Dataset Information

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

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.

SUBMITTER: Naj AC

PROVIDER: S-EPMC3090745 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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

Naj Adam C AC Jun Gyungah G Beecham Gary W GW Wang Li-San LS Vardarajan Badri Narayan BN Buros Jacqueline J Gallins Paul J PJ Buxbaum Joseph D JD Jarvik Gail P GP Crane Paul K PK Larson Eric B EB Bird Thomas D TD Boeve Bradley F BF Graff-Radford Neill R NR De Jager Philip L PL Evans Denis D Schneider Julie A JA Carrasquillo Minerva M MM Ertekin-Taner Nilufer N Younkin Steven G SG Cruchaga Carlos C Kauwe John S K JS Nowotny Petra P Kramer Patricia P Hardy John J Huentelman Matthew J MJ Myers Amanda J AJ Barmada Michael M MM Demirci F Yesim FY Baldwin Clinton T CT Green Robert C RC Rogaeva Ekaterina E St George-Hyslop Peter P Arnold Steven E SE Barber Robert R Beach Thomas T Bigio Eileen H EH Bowen James D JD Boxer Adam A Burke James R JR Cairns Nigel J NJ Carlson Chris S CS Carney Regina M RM Carroll Steven L SL Chui Helena C HC Clark David G DG Corneveaux Jason J Cotman Carl W CW Cummings Jeffrey L JL DeCarli Charles C DeKosky Steven T ST Diaz-Arrastia Ramon R Dick Malcolm M Dickson Dennis W DW Ellis William G WG Faber Kelley M KM Fallon Kenneth B KB Farlow Martin R MR Ferris Steven S Frosch Matthew P MP Galasko Douglas R DR Ganguli Mary M Gearing Marla M Geschwind Daniel H DH Ghetti Bernardino B Gilbert John R JR Gilman Sid S Giordani Bruno B Glass Jonathan D JD Growdon John H JH Hamilton Ronald L RL Harrell Lindy E LE Head Elizabeth E Honig Lawrence S LS Hulette Christine M CM Hyman Bradley T BT Jicha Gregory A GA Jin Lee-Way LW Johnson Nancy N Karlawish Jason J Karydas Anna A Kaye Jeffrey A JA Kim Ronald R Koo Edward H EH Kowall Neil W NW Lah James J JJ Levey Allan I AI Lieberman Andrew P AP Lopez Oscar L OL Mack Wendy J WJ Marson Daniel C DC Martiniuk Frank F Mash Deborah C DC Masliah Eliezer E McCormick Wayne C WC McCurry Susan M SM McDavid Andrew N AN McKee Ann C AC Mesulam Marsel M Miller Bruce L BL Miller Carol A CA Miller Joshua W JW Parisi Joseph E JE Perl Daniel P DP Peskind Elaine E Petersen Ronald C RC Poon Wayne W WW Quinn Joseph F JF Rajbhandary Ruchita A RA Raskind Murray M Reisberg Barry B Ringman John M JM Roberson Erik D ED Rosenberg Roger N RN Sano Mary M Schneider Lon S LS Seeley William W Shelanski Michael L ML Slifer Michael A MA Smith Charles D CD Sonnen Joshua A JA Spina Salvatore S Stern Robert A RA Tanzi Rudolph E RE Trojanowski John Q JQ Troncoso Juan C JC Van Deerlin Vivianna M VM Vinters Harry V HV Vonsattel Jean Paul JP Weintraub Sandra S Welsh-Bohmer Kathleen A KA Williamson Jennifer J Woltjer Randall L RL Cantwell Laura B LB Dombroski Beth A BA Beekly Duane D Lunetta Kathryn L KL Martin Eden R ER Kamboh M Ilyas MI Saykin Andrew J AJ Reiman Eric M EM Bennett David A DA Morris John C JC Montine Thomas J TJ Goate Alison M AM Blacker Deborah D Tsuang Debby W DW Hakonarson Hakon H Kukull Walter A WA Foroud Tatiana M TM Haines Jonathan L JL Mayeux Richard R Pericak-Vance Margaret A MA Farrer Lindsay A LA Schellenberg Gerard D GD

Nature genetics 20110403 5

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)), ...[more]

PMID: 21460841

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Project description:Base excision repair (BER) defects and concomitant oxidative DNA damage accumulation play a role in the etiology and progression of late-onset Alzheimer's disease (LOAD). However, it is not known whether genetic variant(s) of specific BER genes contribute to reduced BER activity in LOAD patients and whether they are associated with risk, development and/or progression of LOAD. Therefore, we performed targeted next generation sequencing for three BER genes, uracil glycosylase (UNG), endonuclease VIII-like DNA glycosylase 1 (NEIL1) and polymerase β (POLβ) including promoter, exonic and intronic regions in peripheral blood samples and postmortem brain tissues (temporal cortex, TC and cerebellum, CE) from LOAD patients, high-pathology control and cognitively normal age-matched controls. In addition, the known LOAD risk factor, APOE was included in this study to test whether any BER gene variants associate with APOE variants, particularly APOE ε4. We show that UNG carry five significant variants (rs1610925, rs2268406, rs80001089, rs1018782 and rs1018783) in blood samples of Turkish LOAD patients compared to age-matched controls and one of them (UNG rs80001089) is also significant in TC from Brazilian LOAD patients (p<0.05). The significant variants present only in CE and TC from LOAD are UNG rs2569987 and POLβ rs1012381950, respectively. There is also significant epistatic relationship (p = 0.0410) between UNG rs80001089 and NEIL1 rs7182283 in TC from LOAD subjects. Our results suggest that significant BER gene variants may be associated with the risk of LOAD in non-APOE ε4 carriers. On the other hand, there are no significant UNG, NEIL1 and POLβ variants that could affect their protein level and function, suggesting that there may be other factors such as post-transcriptional or-translational modifications responsible for the reduced activities and protein levels of these genes in LOAD pathogenesis. Further studies with increased sample size are needed to confirm the relationship between BER variants and LOAD risk.

Dataset Information

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

Publications

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

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