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

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A Genome-Wide Association Study Identifies UTRN Gene Polymorphism for Restless Legs Syndrome in a Korean Population ORIGINAL ARTICLE Print ISSN 1738-3684 / On-line ISSN 1976-3026 https://doi.org/10.4306/pi.2017.14.6.830 OPEN ACCESS A Genome-Wide Association Study Identifies UTRN Gene Polymorphism for Restless Legs Syndrome in a Korean Population Chul-Hyun Cho1*, Ji-Hye Choi2*, Seung-Gul Kang3, Ho-Kyoung Yoon1, Young-Min Park4, Joung-Ho Moon1, Ki-Young Jung5, Jin-Kyu Han6, Hong-Bum Shin7, Hyun Ji Noh8, Yong Seo Koo9, Leen Kim1, Hyun Goo Woo2 , and Heon-Jeong Lee1 1Department of Psychiatry, Korea University College of Medicine, Seoul, Republic of Korea 2Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea 3Department of Psychiatry, School of Medicine, Gachon University, Incheon, Republic of Korea 4Department of Psychiatry, Inje University, Ilsan Paik Hospital, Goyang, Republic of Korea 5Department of Neurology, Seoul University College of Medicine, Seoul, Republic of Korea 6Seoul Sleep Center, Seoul, Republic of Korea 7Kosleep Clinic, Seoul, Republic of Korea 8Broad Institute of MIT and Harvard, Cambridge, MA, USA 9Department of Neurology, Korea University College of Medicine, Seoul, Republic of Korea ObjectiveaaRestless legs syndrome (RLS) is a highly heritable and common neurological sensorimotor disease disturbing sleep. The ob- jective of study was to investigate significant gene for RLS by performing GWA and replication study in a Korean population. MethodsaaWe performed a GWA study for RLS symptom group (n=325) and non-RLS group (n=2,603) from the Korea Genome Epide- miology 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. ResultsaaIn the initial GWA study of RLS, we observed an association of rs11645604 (OR=1.531, p=1.18×10-6) in MPHOSPH6 on chro- mosome 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, respective- ly) 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. ConclusionaaFrom our sequential GWA and replication study, we could hypothesize rs9390170 polymorphism in UTRN is a novel ge- netic marker for susceptibility to RLS. Regarding with utrophin, which is encoded by UTRN, is preferentially expressed in the neuromus- cular synapse and myotendinous junctions, we speculate that utrophin is involved in RLS, particularly related to the neuromuscular as- pects. Psychiatry Investig 2017;14(6):830-838 Key Wordsaa Restless legs syndrome, Genome-wide association study, Replication study, Utrophin, UTRN. INTRODUCTION disease (WED), is a common neurological sensorimotor dis- ease that disables sensory and motor elements. RLS is diag- Restless legs syndrome (RLS), also known as Willis-Ekbom nosed by: 1) an urge to move the legs usually but not always Received: January 2, 2017 Revised: August 7, 2017 Accepted: August 15, 2017 Available online: October 17, 2017 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, E-mail: [email protected] 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, E-mail: [email protected] *These authors contributed equally to this work. cc 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. 830 Copyright © 2017 Korean Neuropsychiatric Association CH Cho et al. accompanied by or felt to be caused by uncomfortable and on BTBD9 in chromosome 6p, and one was on between unpleasant sensations in the legs; 2) the urge to move the legs MAP2K5 and LBXCOR1 on chromosome 15q. The same and any accompanying unpleasant sensations begin or wors- group also reported that PTPRD at 9p23-24 is associated with en during periods of rest or inactivity such as lying down or RLS through a GWA study.14 Stefansson et al.15 also reported sitting; 3) the urge to move the legs and any accompanying un- GWA study results demonstrating an association between RLS pleasant sensations are partially or totally relieved by move- and a locus on chromosome 6p in the fifth intron of BTBD9. ment, such as walking or stretching, at least as long as the activ- Recent GWA studies of RLS identified novel susceptibility loci ity continues; 4) the urge to move the legs and any accompanying on 2p14 and 16q12.1.16 unpleasant sensations during rest or inactivity only occur or Although there have been various genetic association stud- are worse in the evening or night than during the day; and 5) the ies of RLS from various ethnic groups, all of the GWA studies occurrence of the above features is not solely accounted for as of RLS were performed only in Caucasian populations. Be- symptoms primary to another medical or behavioral condition cause there are possible ethnic differences in genetic influ- (e.g., myalgia, venous stasis, leg