Identification of Novel Loci for Alzheimer Disease and Replication of CLU, PICALM, and BIN1 in Caribbean Hispanic Individuals | Genetics and Genomics | JAMA Neurology | JAMA Network
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Abraham  RMoskvina  VSims  R  et al.  A genome-wide association study for late-onset Alzheimer's disease using DNA pooling.  BMC Med Genomics 2008;144PubMedGoogle ScholarCrossref
Beecham  GWMartin  ERLi  YJ  et al.  Genome-wide association study implicates a chromosome 12 risk locus for late-onset Alzheimer disease.  Am J Hum Genet 2009;84 (1) 35- 43PubMedGoogle ScholarCrossref
Bertram  LLange  CMullin  K  et al.  Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE.  Am J Hum Genet 2008;83 (5) 623- 632PubMedGoogle ScholarCrossref
Carrasquillo  MMZou  FPankratz  VS  et al.  Genetic variation in PCDH11X is associated with susceptibility to late-onset Alzheimer's disease.  Nat Genet 2009;41 (2) 192- 198PubMedGoogle ScholarCrossref
Coon  KDMyers  AJCraig  DW  et al.  A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer's disease.  J Clin Psychiatry 2007;68 (4) 613- 618PubMedGoogle ScholarCrossref
Feulner  TMLaws  SMFriedrich  P  et al.  Examination of the current top candidate genes for AD in a genome-wide association study.  Mol Psychiatry 2010;15 (7) 756- 766PubMedGoogle ScholarCrossref
Harold  DAbraham  RHollingworth  P  et al.  Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease.  Nat Genet 2009;41 (10) 1088- 1093PubMedGoogle ScholarCrossref
Heinzen  ELNeed  ACHayden  KM  et al.  Genome-wide scan of copy number variation in late-onset Alzheimer's disease [published online September 11, 2009].  J Alzheimers Dis PubMedGoogle Scholar
Lambert  JCHeath  SEven  G  et al. European Alzheimer's Disease Initiative Investigators, Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease.  Nat Genet 2009;41 (10) 1094- 1099PubMedGoogle ScholarCrossref
Li  HWetten  SLi  L  et al.  Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease.  Arch Neurol 2008;65 (1) 45- 53PubMedGoogle ScholarCrossref
Poduslo  SEHuang  RHuang  JSmith  S Genome screen of late-onset Alzheimer's extended pedigrees identifies TRPC4AP by haplotype analysis.  Am J Med Genet B Neuropsychiatr Genet 2009;150B (1) 50- 55PubMedGoogle ScholarCrossref
Reiman  EMWebster  JAMyers  AJ  et al.  GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers.  Neuron 2007;54 (5) 713- 720PubMedGoogle ScholarCrossref
Seshadri  SFitzpatrick  ALIkram  MA  et al. CHARGE Consortium; GERAD1 Consortium; EADI1 Consortium, Genome-wide analysis of genetic loci associated with Alzheimer disease.  JAMA 2010;303 (18) 1832- 1840PubMedGoogle ScholarCrossref
Brouwers  NSleegers  KVan Broeckhoven  C Molecular genetics of Alzheimer's disease: an update.  Ann Med 2008;40 (8) 562- 583PubMedGoogle ScholarCrossref
Sleegers  KLambert  JCBertram  LCruts  MAmouyel  PVan Broeckhoven  C The pursuit of susceptibility genes for Alzheimer's disease: progress and prospects.  Trends Genet 2010;26 (2) 84- 93PubMedGoogle ScholarCrossref
Rogaeva  EMeng  YLee  JH  et al.  The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease.  Nat Genet 2007;39 (2) 168- 177PubMedGoogle ScholarCrossref
Reitz  CCheng  RRogaeva  E  et al.  Meta-analysis of the association between variants in SORL1 and Alzheimer disease.  Arch Neurol 2011;68 (1) 99- 106Google ScholarCrossref
Gatz  MReynolds  CAFratiglioni  L  et al.  Role of genes and environments for explaining Alzheimer disease.  Arch Gen Psychiatry 2006;63 (2) 168- 174PubMedGoogle ScholarCrossref
Manolio  TACollins  FSCox  NJ  et al.  Finding the missing heritability of complex diseases.  Nature 2009;461 (7265) 747- 753PubMedGoogle ScholarCrossref
McCarthy  MI Exploring the unknown: assumptions about allelic architecture and strategies for susceptibility variant discovery.  Genome Med 2009;1 (7) 66PubMedGoogle ScholarCrossref
Tang  MXStern  YMarder  K  et al.  The APOE-epsilon4 allele and the risk of Alzheimer disease among African Americans, whites, and Hispanics.  JAMA 1998;279 (10) 751- 755PubMedGoogle ScholarCrossref
