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Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study.

ABSTRACT: IMPORTANCE:Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants. OBJECTIVES:To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consortium. DESIGN, SETTING, AND PARTICIPANTS:The Alzheimer Disease Genetics Consortium comprises 14 case-control, prospective, and family-based data sets with data on 9162 participants of white race/ethnicity with Alzheimer disease occurring after age 60 years who also had complete AAO information, gathered between 1989 and 2011 at multiple sites by participating studies. Data on genotyped or imputed single-nucleotide polymorphisms most significantly associated with risk at 10 confirmed LOAD loci were examined in linear modeling of AAO, and individual data set results were combined using a random-effects, inverse variance-weighted meta-analysis approach to determine whether they contribute to variation in AAO. Aggregate effects of all risk loci on AAO were examined in a burden analysis using genotype scores weighted by risk effect sizes. MAIN OUTCOMES AND MEASURES:Age at disease onset abstracted from medical records among participants with LOAD diagnosed per standard criteria. RESULTS:Analysis confirmed the association of APOE with earlier AAO (P = 3.3 × 10(-96)), with associations in CR1 (rs6701713, P = 7.2 × 10(-4)), BIN1 (rs7561528, P = 4.8 × 10(-4)), and PICALM (rs561655, P = 2.2 × 10(-3)) reaching statistical significance (P

SUBMITTER: Naj AC

PROVIDER: S-EPMC4314944 | biostudies-literature | 2014 Nov

REPOSITORIES: biostudies-literature

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Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study.

Naj Adam C AC Jun Gyungah G Reitz Christiane C Kunkle Brian W BW Perry William W Park Yo Son YS Beecham Gary W GW Rajbhandary Ruchita A RA Hamilton-Nelson Kara L KL Wang Li-San LS Kauwe John S K JS Huentelman Matthew J MJ Myers Amanda J AJ Bird Thomas D TD Boeve Bradley F BF Baldwin Clinton T CT Jarvik Gail P GP Crane Paul K PK Rogaeva Ekaterina E Barmada M Michael MM Demirci F Yesim FY Cruchaga Carlos C Kramer Patricia L PL Ertekin-Taner Nilufer N Hardy John J Graff-Radford Neill R NR Green Robert C RC Larson Eric B EB St George-Hyslop Peter H PH Buxbaum Joseph D JD Evans Denis A DA Schneider Julie A JA Lunetta Kathryn L KL Kamboh M Ilyas MI Saykin Andrew J AJ Reiman Eric M EM De Jager Philip L PL 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 Martin Eden R ER Haines Jonathan L JL Mayeux Richard P RP Farrer Lindsay A LA Schellenberg Gerard D GD Pericak-Vance Margaret A MA Albert Marilyn S MS Albin Roger L RL Apostolova Liana G LG Arnold Steven E SE Barber Robert R Barnes Lisa L LL Beach Thomas G TG Becker James T JT Beekly Duane D Bigio Eileen H EH Bowen James D JD Boxer Adam A Burke James R JR Cairns Nigel J NJ Cantwell Laura B LB Cao Chuanhai C Carlson Chris S CS Carney Regina M RM Carrasquillo Minerva M MM Carroll Steven L SL Chui Helena C HC Clark David G DG Corneveaux Jason J Cribbs David H DH Crocco Elizabeth A EA DeCarli Charles C DeKosky Steven T ST Dick Malcolm M Dickson Dennis W DW Duara Ranjan R 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 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 Karydas Anna A Kaye Jeffrey A JA Kim Ronald R Koo Edward H EH Kowall Neil W NW Kramer Joel H JH LaFerla Frank M FM Lah James J JJ Leverenz James B JB Levey Allan I AI Li Ge G Lieberman Andrew P AP Lin Chiao-Feng CF Lopez Oscar L OL Lyketsos Constantine G CG Mack Wendy J WJ 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 Murrell Jill R JR Olichney John M JM Pankratz Vernon S VS Parisi Joseph E JE Paulson Henry L HL Peskind Elaine E Petersen Ronald C RC Pierce Aimee A Poon Wayne W WW Potter Huntington H Quinn Joseph F JF Raj Ashok A Raskind Murray M Reisberg Barry B Ringman John M JM Roberson Erik D ED Rosen Howard J HJ Rosenberg Roger N RN Sano Mary M Schneider Lon S LS Seeley William W WW Smith Amanda G AG Sonnen Joshua A JA Spina Salvatore S Stern Robert A RA Tanzi Rudolph E RE Thornton-Wells Tricia A TA Trojanowski John Q JQ Troncoso Juan C JC Valladares Otto O Van Deerlin Vivianna M VM Van Eldik Linda J LJ Vardarajan Badri N BN Vinters Harry V HV Vonsattel Jean Paul JP Weintraub Sandra S Welsh-Bohmer Kathleen A KA Williamson Jennifer J Wishnek Sarah S Woltjer Randall L RL Wright Clinton B CB Younkin Steven G SG Yu Chang-En CE Yu Lei L

