title: Genetic Modifiers of Age at Onset in Carriers of the G206A Mutation in PSEN1 With Familial Alzheimer Disease Among Caribbean Hispanics.
abstract: OBJECTIVE
  The present study identified potential genetic modifiers that may delay or accelerate age at onset of familial Alzheimer disease (AD) by examining age at onset in PSEN1 mutation carrier families, and further investigation of these modifiers may provide insight into the pathobiology of AD and potential therapeutic measures.
  
  
  OBJECTIVE
  To identify genetic variants that modify age at onset of AD.
  
  
  METHODS
  Using a subset of Caribbean Hispanic families that carry the PSEN1 p.G206A mutation, we performed a 2-stage genome study. The mutation carrier families from an ongoing genetic study served as a discovery set, and the cohort of those with LOAD served as a confirmation set. To identify candidate loci, we performed linkage analysis using 5 p.G206A carrier families (n = 56), and we also performed whole-exome association analysis using 31 p.G206A carriers from 26 families. To confirm the genetic modifiers identified from the p.G206A carrier families, we analyzed the GWAS data for 2888 elderly individuals with LOAD. All study participants were Caribbean Hispanics.
  
  
  METHODS
  Age at onset of AD.
  
  
  RESULTS
  Linkage analysis of AD identified the strongest linkage support at 4q35 (LOD [logarithm of odds] score, 3.69), and the GWAS of age at onset identified variants on 1p13.1, 2q13, 4q25, and 17p11. In the confirmation stage, genewise analysis identified SNX25, PDLIM3, and 3 SH3 domain genes (SORBS2, SH3RF3, and NPHP1) to be significantly associated with LOAD. Subsequent allelic association analysis confirmed SNX25, PDLIM3, and SORBS2 as genetic modifiers of age at onset of EOAD and LOAD and provided modest support for SH3RF3 and NPHP1.
  
  
  CONCLUSIONS
  Our 2-stage analysis revealed that SNX25, PDLIM3, and SORBS2 may serve as genetic modifiers of age at onset in both EOAD and LOAD.
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York2Gertrude H. Sergievsky Center, Columbia University, New York, New York3Department of Epidemiology, School of Public Health, Columbia Univer.
authors.forename: Joseph H
authors.initials: JH
authors.lastname: Lee
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York2Gertrude H. Sergievsky Center, Columbia University, New York, New York.
authors.forename: Rong
authors.initials: R
authors.lastname: Cheng
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York2Gertrude H. Sergievsky Center, Columbia University, New York, New York.
authors.forename: Badri
authors.initials: B
authors.lastname: Vardarajan
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York4Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Rafael
authors.initials: R
authors.lastname: Lantigua
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York.
authors.forename: Dolly
authors.initials: D
authors.lastname: Reyes-Dumeyer
authors.affiliation: Genentech, South San Francisco, California.
authors.forename: Ward
authors.initials: W
authors.lastname: Ortmann
authors.affiliation: Genentech, South San Francisco, California.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.affiliation: Genentech, South San Francisco, California.
authors.forename: Tushar
authors.initials: T
authors.lastname: Bhangale
authors.affiliation: Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York.
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Behrens
authors.affiliation: School of Medicine, Pontificia Universidad Catolica Madre y Maestra, Santiago, Dominican Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Medrano
authors.affiliation: Department of Internal Medicine, University of Puerto Rico School of Medicine, San Juan, Puerto Rico.
authors.forename: Ivonne Z
authors.initials: IZ
authors.lastname: Jiménez-Velázquez
authors.affiliation: The Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, New York2Gertrude H. Sergievsky Center, Columbia University, New York, New York3Department of Epidemiology, School of Public Health, Columbia Univer.
authors.forename: Richard
authors.initials: R
authors.lastname: Mayeux
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D017668:Age of Onset; D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D017691:Caribbean Region / Q000453:epidemiology / Q000208:ethnology; D019295:Computational Biology; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006630:Hispanic or Latino / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D060588:LIM Domain Proteins / Q000235:genetics; D008297:Male; D015201:Meta-Analysis as Topic; D008840:Microfilament Proteins / Q000235:genetics; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D053764:Presenilin-1 / Q000235:genetics*; D016601:RNA-Binding Proteins; D058305:Sorting Nexins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018398:Homeodomain Proteins; D060588:LIM Domain Proteins; D008840:Microfilament Proteins; C108834:PDLIM3 protein, human; C508853:PSEN1 protein, human; D053764:Presenilin-1; D016601:RNA-Binding Proteins; C517049:SNX25 protein, human; C490755:SORBS2 protein, human; D058305:Sorting Nexins