Romas  SNSantana  VWilliamson  J  et al.  Familial Alzheimer disease among Caribbean Hispanics: a reexamination of its association with APOE.  Arch Neurol 2002;59 (1) 87- 91PubMedGoogle ScholarCrossref
Stern  YAndrews  HPittman  J  et al.  Diagnosis of dementia in a heterogeneous population: development of a neuropsychological paradigm-based diagnosis of dementia and quantified correction for the effects of education.  Arch Neurol 1992;49 (5) 453- 460PubMedGoogle ScholarCrossref
Folstein  MFFolstein  SEMcHugh  PR “Mini-mental state”: a practical method for grading the cognitive state of patients for the clinician.  J Psychiatr Res 1975;12 (3) 189- 198PubMedGoogle ScholarCrossref
Kaplan  EGoodglass  HWeintraub  S Boston Naming Test.  Philadelphia, PA Lea & Febiger1983;
Benton  A FAS Test. Spreen  OBenton  A Neurosensory Center Comprehensive Examination for Aphasia Victoria, BC, Canada University of Victoria1967;Google Scholar
Goodglass  HKaplan  E The Assessment of Aphasia and Related Disorders. 2nd ed. Philadelphia, PA Lea & Febiger1983;
Wechsler  D WAIS-R Manual.  New York, NY The Psychological Corp1981;
Mattis  S Mental status examination for organic mental syndrome in the elderly patient. Bellak  LKarasu  T Geriatric Psychiatry New York, NY Grune & Statton1976;Google Scholar
Rosen  W The Rosen Drawing Test.  Bronx, NY Veterans Administration Medical Center1981;
Benton  AL The Benton Visual Retention Test.  New York, NY The Psychological Corp1955;
Buschke  HFuld  PA Evaluating storage, retention, and retrieval in disordered memory and learning.  Neurology 1974;24 (11) 1019- 1025PubMedGoogle ScholarCrossref
McKhann  GDrachman  DFolstein  MKatzman  RPrice  DStadlan  EM Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA Work Group under the auspices of Department of Health and Human Services Task Force on Alzheimer's Disease.  Neurology 1984;34 (7) 939- 944PubMedGoogle ScholarCrossref
Hartl  DLClark  AG Principles of Population Genetics. 4th ed. Sunderland, MA Sinauer Associates2007;
Pritchard  JKStephens  MDonnelly  P Inference of population structure using multilocus genotype data.  Genetics 2000;155 (2) 945- 959PubMedGoogle Scholar
Purcell  SNeale  BTodd-Brown  K  et al.  PLINK: a tool set for whole-genome association and population-based linkage analyses.  Am J Hum Genet 2007;81 (3) 559- 575PubMedGoogle ScholarCrossref
Pacini  AToscano  ACesati  V  et al.  NAPOR-3 RNA binding protein is required for apoptosis in hippocampus.  Brain Res Mol Brain Res 2005;140 (1-2) 34- 44PubMedGoogle ScholarCrossref
Kamide  KKokubo  YYang  J  et al.  Hypertension susceptibility genes on chromosome 2p24-p25 in a general Japanese population.  J Hypertens 2005;23 (5) 955- 960PubMedGoogle ScholarCrossref
Grupe  ALi  YRowland  C  et al.  A scan of chromosome 10 identifies a novel locus showing strong association with late-onset Alzheimer disease.  Am J Hum Genet 2006;78 (1) 78- 88PubMedGoogle ScholarCrossref
Tycko  BFeng  LNguyen  L  et al.  Polymorphisms in the human apolipoprotein-J/clusterin gene: ethnic variation and distribution in Alzheimer's disease.  Hum Genet 1996;98 (4) 430- 436PubMedGoogle ScholarCrossref
Bushlin  IPetralia  RSWu  F  et al.  Clathrin assembly protein AP180 and CALM differentially control axogenesis and dendrite outgrowth in embryonic hippocampal neurons.  J Neurosci 2008;28 (41) 10257- 10271PubMedGoogle ScholarCrossref
Harel  AWu  FMattson  MPMorris  CMYao  PJ Evidence for CALM in directing VAMP2 trafficking.  Traffic 2008;9 (3) 417- 429PubMedGoogle ScholarCrossref
Luchsinger  JAReitz  CHonig  LSTang  MXShea  SMayeux  R Aggregation of vascular risk factors and risk of incident Alzheimer disease.  Neurology 2005;65 (4) 545- 551PubMedGoogle ScholarCrossref
Pedersen  NL Reaching the limits of genome-wide significance in Alzheimer disease: back to the environment.  JAMA 2010;303 (18) 1864- 1865PubMedGoogle ScholarCrossref
Original Contribution
March 2011