JAMA neurology 20141101 11

<h4>Importance</h4>Because APOE locus variants contribute to risk of late-onset Alzheimer disease (LOAD) and to differences in age at onset (AAO), it is important to know whether other established LOAD risk loci also affect AAO in affected participants.<h4>Objectives</h4>To investigate the effects of known Alzheimer disease risk loci in modifying AAO and to estimate their cumulative effect on AAO variation using data from genome-wide association studies in the Alzheimer Disease Genetics Consorti ...[more]

PMID: 25199842

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Project description:CONTEXT:Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD). OBJECTIVES:To identify and strengthen additional loci associated with AD and confirm these in an independent sample and to examine the contribution of recently identified genes to AD risk prediction in a 3-stage analysis of new and previously published GWAS on more than 35,000 persons (8371 AD cases). DESIGN, SETTING, AND PARTICIPANTS:In stage 1, we identified strong genetic associations (P < 10(-3)) in a sample of 3006 AD cases and 14,642 controls by combining new data from the population-based Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (1367 AD cases [973 incident]) with previously reported results from the Translational Genomics Research Institute and the Mayo AD GWAS. We identified 2708 single-nucleotide polymorphisms (SNPs) with P < 10(-3). In stage 2, we pooled results for these SNPs with the European AD Initiative (2032 cases and 5328 controls) to identify 38 SNPs (10 loci) with P < 10(-5). In stage 3, we combined data for these 10 loci with data from the Genetic and Environmental Risk in AD consortium (3333 cases and 6995 controls) to identify 4 SNPs with P < 1.7x10(-8). These 4 SNPs were replicated in an independent Spanish sample (1140 AD cases and 1209 controls). Genome-wide association analyses were completed in 2007-2008 and the meta-analyses and replication in 2009. MAIN OUTCOME MEASURE:Presence of Alzheimer disease. RESULTS:Two loci were identified to have genome-wide significance for the first time: rs744373 near BIN1 (odds ratio [OR],1.13; 95% confidence interval [CI],1.06-1.21 per copy of the minor allele; P = 1.59x10(-11)) and rs597668 near EXOC3L2/BLOC1S3/MARK4 (OR, 1.18; 95% CI, 1.07-1.29; P = 6.45x10(-9)). Associations of these 2 loci plus the previously identified loci CLU and PICALM with AD were confirmed in the Spanish sample (P < .05). However, although CLU and PICALM were confirmed to be associated with AD in this independent sample, they did not improve the ability of a model that included age, sex, and APOE to predict incident AD (improvement in area under the receiver operating characteristic curve from 0.847 to 0.849 in the Rotterdam Study and 0.702 to 0.705 in the Cardiovascular Health Study). CONCLUSIONS:Two genetic loci for AD were found for the first time to reach genome-wide statistical significance. These findings were replicated in an independent population. Two recently reported associations were also confirmed. These loci did not improve AD risk prediction. While not clinically useful, they may implicate biological pathways useful for future research.

Dataset Information

Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study.

Publications

Effects of multiple genetic loci on age at onset in late-onset Alzheimer disease: a genome-wide association study.

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