Beecham Gary W, Dickson Dennis W, Scott William K, Martin Eden R, Schellenberg Gerard, Nuytemans Karen, Larson Eric B, Buxbaum Joseph D, Trojanowski John Q, Van Deerlin Vivianna M, Hurtig Howard I, Mash Deborah C, Beach Thomas G, Troncoso Juan C, Pletnikova Olga, Frosch Matthew P, Ghetti Bernardino, Foroud Tatiana M, Honig Lawrence S, Marder Karen, Vonsattel Jean Paul, Goldman Samuel M, Vinters Harry V, Ross Owen A, Wszolek Zbigniew K, Wang Liyong, Dykxhoorn Derek M, Pericak-Vance Margaret A, Montine Thomas J, Leverenz James B, Dawson Ted M, Vance Jeffery M
From the John P. Hussman Institute for Human Genomics (G.W.B., W.K.S., E.R.M., K.N., L.W., D.M.D., M.A.P.-V., J.M.V.) and University of Miami Brain Endowment Bank (D.C.M.), Miller School of Medicine, University of Miami, FL; Departments of Neuroscience (D.W.D., O.A.R.) and Neurology (Z.K.W.), Mayo Clinic Florida, Jacksonville; Department of Pathology & Laboratory Medicine (G.S., J.Q.T., V.M.V.D., H.I.H.), Perelman School of Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania, Philadelphia; Group Health Research Institute (E.B.L.), Seattle, WA; Departments of Psychiatry, and Genetics and Genomic Sciences (J.D.B.), Mount Sinai School of Medicine, New York, NY; Arizona Alzheimer's Consortium (T.G.B.), Phoenix; Sun Health Research Institute (T.G.B.), Sun City, AZ; Division of Neuropathology, Department of Pathology (J.C.T., O.P.), and Department of Neurology and the Solomon H. Snyder Department of Neuroscience (T.M.D.), Johns Hopkins University School of Medicine, Baltimore, MD; Kubik Laboratory for Neuropathology (M.P.F.), Massachusetts General Hospital and Harvard Medical School, Charlestown, MA; Department of Pathology and Laboratory Medicine, Indiana Alzheimer Disease Center (B.G.), and Department of Medical and Molecular Genetics (T.M.F.), Indiana University School of Medicine, Indianapolis; Departments of Neurology (L.S.H., K.M.) and Psychiatry (K.M.), Gertrude H. Sergievsky Center, and Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York; Department of Pathology and Cell Biology (J.P.V.), Taub Institute for Research on Alzheimer's Disease and the Aging Brain, New York, NY; The Parkinson's Institute (S.M.G.), Sunnyvale, CA; Departments of Pathology and Laboratory Medicine (Neuropathology) and Neurology (H.V.V.), David Geffen School of Medicine at University of California Los Angeles; Department of Pathology (T.J.M.), University of Washington School of Medicine, Seattle; VA Puget Sound Health Care System (
Neurology. 2015 Mar 10;84(10):972-80. doi: 10.1212/WNL.0000000000001332. Epub 2015 Feb 6.
To minimize pathologic heterogeneity in genetic studies of Parkinson disease (PD), the Autopsy-Confirmed Parkinson Disease Genetics Consortium conducted a genome-wide association study using both patients with neuropathologically confirmed PD and controls.
Four hundred eighty-four cases and 1,145 controls met neuropathologic diagnostic criteria, were genotyped, and then imputed to 3,922,209 variants for genome-wide association study analysis.
A small region on chromosome 1 was strongly associated with PD (rs10788972; p = 6.2 × 10(-8)). The association peak lies within and very close to the maximum linkage peaks of 2 prior positive linkage studies defining the PARK10 locus. We demonstrate that rs10788972 is in strong linkage disequilibrium with rs914722, the single nucleotide polymorphism defining the PARK10 haplotype previously shown to be significantly associated with age at onset in PD. The region containing the PARK10 locus was significantly reduced from 10.6 megabases to 100 kilobases and contains 4 known genes: TCEANC2, TMEM59, miR-4781, and LDLRAD1.
We confirm the association of a PARK10 haplotype with the risk of developing idiopathic PD. Furthermore, we significantly reduce the size of the PARK10 region. None of the candidate genes in the new PARK10 region have been previously implicated in the biology of PD, suggesting new areas of potential research. This study strongly suggests that reducing pathologic heterogeneity may enhance the application of genetic association studies to PD.
为了尽量减少帕金森病（PD）基因研究中的病理异质性，经尸检确诊的帕金森病遗传学联盟开展了一项全基因组关联研究，研究对象包括经神经病理学确诊的PD患者和对照。
484例病例和1145例对照符合神经病理学诊断标准，进行基因分型，然后推算出3922209个变异，用于全基因组关联研究分析。
1号染色体上的一个小区域与PD密切相关（rs10788972；p = 6.2×10⁻⁸）。该关联峰位于之前两项定义PARK10位点的阳性连锁研究的最大连锁峰之内且非常接近。我们证明rs10788972与rs914722处于强连锁不平衡状态，rs914722是定义PARK10单倍型的单核苷酸多态性，之前已证明其与PD发病年龄显著相关。包含PARK10位点的区域从10.6兆碱基显著缩小至100千碱基，包含4个已知基因：TCEANC2、TMEM59、miR - 4781和LDLRAD1。
我们证实了PARK10单倍型与特发性PD发病风险的关联。此外，我们显著缩小了PARK10区域的大小。新的PARK10区域中的候选基因之前均未涉及PD生物学研究，提示了潜在的新研究领域。这项研究强烈表明，减少病理异质性可能会增强基因关联研究在PD中的应用。
