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Ann Neurol. 2012 Mar;71(3):370-84. doi: 10.1002/ana.22687.

Meta-analysis of Parkinson's disease: identification of a novel locus, RIT2.

Collaborators (739)

Factor S, Higgins D, Evans S, Shill H, Stacy M, Danielson J, Marlor L, Williamson K, Jankovic J, Hunter C, Simon D, Ryan P, Scollins L, Saunders-Pullman R, Boyar K, Costan-Toth C, Ohmann E, Sudarsky L, Joubert C, Friedman J, Chou K, Fernandez H, Lannon M, Galvez-Jimenez N, Podichetty A, Thompson K, Lewitt P, DeAngelis M, O'Brien C, Seeberger L, Dingmann C, Judd D, Marder K, Fraser J, Harris J, Bertoni J, Peterson C, Rezak M, Medalle G, Chouinard S, Panisset M, Hall J, Poiffaut H, Calabrese V, Roberge P, Wojcieszek J, Belden J, Jennings D, Marek K, Mendick S, Reich S, Dunlop B, Jog M, Horn C, Uitti R, Turk M, Ajax T, Mannetter J, Sethi K, Carpenter J, Dill B, Hatch L, Ligon K, Narayan S, Blindauer K, Abou-Samra K, Petit J, Elmer L, Aiken E, Davis K, Schell C, Wilson S, Velickovic M, Koller W, Phipps S, Feigin A, Gordon M, Hamann J, Licari E, Marotta-Kollarus M, Shannon B, Winnick R, Simuni T, Videnovic A, Kaczmarek A, Williams K, Wolff M, Rao J, Cook M, Fernandez M, Kostyk S, Hubble J, Campbell A, Reider C, Seward A, Camicioli R, Carter J, Nutt J, Andrews P, Morehouse S, Stone C, Mendis T, Grimes D, Alcorn-Costa C, Gray P, Haas K, Vendette J, Sutton J, Hutchinson B, Young J, Rajput A, Rajput A, Klassen L, Shirley T, Manyam B, Simpson P, Whetteckey J, Wulbrecht B, Truong D, Pathak M, Frei K, Luong N, Tra T, Tran A, Vo J, Lang A, Kleiner-Fisman G, Nieves A, Johnston L, So J, Podskalny G, Giffin L, Atchison P, Allen C, Martin W, Wieler M, Suchowersky O, Furtado S, Klimek M, Hermanowicz N, Niswonger S, Shults C, Fontaine D, Aminoff M, Christine C, Diminno M, Hevezi J, Dalvi A, Kang U, Richman J, Uy S, Young J, Dalvi A, Sahay A, Gartner M, Schwieterman D, Hall D, Leehey M, Culver S, Derian T, Demarcaida T, Thurlow S, Rodnitzky R, Dobson J, Lyons K, Pahwa R, Gales T, Thomas S, Shulman L, Reich S, Weiner W, Dustin K, Lyons K, Singer C, Koller W, Weiner W, Zelaya L, Tuite P, Hagen V, Rolandelli S, Schacherer R, Kosowicz J, Gordon P, Werner J, Serrano C, Roque S, Kurlan R, Berry D, Gardiner I, Hauser R, Sanchez-Ramos J, Zesiewicz T, Delgado H, Price K, Rodriguez P, Wolfrath S, Pfeiffer R, Davis L, Pfeiffer B, Dewey R, Hayward B, Johnson A, Meacham M, Estes B, Walker F, Hunt V, O'Neill C, Racette B, Good L, Rundle M, Lew M, Suchowersky O, Klein C, Golbe L, Mark MH, Growdon J, Huggins N, Wooten GF, Watts R, Guttman M, Racette B, Perlmutter J, Marlor L, Shill H, Singer C, Goldwurm S, Pezzoli G, Saint-Hilaire MH, Massood T, Baker K, Itin I, Litvan I, Nicholson G, Corbett A, Nance M, Drasby E, Isaacson S, Burn D, Chinnery P, Pramstaller P, Al-hinti J, Moller A, Ostergaard K, Sherman S, Roxburgh R, Snow B, Slevin J, Cambi F, Kay D, Montimurro J, Kusel V, Samii A, Martinez E, Yearout D, Nutt J, Agarwal P, Griffith A, Roberts JW, Higgins DS, Molho E, Rosen A, Jauregui CA, Nance MA, Watts RL, Hubble JP, Koller WC, Lyons K, Pahwa R, Stern MB, Colcher A, Hiner BC, Jankovic J, Ondo WG, Allen FH Jr, Goetz CG, Small GW, Masterman D, Mastaglia F, Scott BL, Singer C, Nahab F, Pericak-Vance MA, Haines JL, Chou K, Wernette K, Shannon K, Jaglin J, Carter J, Andrews P, Jankovic J, Shahed J, Hunter C, Wooten FG, Keller MF, Tanner C, Stewart T, Lawrence C, Smith K, Singer C, Quesada M, Siderowf A, Reichwein S, Hauser R, Wolfrath S, Piper G, Racette B, Deppen P, Ammel M, Dawson T, Dunlop B, Suchowersky O, Derwent L, Lew MF, Villa M, Sethi K, Dill B, Narayan S, Burns R, Marlor L, Watts RL, McMurray R, Sudarsky L, Hage G, Truong D, Tran AH, Tran M, Aminoff MJ, Roth J, Simon DK, Scollins L, Paul L, Rose P, Simuni T, Williams K, Dewey R, Hayward B, Johnson A, Gode A, Leehey M, Bainbridge J, Scott B, Field J, Zweig R, Hilliard C, Bodis-Wollner I, Glazman S, Hamill R, Homan C, Lennox S, Potter C, Elble R, Young C, Lokaitis B, Kelly D, Ross GW, Terashita S, Schneider J, Sendek S, Gollomp S, Gollomp R, Raza S, Coffey