Identification of Novel Loci for Alzheimer Disease and Replication of CLU, PICALM, and BIN1 in Caribbean Hispanic Individuals

Author Affiliations

Author Affiliations: Taub Institute for Research on Alzheimer's Disease and the Aging Brain (Drs Lee, Cheng, Barral, Reitz, Lantigua, and Mayeux), Gertrude H. Sergievsky Center (Drs Lee and Mayeux), and Departments of Neurology (Drs Barral, Reitz, and Mayeux), Psychiatry (Dr Mayeux), and Medicine (Dr Lantigua), College of Physicians and Surgeons, and Department of Epidemiology, School of Public Health (Drs Lee and Mayeux), Columbia University, New York, New York; Universidad Tecnológica de Santiago, Santiago, Dominican Republic (Dr Medrano); Department of Internal Medicine, University of Puerto Rico School of Medicine, San Juan, Puerto Rico (Dr Jiménez-Velazquez); Centre for Research in Neurodegenerative Diseases, Departments of Medicine, Laboratory Medicine and Pathobiology, and Medical Biophysics, University of Toronto, and Toronto Western Hospital Research Institute, Toronto, Ontario, Canada (Drs Rogaeva and St. George-Hyslop); and Cambridge Institute for Medical Research and Department of Clinical Neurosciences, University of Cambridge, Cambridge, England (Dr St. George-Hyslop).

Arch Neurol. 2011;68(3):320-328. doi:10.1001/archneurol.2010.292

Numerous genome-wide association studies (GWAS) have been published for late-onset Alzheimer disease (LOAD).1-13 Aside from APOE, additional candidate susceptibility genes identified using GWAS methods for LOAD have included GAB2, GALP, 14q32.13, LOC651924, PGBD1, TNK1, CR1, CLU, PICALM, and BIN1.14,15 In addition, variants in SORL1 identified by Rogaeva et al16 have been replicated in several independent cohorts and were significantly associated with LOAD in a meta-analysis.17 Difficulties inherent to the genetics of complex diseases (eg, etiologic heterogeneity, gene × environment and gene × gene interactions, and methylation) remain with these studies, and much work needs to be done. For example, the strength of association, or effect size, as measured by odds ratios (ORs) varies widely across studies and is generally small. Yet, these GWAS have identified a number of candidate genes that need to be replicated and their functional roles determined. Despite the increasing number of identified susceptibility genetic variants, a relatively large proportion of genetic variance remains unexplained.18 This has much to do with both the complexity of the genetics and inadequacy of heritability as a measure of genetic contribution. Similar phenomena have been observed in other common, complex genetic diseases and invoked a term, genetic dark matter, in GWAS.19,20