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Genome-wide analysis of genetic loci associated with Alzheimer disease.

ABSTRACT: 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.

SUBMITTER: Seshadri S

PROVIDER: S-EPMC2989531 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Genome-wide analysis of genetic loci associated with Alzheimer disease.

Seshadri Sudha S Fitzpatrick Annette L AL Ikram M Arfan MA DeStefano Anita L AL Gudnason Vilmundur V Boada Merce M Bis Joshua C JC Smith Albert V AV Carassquillo Minerva M MM Lambert Jean Charles JC Harold Denise D Schrijvers Elisabeth M C EM Ramirez-Lorca Reposo R Debette Stephanie S Longstreth W T WT Janssens A Cecile J W AC Pankratz V Shane VS Dartigues Jean François JF Hollingworth Paul P Aspelund Thor T Hernandez Isabel I Beiser Alexa A Kuller Lewis H LH Koudstaal Peter J PJ Dickson Dennis W DW Tzourio Christophe C Abraham Richard R Antunez Carmen C Du Yangchun Y Rotter Jerome I JI Aulchenko Yurii S YS Harris Tamara B TB Petersen Ronald C RC Berr Claudine C Owen Michael J MJ Lopez-Arrieta Jesus J Varadarajan Badri N BN Becker James T JT Rivadeneira Fernando F Nalls Michael A MA Graff-Radford Neill R NR Campion Dominique D Auerbach Sanford S Rice Kenneth K Hofman Albert A Jonsson Palmi V PV Schmidt Helena H Lathrop Mark M Mosley Thomas H TH Au Rhoda R Psaty Bruce M BM Uitterlinden Andre G AG Farrer Lindsay A LA Lumley Thomas T Ruiz Agustin A Williams Julie J Amouyel Philippe P Younkin Steve G SG Wolf Philip A PA Launer Lenore J LJ Lopez Oscar L OL van Duijn Cornelia M CM Breteler Monique M B MM

JAMA 20100501 18

<h4>Context</h4>Genome-wide association studies (GWAS) have recently identified CLU, PICALM, and CR1 as novel genes for late-onset Alzheimer disease (AD).<h4>Objectives</h4>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).<h4>Design, setting, and participant ...[more]

PMID: 20460622

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Project description: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 <?.005). Risk alleles individually reduced AAO by 3 to 6 months. Burden analyses demonstrated that APOE contributes to 3.7% of the variation in AAO (R(2) = 0.256) over baseline (R(2) = 0.221), whereas the other 9 loci together contribute to 2.2% of the variation (R(2) = 0.242). CONCLUSIONS AND RELEVANCE:We confirmed an association of APOE (OMIM 107741) variants with AAO among affected participants with LOAD and observed novel associations of CR1 (OMIM 120620), BIN1 (OMIM 601248), and PICALM (OMIM 603025) with AAO. In contrast to earlier hypothetical modeling, we show that the combined effects of Alzheimer disease risk variants on AAO are on the scale of, but do not exceed, the APOE effect. While the aggregate effects of risk loci on AAO may be significant, additional genetic contributions to AAO are individually likely to be small.

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Genome-wide analysis of genetic loci associated with Alzheimer disease.

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Genome-wide analysis of genetic loci associated with Alzheimer disease.

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