korea University College of Medicine, 73 Inchon-ro, Seongbuk-gu, Seoul 02841, Republic of Korea. Tel: +82-2-920-5815, Fax: +82-2-929-7679, leehjeong@ 123456korea.ac.kr

^*These authors contributed equally to this work.

Article

DOI: 10.4306/pi.2017.14.6.830

PMC ID: 5714726

SO-VID: 60febe26-2b21-44c3-9861-8c432624a272

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 02 January 2017

Date revision received : 07 August 2017

Date accepted : 15 August 2017

Funding

Funded by: Center for Disease Control and Prevention;

Award ID: 4845-301

Award ID: 4851-302

Award ID: 4851-307

Award ID: KBP-2013-000

Funded by: National Research Foundation of Korea, CrossRef http://dx.doi.org/10.13039/501100003725;

A Genome-Wide Association Study Identifies UTRN Gene Polymorphism for Restless Legs Syndrome in a Korean Population

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Abstract

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New Psychiatry

Most cited references 22

Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health.

Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions.

A genetic risk factor for periodic limb movements in sleep.

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