DJ, Leblanc PR, Cambi F, Wagner R, Bergman K, Hinson V, Salak V, Rao J, Cook M, Alcalay RN, Caccappolo E, Mejia-Santana H, Tang MX, Rosado L, Reilly MO, Ruiz D, Ross B, Verbitsky M, Kisselev S, Louis ED, Andrews H, Waters C, Fahn S, Cote L, Frucht S, Ford B, Ottman R, Clark LN, Comella C, Colcher A, Siderowf A, Jennings D, Nance M, Bressman S, Scott WK, Tanner C, Mickel S, Rezak M, Novak K, Friedman JH, Pfeiffer R, Marsh L, Hiner B, Green R, Kowall N, Farrer L, Williamson J, Santana V, Schmechel D, Gaskell P, Welsh-Bohmer K, Pericak-Vance M, Ghetti B, Farlow MR, Horner K, Growdon JH, Blacker D, Wills AM, Tanzi RE, Hyman BT, Boeve B, Kuntz K, Norgaard L, Larson N, Kistler D, Parfitt F, Haddwow J, Silverman J, Beeri MS, Sano M, Wang J, Lally R, Johnson N, Mesulum M, Weintraub S, Bigio E, Kaye J, Kramer P, Payne-Murphy J, Bennett D, Jacobs H, Chang JS, Arends D, Harrell L, Bartzokis G, Cummings J, Lu PH, Toland U, Markesbery W, Smith C, Brickhouse A, Trojanowski J, Van Deerlin V, Wood EM, DeKosky S, Sweet R, Weamer E, Chui IH, Varpetian A, Diaz-Arrastia R, Rosenberg R, Davis B, Bird T, Rumbaugh M, Schellenberg GD, Raskind M, Goate A, Morris J, Norton J, Levitch D, Grant B, Coats M, Koller W, Olanow CW, Rodnitzky R, Fink JS, Growdon JH, Paulson G, Kurlan R, Friedman JH, Gancher S, Nutt J, Rajput AH, Bennett JB, Wooten GF, LeWitt P, Goetz C, Tanner C, Shannon K, Suchowersky O, Brin MF, Bressman SB, Weiner WJ, Sanchez-Ramos J, Jankovic J, Penney JB, Lang A, Hoehn M, Tetrud J, Grimes JD, Pfeiffer R, Shults C, Thal L, Gauthier S, Golbe LI, Perlmutter JS, Moses H 3rd, Reich SG, Hurtig HI, Stern M, Barter R, Vetere-Overfield B, Gauger L, Malapira T, Dobson J, Atamian S, Tennis M, Cohen JB, Desclos G, Hoffman E, Denio L, Huber S, Woike T, Zoog K, Mendell R, Dudte K, Behr J, Gardiner IF, Lannon M, Carter J, Northrup S, Kanigan B, Turk M, Landow E, Schlick P, Mistura K, Carroll VS, Thelen JA, Demong C, Winfield L, Moskowitz C, Ingenito A, Sheldon C, Cornelius L, Heiberg D, Dunne C, Brady J, Kierans C, Belle-Scantlebury L, Duff J, Weber H, Savoini D, Lewis P, Kutner SJ, Gray P, Glaeske C, Hofman R, Pay MM, Salmon D, McFaul F, Amyot D, Bergen M, McGee-Minnich L, O'Donnell P, Ferrise S, Shallow K, Pelusio RM, Rudolph A, Miller C, Linsner M, Connorton J, Nusbaum J, Casaceli C, Irvine C, Orme C, Wixsom GJ, Schirazi M, Sotack J, Randolph H, Nobel R, Baker D, LaDonna D, Rothfuss ME, Doerr L, Rumfola L, Kavanaugh B, Wendel J, Odoroff C, Oakes D, McDermott M, Eberly S, Plumb S, Watts A, Yorkey L, Choi A, Gerwitz K, Evans P, Dellapena L, Singletary V, Herndon R, Tariot P, Bell E, Griggs RC, Hall WJ, Chase TN, Cohen G, Fleiss J, Mayeux R, Jacobs L, Moss AJ, Melamed E, Roth R, Galloway M, Irwin I, LeWitt P, Vatassery G, Como P, St Cyr J, Stern Y, Williams J, Wilson R, Stadlan EM, Alter M, Bergmann K, Park H, Cedarbaum J, Ellenberg J, Kibler R, State W, Galloway MP, Kaplan M, Lodhi R, Keegan MJ, Matthews B, Novak EA, Irwin I, Norkus E, Flood D, McNeill T, Harary N, Koek L, Creveling RL, Bwala G, Scherzer CR, Hyman BT, Ivinson AJ, Maher NE, Sarokhan AK, Lockhart KC, Santarlasci A, Sudarsky LR, Hart E, Growdon JH, Schwarzschild MA, Hung AY, Flaherty AW, Blacker D, Unni VK, Viswanathan A, Mejia NI, Gomperts SN, Albers MW, Swords KE, Rudel RK, Hirschberger JT, Padilla OA, Schlossmacher M, Ascherio A, Ravina BM, Khadka B, Padilla OA, Zheng B, Locascio JJ, Roderick SS, Kan CG, Liao Z, Tanner CM, Ross GW, Abbott RD, Langston JW, Tanner CM, Roucoux D, Yerabati S, Smith A, Hauser RA, Delaney D, Wolfrath SC, Nemeth J, Mclain T, Jankovic J, Hunter C, Shinawi L, Factor SA, Flores KR, Ingram C, Bressman S, Deligtisch A, Boyar K, Wolff A, Marras C, Enjati M, Lyons K, Mack C, Langhammer A, Gales T, Ross GW, Wakashige FK, Lu M, Comyns K, Korell M, Sterling L, VanVeghten R, Padua M, Wright J, Allred B, Bushman L, Bynum M, Cage C, Carroll A, Chang M, Cook R, Ferriter E, Franco M, Gorman K, Kemp M, Knutson S, Lavoie S, Mills E, Nguyen C, Niedle P, Pia J, Priestley B, Sims V, Soetmelk JA, Song B, Stang B, Staver M, Stover A.

