Genome-wide association of familial late-onset alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE

Ellen M. Wijsman, Nathan D. Pankratz, Yoonha Choi, Joseph H. Rothstein, Kelley M. Faber, Rong Cheng, Joseph H. Lee, Thomas D. Bird, David A. Bennett, Ramon Diaz-Arrastia, Alison M. Goate, Martin Farlow, Bernardino Ghetti, Robert A. Sweet, Tatiana Foroud, Richard Mayeux

Research output: Contribution to journalArticle

148 Citations (Scopus)

Abstract

Late-onset Alzheimer's disease (LOAD) is the most common form of dementia in the elderly. The National Institute of Aging-Late Onset Alzheimer's Disease Family Study and the National Cell Repository for Alzheimer's Disease conducted a joint genome-wide association study (GWAS) of multiplex LOAD families (3,839 affected and unaffected individuals from 992 families plus additional unrelated neurologically evaluated normal subjects) using the 610 IlluminaQuad panel. This cohort represents the largest family-based GWAS of LOAD to date, with analyses limited here to the European-American subjects. SNPs near APOE gave highly significant results (e.g., rs2075650, p = 3.2×10-81), but no other genome-wide significant evidence for association was obtained in the full sample. Analyses that stratified on APOE genotypes identified SNPs on chromosome 10p14 in CUGBP2 with genome-wide significant evidence for association within APOE ε4 homozygotes (e.g., rs201119, p = 1.5×10-8). Association in this gene was replicated in an independent sample consisting of three cohorts. There was evidence of association for recently-reported LOAD risk loci, including BIN1 (rs7561528, p = 0.009 with, and p = 0.03 without, APOE adjustment) and CLU (rs11136000, p = 0.023 with, and p = 0.008 without, APOE adjustment), with weaker support for CR1. However, our results provide strong evidence that association with PICALM (rs3851179, p = 0.69 with, and p = 0.039 without, APOE adjustment) and EXOC3L2 is affected by correlation with APOE, and thus may represent spurious association. Our results indicate that genetic structure coupled with ascertainment bias resulting from the strong APOE association affect genome-wide results and interpretation of some recently reported associations. We show that a locus such as APOE, with large effects and strong association with disease, can lead to samples that require appropriate adjustment for this locus to avoid both false positive and false negative evidence of association. We suggest that similar adjustments may also be needed for many other large multi-site studies.

Original languageEnglish
Article numbere1001308
JournalPLoS Genetics
Volume7
Issue number2
DOIs
StatePublished - Feb 2011

Fingerprint

Alzheimer disease
Social Adjustment
Alzheimer Disease
genome
Genome
Genome-Wide Association Study
loci
Single Nucleotide Polymorphism
family studies
dementia
Genetic Structures
Homozygote
homozygosity
sampling
Dementia
Alzheimer disease type 2
repository
genetic structure
Chromosomes
Genotype

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Wijsman, E. M., Pankratz, N. D., Choi, Y., Rothstein, J. H., Faber, K. M., Cheng, R., ... Mayeux, R. (2011). Genome-wide association of familial late-onset alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. PLoS Genetics, 7(2), [e1001308]. https://doi.org/10.1371/journal.pgen.1001308

Genome-wide association of familial late-onset alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. / Wijsman, Ellen M.; Pankratz, Nathan D.; Choi, Yoonha; Rothstein, Joseph H.; Faber, Kelley M.; Cheng, Rong; Lee, Joseph H.; Bird, Thomas D.; Bennett, David A.; Diaz-Arrastia, Ramon; Goate, Alison M.; Farlow, Martin; Ghetti, Bernardino; Sweet, Robert A.; Foroud, Tatiana; Mayeux, Richard.

In: PLoS Genetics, Vol. 7, No. 2, e1001308, 02.2011.

Research output: Contribution to journalArticle

Wijsman, EM, Pankratz, ND, Choi, Y, Rothstein, JH, Faber, KM, Cheng, R, Lee, JH, Bird, TD, Bennett, DA, Diaz-Arrastia, R, Goate, AM, Farlow, M, Ghetti, B, Sweet, RA, Foroud, T & Mayeux, R 2011, 'Genome-wide association of familial late-onset alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE', PLoS Genetics, vol. 7, no. 2, e1001308. https://doi.org/10.1371/journal.pgen.1001308
Wijsman, Ellen M. ; Pankratz, Nathan D. ; Choi, Yoonha ; Rothstein, Joseph H. ; Faber, Kelley M. ; Cheng, Rong ; Lee, Joseph H. ; Bird, Thomas D. ; Bennett, David A. ; Diaz-Arrastia, Ramon ; Goate, Alison M. ; Farlow, Martin ; Ghetti, Bernardino ; Sweet, Robert A. ; Foroud, Tatiana ; Mayeux, Richard. / Genome-wide association of familial late-onset alzheimer's disease replicates BIN1 and CLU and nominates CUGBP2 in interaction with APOE. In: PLoS Genetics. 2011 ; Vol. 7, No. 2.
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