迟发性帕金森病常见及罕见变异分析
Analysis of common and rare variants in late-onset Parkinson disease.
作者信息
Rudakou Uladzislau, Ruskey Jennifer A, Krohn Lynne, Laurent Sandra B, Spiegelman Dan, Greenbaum Lior, Yahalom Gilad, Desautels Alex, Montplaisir Jacques Y, Fahn Stanley, Waters Cheryl H, Levy Oren, Kehoe Caitlin M, Narayan Sushma, Dauvilliers Yves, Dupré Nicolas, Hassin-Baer Sharon, Alcalay Roy N, Rouleau Guy A, Fon Edward A, Gan-Or Ziv
机构信息
Department of Human Genetics (U.R., L.K., G.A.R, Z.G.-O.), McGill University, Montréal; Montreal Neurological Institute (U.R., J.A.R., L.K., S.B.L., D.S., G.A.R., E.A.F.Z.G.-O.), McGill University; Department of Neurology and Neurosurgery (J.A.R., S.B.L., D.S., G.A.R., E.A.F., Z.G.-O.), McGill University, Montréal, Québec, Canada; The Danek Gertner Institute of Human Genetics, Sheba Medical Center (L.G.); The Joseph Sagol Neuroscience Center (L.G., S.H.-B.), Sheba Medical Center, Tel Hashomer, Ramat Gan; Sackler School of Medicine (L.G., G.Y., S.H.-B.), Tel-Aviv University; Department of Neurology (G.Y., S.H.-B.), Sheba Medical Center; Movement Disorders Institute (G.Y., S.H.-B.), Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel; Centre d'Études Avancées en Médecine du Sommeil (A.D., J.Y.M.), Hôpital du Sacré-Cœur de Montréal; Department of Neurosciences (A.D.), Université de Montréal; Department of Psychiatry (J.Y.M.), Université de Montréal, Québec, Canada; Department of Neurology (S.F., C.H.W., O.L., C.M.K., S.N., R.N.A.), College of Physicians and Surgeons, Columbia University Medical Center, New York; Department of Neurology (Y.D.), National Reference Center for Narcolepsy, Sleep Unit, Gui-de-Chauliac Hospital, CHU Montpellier, University of Montpellier, Inserm, France; Division of Neurosciences (N.D.), CHU de Québec, Université Laval; Department of Medicine (N.D.), Faculty of Medicine, Université Laval, Québec City, Canada; and Taub Institute for Research on Alzheimer's Disease and the Aging Brain (R.N.A.), College of Physicians and Surgeons, Columbia University Medical Center, New York.
出版信息
Neurol Genet. 2020 Jan 9;6(1):385. doi: 10.1212/NXG.0000000000000385. eCollection 2020 Feb.
OBJECTIVE
We aimed to study the role of coding variants in a large cohort of patients with late-onset Parkinson disease (PD) (LOPD).
METHODS
and its untranslated regions were sequenced using targeted next-generation sequencing in 1,567 patients with PD and 1,667 controls from 3 cohorts. Association tests of rare potential homozygous and compound heterozygous variants and burden tests for rare heterozygous variants were performed. Common variants were analyzed using logistic regression adjusted for age and sex in each of the cohorts, followed by a meta-analysis.
RESULTS
No biallelic carriers of rare variants were found among patients, and 2 carriers of compound heterozygous variants were found in 2 controls. There was no statistically significant burden of rare (minor allele frequency [MAF] <1%) or very rare (MAF <0.1%) coding variants in PD. A haplotype including the p.R153H-p.I398I-p.I1132V-p.Q2376Q variants was nominally associated with a reduced risk for PD (meta-analysis of the tagging SNP p.I1132V [odds ratio = 0.48, 95% confidence interval = 0.28-0.82, = 0.0052]). This haplotype was not in linkage disequilibrium with the known genome-wide association study top hit.
CONCLUSIONS
Our results do not support a role for rare heterozygous or biallelic variants in LOPD. Additional genetic replication and functional studies are needed to examine the role of the haplotype identified here associated with reduced risk for PD.
目的
我们旨在研究编码变异在一大群晚发性帕金森病（LOPD）患者中的作用。
方法
对来自3个队列的1567例帕金森病患者和1667例对照进行靶向二代测序，以对其编码区及其非翻译区进行测序。进行罕见潜在纯合和复合杂合变异的关联测试以及罕见杂合变异的负荷测试。在每个队列中，使用经年龄和性别校正的逻辑回归分析常见变异，随后进行荟萃分析。
结果
在患者中未发现罕见变异的双等位基因携带者，在2例对照中发现2例复合杂合变异携带者。帕金森病中罕见（次要等位基因频率[MAF]<1%）或极罕见（MAF<0.1%）编码变异没有统计学上显著的负荷。一个包括p.R153H-p.I398I-p.I1132V-p.Q2376Q变异的单倍型名义上与帕金森病风险降低相关（标签单核苷酸多态性p.I1132V的荟萃分析[比值比=0.48，95%置信区间=0.28-0.82，P=0.0052]）。该单倍型与已知的全基因组关联研究最显著位点不存在连锁不平衡。
结论
我们的结果不支持罕见杂合或双等位基因变异在晚发性帕金森病中的作用。需要进一步的基因复制和功能研究来检验此处鉴定的与帕金森病风险降低相关的单倍型的作用。
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