Abstract

OBJECTIVE:

Genome-wide association (GWAS) methods have identified genes contributing to Parkinson's disease (PD); we sought to identify additional genes associated with PD susceptibility.

METHODS:

A 2-stage design was used. First, individual level genotypic data from 5 recent PD GWAS (Discovery Sample: 4,238 PD cases and 4,239 controls) were combined. Following imputation, a logistic regression model was employed in each dataset to test for association with PD susceptibility and results from each dataset were meta-analyzed. Second, 768 single-nucleotide polymorphisms (SNPs) were genotyped in an independent Replication Sample (3,738 cases and 2,111 controls).

RESULTS:

Genome-wide significance was reached for SNPs in SNCA (rs356165; G: odds ratio [OR]=1.37; p=9.3×10(-21)), MAPT (rs242559; C: OR=0.78; p=1.5×10(-10)), GAK/DGKQ (rs11248051; T: OR=1.35; p=8.2×10(-9)/rs11248060; T: OR=1.35; p=2.0×10(-9)), and the human leukocyte antigen (HLA) region (rs3129882; A: OR=0.83; p=1.2×10(-8)), which were previously reported. The Replication Sample confirmed the associations with SNCA, MAPT, and the HLA region and also with GBA (E326K; OR=1.71; p=5×10(-8) Combined Sample) (N370; OR=3.08; p=7×10(-5) Replication sample). A novel PD susceptibility locus, RIT2, on chromosome 18 (rs12456492; p=5×10(-5) Discovery Sample; p=1.52×10(-7) Replication sample; p=2×10(-10) Combined Sample) was replicated. Conditional analyses within each of the replicated regions identified distinct SNP associations within GBA and SNCA, suggesting that there may be multiple risk alleles within these genes.

INTERPRETATION:

We identified a novel PD susceptibility locus, RIT2, replicated several previously identified loci, and identified more than 1 risk allele within SNCA and GBA.

Copyright © 2012 American Neurological Association.

PMID:
22451204
[PubMed - indexed for MEDLINE]
PMCID:
PMC3354734
Free PMC Article

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