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Meta-Analysis
. 2011 May;43(5):436-41.
doi: 10.1038/ng.801. Epub 2011 Apr 3.

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

Adam C Naj  1 , Gyungah Jun, Gary W Beecham, Li-San Wang, Badri Narayan Vardarajan, Jacqueline Buros, Paul J Gallins, Joseph D Buxbaum, Gail P Jarvik, Paul K Crane, Eric B Larson, Thomas D Bird, Bradley F Boeve, Neill R Graff-Radford, Philip L De Jager, Denis Evans, Julie A Schneider, Minerva M Carrasquillo, Nilufer Ertekin-Taner, Steven G Younkin, Carlos Cruchaga, John S K Kauwe, Petra Nowotny, Patricia Kramer, John Hardy, Matthew J Huentelman, Amanda J Myers, Michael M Barmada, F Yesim Demirci, Clinton T Baldwin, Robert C Green, Ekaterina Rogaeva, Peter St George-Hyslop, Steven E Arnold, Robert Barber, Thomas Beach, Eileen H Bigio, James D Bowen, Adam Boxer, James R Burke, Nigel J Cairns, Chris S Carlson, Regina M Carney, Steven L Carroll, Helena C Chui, David G Clark, Jason Corneveaux, Carl W Cotman, Jeffrey L Cummings, Charles DeCarli, Steven T DeKosky, Ramon Diaz-Arrastia, Malcolm Dick, Dennis W Dickson, William G Ellis, Kelley M Faber, Kenneth B Fallon, Martin R Farlow, Steven Ferris, Matthew P Frosch, Douglas R Galasko, Mary Ganguli, Marla Gearing, Daniel H Geschwind, Bernardino Ghetti, John R Gilbert, Sid Gilman, Bruno Giordani, Jonathan D Glass, John H Growdon, Ronald L Hamilton, Lindy E Harrell, Elizabeth Head, Lawrence S Honig, Christine M Hulette, Bradley T Hyman, Gregory A Jicha, Lee-Way Jin, Nancy Johnson, Jason Karlawish, Anna Karydas, Jeffrey A Kaye, Ronald Kim, Edward H Koo, Neil W Kowall, James J Lah, Allan I Levey, Andrew P Lieberman, Oscar L Lopez, Wendy J Mack, Daniel C Marson, Frank Martiniuk, Deborah C Mash, Eliezer Masliah, Wayne C McCormick, Susan M McCurry, Andrew N McDavid, Ann C McKee, Marsel Mesulam, Bruce L Miller, Carol A Miller, Joshua W Miller, Joseph E Parisi, Daniel P Perl, Elaine Peskind, Ronald C Petersen, Wayne W Poon, Joseph F Quinn, Ruchita A Rajbhandary, Murray Raskind, Barry Reisberg, John M Ringman, Erik D Roberson, Roger N Rosenberg, Mary Sano, Lon S Schneider, William Seeley, Michael L Shelanski, Michael A Slifer, Charles D Smith, Joshua A Sonnen, Salvatore Spina, Robert A Stern, Rudolph E Tanzi, John Q Trojanowski, Juan C Troncoso, Vivianna M Van Deerlin, Harry V Vinters, Jean Paul Vonsattel, Sandra Weintraub, Kathleen A Welsh-Bohmer, Jennifer Williamson, Randall L Woltjer, Laura B Cantwell, Beth A Dombroski, Duane Beekly, Kathryn L Lunetta, Eden R Martin, M Ilyas Kamboh, Andrew J Saykin, Eric M Reiman, David A Bennett, John C Morris, Thomas J Montine, Alison M Goate, Deborah Blacker, Debby W Tsuang, Hakon Hakonarson, Walter A Kukull, Tatiana M Foroud, Jonathan L Haines, Richard Mayeux, Margaret A Pericak-Vance, Lindsay A Farrer, Gerard D Schellenberg
Affiliations
Meta-Analysis

Common variants at MS4A4/MS4A6E, CD2AP, CD33 and EPHA1 are associated with late-onset Alzheimer's disease

Adam C Naj et al. Nat Genet. 2011 May.

Abstract

The Alzheimer Disease Genetics Consortium (ADGC) performed a genome-wide association study of late-onset Alzheimer disease using a three-stage design consisting of a discovery stage (stage 1) and two replication stages (stages 2 and 3). Both joint analysis and meta-analysis approaches were used. We obtained genome-wide significant results at MS4A4A (rs4938933; stages 1 and 2, meta-analysis P (P(M)) = 1.7 × 10(-9), joint analysis P (P(J)) = 1.7 × 10(-9); stages 1, 2 and 3, P(M) = 8.2 × 10(-12)), CD2AP (rs9349407; stages 1, 2 and 3, P(M) = 8.6 × 10(-9)), EPHA1 (rs11767557; stages 1, 2 and 3, P(M) = 6.0 × 10(-10)) and CD33 (rs3865444; stages 1, 2 and 3, P(M) = 1.6 × 10(-9)). We also replicated previous associations at CR1 (rs6701713; P(M) = 4.6 × 10(-10), P(J) = 5.2 × 10(-11)), CLU (rs1532278; P(M) = 8.3 × 10(-8), P(J) = 1.9 × 10(-8)), BIN1 (rs7561528; P(M) = 4.0 × 10(-14), P(J) = 5.2 × 10(-14)) and PICALM (rs561655; P(M) = 7.0 × 10(-11), P(J) = 1.0 × 10(-10)), but not at EXOC3L2, to late-onset Alzheimer's disease susceptibility.

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Figures

Figure 1
Figure 1
Regional association plots from the three-stage meta-analysis with LOAD. PM values for association are shown for: (A) MS4A gene cluster, (B) CD2AP, (C) EPHA1, and (D) CD33. For each locus, the genomic position (NCBI Build 37.1) is plotted on the X-axis against –log10(P-value) on the Y-axis. For the SNP with the lowest P-value at each locus in Stage 1 analyses, three P-values for association are shown: P1 meta-analysis of the ADGC Discovery (Stage 1) dataset (highlighted with a black diamond), P1+2 meta-analysis of the Combined ADGC Discovery and Replication (Stages 1 + 2) datasets (highlighted with a blue diamond), and P1+2+3 meta-analysis of the combined ADGC dataset and the external replication (Stages 1 + 2 + 3) datasets (highlighted with a red diamond). Computed estimates of linkage disequilibrium (r2) with the most significant SNP at each locus are shown as an orange diamond for r2 ≥ 0.8, a yellow diamond for 0.5 ≤ r2 < 0.8, a grey diamond for 0.2 ≤ r2 < 0.5, and a white diamond for r2 < 0.2. Genes in each region are indicated at the bottom of each panel. The length and the direction of the arrowhead represent the scaled size and the direction of the gene, respectively.
See this image and copyright information in PMC

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