Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families

Carlos Cruchaga, Sumitra Chakraverty, Kevin Mayo, Francesco L M Vallania, Robi D. Mitra, Kelley Faber, Jennifer Williamson, Tom Bird, Ramon Diaz-Arrastia, Tatiana Foroud, Bradley F. Boeve, Neill R. Graff-Radford, Pamela St. Jean, Michael Lawson, Margaret G. Ehm, Richard Mayeux, Alison M. Goate, the NIA-LOAD - NCRAD Family Study Consortium for the NIA-LOAD - NCRAD Family Study Consortium

Research output: Contribution to journalArticle

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Abstract

Pathogenic mutations in APP, PSEN1, PSEN2, MAPT and GRN have previously been linked to familial early onset forms of dementia. Mutation screening in these genes has been performed in either very small series or in single families with late onset AD (LOAD). Similarly, studies in single families have reported mutations in MAPT and GRN associated with clinical AD but no systematic screen of a large dataset has been performed to determine how frequently this occurs. We report sequence data for 439 probands from late-onset AD families with a history of four or more affected individuals. Sixty sequenced individuals (13.7%) carried a novel or pathogenic mutation. Eight pathogenic variants, (one each in APP and MAPT, two in PSEN1 and four in GRN) three of which are novel, were found in 14 samples. Thirteen additional variants, present in 23 families, did not segregate with disease, but the frequency of these variants is higher in AD cases than controls, indicating that these variants may also modify risk for disease. The frequency of rare variants in these genes in this series is significantly higher than in the 1,000 genome project (p = 5.09×10 -5; OR = 2.21; 95%CI = 1.49-3.28) or an unselected population of 12,481 samples (p = 6.82×10 -5; OR = 2.19; 95%CI = 1.347-3.26). Rare coding variants in APP, PSEN1 and PSEN2, increase risk for or cause late onset AD. The presence of variants in these genes in LOAD and early-onset AD demonstrates that factors other than the mutation can impact the age at onset and penetrance of at least some variants associated with AD. MAPT and GRN mutations can be found in clinical series of AD most likely due to misdiagnosis. This study clearly demonstrates that rare variants in these genes could explain an important proportion of genetic heritability of AD, which is not detected by GWAS.

Original languageEnglish
Article numbere31039
JournalPLoS One
Volume7
Issue number2
DOIs
StatePublished - Feb 1 2012

Fingerprint

Alzheimer disease
Alzheimer Disease
Genes
mutation
Mutation
genes
penetrance
dementia
Penetrance
Genome-Wide Association Study
Diagnostic Errors
Screening
Age of Onset
Dementia
heritability
Genome
screening
sampling
genome
Population

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Cruchaga, C., Chakraverty, S., Mayo, K., Vallania, F. L. M., Mitra, R. D., Faber, K., ... for the NIA-LOAD - NCRAD Family Study Consortium, T. NIA-LOAD. . NCRAD. F. S. C. (2012). Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One, 7(2), [e31039]. https://doi.org/10.1371/journal.pone.0031039

Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. / Cruchaga, Carlos; Chakraverty, Sumitra; Mayo, Kevin; Vallania, Francesco L M; Mitra, Robi D.; Faber, Kelley; Williamson, Jennifer; Bird, Tom; Diaz-Arrastia, Ramon; Foroud, Tatiana; Boeve, Bradley F.; Graff-Radford, Neill R.; St. Jean, Pamela; Lawson, Michael; Ehm, Margaret G.; Mayeux, Richard; Goate, Alison M.; for the NIA-LOAD - NCRAD Family Study Consortium, the NIA-LOAD - NCRAD Family Study Consortium.

In: PLoS One, Vol. 7, No. 2, e31039, 01.02.2012.

Research output: Contribution to journalArticle

Cruchaga, C, Chakraverty, S, Mayo, K, Vallania, FLM, Mitra, RD, Faber, K, Williamson, J, Bird, T, Diaz-Arrastia, R, Foroud, T, Boeve, BF, Graff-Radford, NR, St. Jean, P, Lawson, M, Ehm, MG, Mayeux, R, Goate, AM & for the NIA-LOAD - NCRAD Family Study Consortium, TNIA-LOADNCRADFSC 2012, 'Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families', PLoS One, vol. 7, no. 2, e31039. https://doi.org/10.1371/journal.pone.0031039
Cruchaga C, Chakraverty S, Mayo K, Vallania FLM, Mitra RD, Faber K et al. Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. PLoS One. 2012 Feb 1;7(2). e31039. https://doi.org/10.1371/journal.pone.0031039
Cruchaga, Carlos ; Chakraverty, Sumitra ; Mayo, Kevin ; Vallania, Francesco L M ; Mitra, Robi D. ; Faber, Kelley ; Williamson, Jennifer ; Bird, Tom ; Diaz-Arrastia, Ramon ; Foroud, Tatiana ; Boeve, Bradley F. ; Graff-Radford, Neill R. ; St. Jean, Pamela ; Lawson, Michael ; Ehm, Margaret G. ; Mayeux, Richard ; Goate, Alison M. ; for the NIA-LOAD - NCRAD Family Study Consortium, the NIA-LOAD - NCRAD Family Study Consortium. / