PT651. The role of Ca2+-dependent hyperpolarization pathway underlying sleep homeostasis

Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible urge to move the legs during night, unpleasant sensation in the lower limbs, and disturbed sleep. To search sequence variations contributing to RLS, we performed a genome-wide association study (GWAS) in the population dataset from the Korea Association Resource (KARE) project collected the Ansung and Ansan cohorts. We conducted a GWAS for RLS symptom group (n=325) which has at least one of 4 basic criteria of RLS and controls (n=2,603) using 352,228 SNPs. We observed rs11645604 (odds ratio = 1.531; P = 1.18 x 10–6) in MPHOSPH6 on chromosome 16q23.3, rs1918752 (odds ratio = 0.6582; P = 1.93 x 10–6) and rs9390170 (odds ratio = 0.6778; P = 7.67 x 10–6) in UTRN on chromosome 6q24. And we performed a replication study in our own RLS sample to reconfirm our GWAS finding as well as previous GWAS results. We selected several candidate SNPs in MPHOSPH6 and UTRN according to our GWAS results, as well in MEIS1, BTBD9, and PTPRD according to previous GWAS results. We found the most significant of which was rs9390170 in UTRN (odds ratio = 1.6121; P = 0.0379) in the recessive model and rs3923809 in BTBD9 (odds ratio = 1.3136; P = 0.044) in the allele model from case-control association analysis on 228 RLS cases and 229 controls. And rs6710341/ rs2300478 in MEIS1 showed significant finding (overall P = 1.15 x 10–6; permutation P = 0) from case-control haplotype analysis. In this study, we reconfirmed rs3923809 in BTBD9 and rs6710341/ rs2300478 in MEIS1 as significant sequence variations contributing RLS. In addition, we found the possibility of novel sequence variation which is rs9390170 in UTRN. UTRN encodes dystrophin-related protein 1, and its known function is related to neuromuscular system. Keyword: genome-wide association study, restless legs syndrome, replication study, UTRN PT651 The role of Ca2+-dependent hyperpolarization pathway underlying sleep homeostasis Shoi Shi1, Koji L Ode1, Hiroki R. Ueda1,2 1 Department of Systems Pharmacology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan, 2 Laboratory for Synthetic Biology, RIKEN Quantitative Biology Center, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe, Hyogo 650-