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Large genome-wide association study identifies three novel risk variants for restless legs syndrome.

ABSTRACT: Restless legs syndrome (RLS) is a common neurological sensorimotor disorder often described as an unpleasant sensation associated with an urge to move the legs. Here we report findings from a meta-analysis of genome-wide association studies of RLS including 480,982 Caucasians (cases?=?10,257) and a follow up sample of 24,977 (cases?=?6,651). We confirm 19 of the 20 previously reported RLS sequence variants at 19 loci and report three novel RLS associations; rs112716420-G (OR?=?1.25, P?=?1.5?×?10^-18), rs10068599-T (OR?=?1.09, P?=?6.9?×?10^-10) and rs10769894-A (OR?=?0.90, P?=?9.4?×?10^-14). At four of the 22 RLS loci, cis-eQTL analysis indicates a causal impact on gene expression. Through polygenic risk score for RLS we extended prior epidemiological findings implicating obesity, smoking and high alcohol intake as risk factors for RLS. To improve our understanding, with the purpose of seeking better treatments, more genetics studies yielding deeper insights into the disease biology are needed.

SUBMITTER: Didriksen M

PROVIDER: S-EPMC7689502 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Large genome-wide association study identifies three novel risk variants for restless legs syndrome.

Didriksen Maria M Nawaz Muhammad Sulaman MS Dowsett Joseph J Bell Steven S Erikstrup Christian C Pedersen Ole B OB Sørensen Erik E Jennum Poul J PJ Burgdorf Kristoffer S KS Burchell Brendan B Butterworth Adam S AS Soranzo Nicole N Rye David B DB Trotti Lynn Marie LM Saini Prabhjyot P Stefansdottir Lilja L Magnusson Sigurdur H SH Thorleifsson Gudmar G Sigmundsson Thordur T Sigurdsson Albert P AP Van Den Hurk Katja K Quee Franke F Tanck Michael W T MWT Ouwehand Willem H WH Roberts David J DJ Earley Eric J EJ Busch Michael P MP Mast Alan E AE Page Grier P GP Danesh John J Di Angelantonio Emanuele E Stefansson Hreinn H Ullum Henrik H Stefansson Kari K

Communications biology 20201125 1

Restless legs syndrome (RLS) is a common neurological sensorimotor disorder often described as an unpleasant sensation associated with an urge to move the legs. Here we report findings from a meta-analysis of genome-wide association studies of RLS including 480,982 Caucasians (cases = 10,257) and a follow up sample of 24,977 (cases = 6,651). We confirm 19 of the 20 previously reported RLS sequence variants at 19 loci and report three novel RLS associations; rs112716420-G (OR = 1.25, P = 1.5 × 10 ...[more]

PMID: 33239738

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Project description:ImportanceRestless legs syndrome is a common neurologic disorder that is more prevalent in women than in men, and it has been suggested that female hormones may be involved in the disorder's pathophysiology.ObjectiveTo determine whether women who underwent premenopausal bilateral oophorectomy were at increased risk of restless legs syndrome.Design, setting, and participantsThis cohort study was performed using data from the Mayo Clinic Cohort Study of Oophorectomy and Aging-2 for a population in Olmsted County, Minnesota. There were 1653 women who underwent premenopausal bilateral oophorectomy before the age of 50 years for a benign indication between 1988 and 2007 and 1653 age-matched women (of same age plus or minus 1 year) in a reference group. Follow-up was conducted until the end of the study period (ie, December 31, 2014). Data were analyzed from January to July 2020.ExposuresUndergoing bilateral oophorectomy, as shown in medical record documentation.Main outcomes and measuresDiagnosis of restless legs syndrome, as defined using Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) criteria, was recorded.ResultsAmong 3306 women, the median (interquartile range) age at baseline was 44.0 (40.0-47.0) years. Women who underwent bilateral oophorectomy, compared with women who did not undergo this procedure, had a greater number of chronic conditions at the index date (eg, 300 women [18.1%] vs 171 women [10.3%] with ≥3 chronic conditions; overall P < .001), were more likely to have obesity (576 women [34.8%] vs 442 women [27.1%]; overall P < .001), and were more likely to have a history of anemia of any type (573 women [34.7%] vs 225 women [13.6%]; P < .001), iron deficiency anemia (347 women [21.0%] vs 135 women [8.2%]; P < .001), and restless legs syndrome before the index date (32 women [1.9%] vs 14 women [0.8%]; P = .008). Women who underwent bilateral oophorectomy prior to natural menopause had a higher risk of restless legs syndrome after the index date compared with women in the reference group (120 diagnoses vs 74 diagnoses), with an adjusted hazard ratio (HR) of 1.44 (95% CI, 1.08-1.92; P = .01). After stratification by indication for the bilateral oophorectomy, there was an increased risk of restless legs syndrome among women without a benign ovarian condition (HR, 1.52; 95% CI, 1.03-2.25; P = .04) but not among women with a benign condition (HR, 1.25; 95% CI, 0.80-1.96; P = .34). Treatment with estrogen therapy through the age of 46 years in women who underwent bilateral oophorectomy at younger ages was not associated with a difference in risk.Conclusions and relevanceThis cohort study found that risk of restless legs syndrome was increased among women who underwent bilateral oophorectomy prior to menopause, especially those without a benign ovarian indication.

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Large genome-wide association study identifies three novel risk variants for restless legs syndrome.

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Large genome-wide association study identifies three novel risk variants for restless legs syndrome.

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