edema, arthritis, leg cramps, ence, it would be advantageous to perform GWA studies of positional discomfort, habitual foot tapping).1 As a result, pa- RLS in ethnically diverse populations. tients with RLS often suffer from sleep initiation and main- We performed a GWA study of RLS to find susceptibility tenance disorders. A recent study in North American and genes for RLS in Korean cohort samples, and tried to replicate Western European populations reported that general preva- the results from our study as well as the previous GWA stud- lence rates of RLS ranged from 4% to 29% in adults.2 The prev- ies in Caucasian populations in the independent clinical sam- alence of RLS increases with age, and RLS is more common ples of RLS and non-RLS controls in a Korean population. among women than men.3 RLS has a negative impact on phys- ical as well as mental health, resulting in poor quality of life. In MetHods spite of these observations, the pathogenesis of RLS is not clearly understood. RLS is known to be associated with iron Subjects deficiency, and RLS pathologic studies have reported reduced Subjects for the GWA study were collected from the An- brain and cerebrospinal fluid iron and iron-associated pro- sung and Ansan cohorts of the Korea Association Resource teins.4 Genetic predisposition and dopaminergic dysfunction (KARE) project: 7,515 participants ranging in age from 40 are also thought to be underlying factors in RLS.5 RLS is re- to 69 years. These cohorts were investigated as part of the lieved by administration of dopamine agonists, which are cur- Korea Genome Epidemiology Study (KoGES). Epidemio- rently the best-studied therapeutic regimen. Dopaminergic logical information of the cohorts contains more than 260 agents, which were developed for Parkinson’s disease, have ef- traits, including demographic information, medical and fami- fect on RLS via unknown mode of action.6 Other treatments ly disease histories, health condition, and lifestyle such as sleep of RLS are also aimed at reducing symptoms and include pattern.17 We focused on RLS symptoms based on question- opioids, sedative hypnotics, anticonvulsants, and benzodiaze- naire results and medical history that may be related to RLS- pines.7 Unfortunately, there is currently no treatment of choice like symptoms such as diabetes mellitus, thyroid disease, kid- for curing RLS. Pharmacological, neuroimaging, and neuro- ney disease, and spinal cord disease. Written informed consent physiological studies suggest that the essential symptoms orig- and ethics committee approval had already been obtained in inate in the central nervous system, yet the underlying mecha- the process of establishing the KoGES.18 The RLS clinical sam- nism remains unclear.8 ples for the replication study were collected from multiple A familial inclination has been reported, particularly in centers including the Korea University Hospital Sleep Clinic early-onset RLS.9 More than 50% of RLS-affected subjects re- and two private sleep clinics in Seoul, South Korea. All the ported a family history of RLS,10 and the heritability of RLS subjects visited sleep clinics due to insomnia. Sleep specialists was reported in large and extended multiplex pedigrees (h2= (HJL, KYJ, JKH, or HBS) made diagnoses based on patients’ 0.6).11 The results of linkage analysis suggested six loci related signs and symptoms, medical and family histories, physical to recessive or dominant inheritance; 12q, 14q, 9p, 2q, 20p, exams, and test results. The sleep specialists ruled out other and 19p (RLS1-6, respectively), but no specific genes.12 There conditions that have symptoms similar to those of RLS. Sex- were two noteworthy genome-wide association (GWA) stud- and age-matched healthy controls were selected based on RLS ies showing an association of RLS with genetic components. symptom evaluation and medical and family histories. Writ- Winkelmann et al.13 reported GWA study results showing ge- ten informed consent from the patients and approval from nome-wide significant association between RLS and three ge- the Institutional Review Board (IRB) of Korea University netic loci: one was on MEIS1 within chromosome 2p, one was Hospital were obtained in the process of establishing the rep- www.psychiatryinvestigation.org 831 UTRN Gene for RLS lication study (IRB No. IEC107014). the evening or nighttime than during the day or only occur in the evening or night.6 Responders of the questionnaires were Genotyping and quality control divided into the RLS symptom group and non-RLS group, Genomic DNAs for the GWA study were extracted from whereas non-responders were categorized as the missing group.
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