与快速眼动睡眠行为障碍相关的新关联。
Novel Associations of and With REM Sleep Behavior Disorder.
机构信息
From the Department of Human Genetics (K.M., E.Y., U.R., L.K., G.A.R., Z.G.-O.), Montreal Neurological Institute (K.M., E.Y., U.R., L.K., J.A.R., F.A., S.B.L., D.S., G.A.R., R.B.P., Z.G.-O.), Department of Neurology and Neurosurgery (J.A.R., F.A., S.B.L., D.S., G.A.R., R.B.P., Z.G.-O.), Centre de Recherche en Biologie Structurale (J.-F.T.), and Department of Pharmacology and Therapeutics (J.-F.T.), McGill University, Montréal, Quebec, Canada; Sleep Disorders Unit (I.A.), Pitié Salpêtrière Hospital, Paris Brain Institute and Sorbonne University, France; Oxford Parkinson's Disease Centre (OPDC) (M.T.M.H.) and Nuffield Department of Clinical Neurosciences (M.T.M.H.), University of Oxford, UK; Center for Advanced Research in Sleep Medicine (J.Y.M., J.-F.G., A.D., R.B.P.), Centre Intégré Universitaire de Santé et de Services Sociaux du Nord-de-l'Île-de-Montréal-Hôpital du Sacré-Coeur de Montréal; Departments of Psychiatry (J.Y.M.) and Neurosciences (A.D.), Université de Montréal; Department of Psychology (J.-F.G.), Université du Québec à Montréal, Canada; National Reference Center for Narcolepsy (Y.D.), Sleep Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm U1061, France; Clinical Neurology Unit (G.L.G., M.V., F.J., A.B.), Department of Neurosciences, University Hospital of Udine; DMIF (G.L.G.) and Department of Medicine (DAME) (M.V.), University of Udine, Italy; Sleep Disorders Clinic (B.H., A.S., E.H.), Department of Neurology, Medical University of Innsbruck, Austria; Department of Neurology (K.S., D.K.) and Centre of Clinical Neuroscience (K.S., D.K.), Charles University, First Faculty of Medicine and General University Hospital, Prague, Czech Republic; Department of Neurology (W.O., A.J., F.S.-D.), Philipps University, Marburg, Germany; Department of Biomedical, Metabolic and Neural Sciences (G.P.), University of Modena and Reggio-Emilia; IRCCS (G.P.), Institute of Neurological Sciences of Bologna; Neurology Unit (E.A.), Movement Disorders Division, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona; Department of Medical Sciences and Public Health (M.F., M.P.), Sleep Disorder Research Center, University of Cagliari, Italy; Paracelsus-Elena-Klinik (B.M., C.T., F.S.-D.), Kassel; Department of Neurosurgery (B.M., C.T.), University Medical Centre Göttingen, Germany; Sleep and Neurology Unit (V.C.D.C.), Beau Soleil Clinic; EuroMov Digital Health in Motion (V.C.D.C.), University of Montpellier IMT Mines Ales; University Lille North of France (C.C.M.), Department of Clinical Neurophysiology and Sleep Center, CHU Lille; Department of Sleep Medicine and Neuromuscular Disorders (A.H.), University of Müenster, Germany; Department of Neurological Sciences (L.F.-S.), Università Vita-Salute San Raffaele, Milan, Italy; Laboratory for Sleep Disorders (F.D., M.V.) and Department of Neurology (F.D., M.V.), St. Dimpna Regional Hospital, Geel; Department of Neurology (F.D.), University Hospital Antwerp, Edegem, Belgium; Sleep Disorder Unit (B.A.), Carémeau Hospital, University Hospital of Nîmes, France; and Department of Neurology (B.F.B.), Mayo Clinic, Rochester, MN.
出版信息
Neurology. 2021 Mar 9;96(10):e1402-e1412. doi: 10.1212/WNL.0000000000011464. Epub 2021 Jan 4.
OBJECTIVE
To examine the role of genes identified through genome-wide association studies (GWASs) of Parkinson disease (PD) in the risk of isolated REM sleep behavior disorder (iRBD).
METHODS
We fully sequenced 25 genes previously identified in GWASs of PD in a total of 1,039 patients with iRBD and 1,852 controls. The role of rare heterozygous variants in these genes was examined with burden tests. The contribution of biallelic variants was further tested. To examine the potential effect of rare nonsynonymous variants on the protein structure, we performed in silico structural analysis. Finally, we examined the association of common variants using logistic regression adjusted for age and sex.
RESULTS
We found an association between rare heterozygous nonsynonymous variants in and iRBD ( = 0.0003 at coverage >50× and 0.0004 at >30×), driven mainly by 3 nonsynonymous variants (p.V85M, p.I101V, and p.V272M) found in 22 (1.2%) controls vs 2 (0.2%) patients. All 3 variants seem to be loss-of-function variants with a potential effect on the protein structure and stability. Rare noncoding heterozygous variants in were also associated with iRBD ( = 0.0006 at >30×). We found no association between rare heterozygous variants in the rest of genes and iRBD. Several carriers of biallelic variants were identified, yet there was no overrepresentation in iRBD.
CONCLUSION
Our results suggest that rare coding variants in and rare noncoding variants in are associated with iRBD. Additional studies are required to replicate these results and to examine whether loss of function of could be a therapeutic target.
目的
探讨全基因组关联研究（GWAS）鉴定的帕金森病（PD）相关基因在孤立性 REM 睡眠行为障碍（iRBD）风险中的作用。
方法
我们对 1039 例 iRBD 患者和 1852 例对照者进行了 25 个先前在 PD GWAS 中鉴定的基因的全外显子测序。使用负担测试来检查这些基因中罕见杂合变异的作用。进一步测试双等位基因变异的贡献。为了研究罕见非同义变异对蛋白质结构的潜在影响，我们进行了计算机结构分析。最后，我们使用调整年龄和性别的逻辑回归检验常见变异的关联。
结果
我们发现 中的罕见杂合非同义变异与 iRBD 之间存在关联（覆盖度>50×时为 0.0003，覆盖度>30×时为 0.0004），主要由 22 例对照者（1.2%）而非 2 例患者（0.2%）中发现的 3 个非同义变异（p.V85M、p.I101V 和 p.V272M）驱动。所有 3 个变异似乎都是功能丧失型变异，可能对蛋白质结构和稳定性有影响。 中的罕见非编码杂合变异也与 iRBD 相关（覆盖度>30×时为 0.0006）。我们没有发现其余基因中的罕见杂合变异与 iRBD 之间的关联。尽管鉴定出了几个双等位基因变异的携带者，但 iRBD 中没有过度表达。
结论
我们的研究结果表明， 中的罕见编码变异和 中的罕见非编码变异与 iRBD 相关。需要进一步的研究来复制这些结果，并研究 是否丧失功能可能成为治疗靶点。
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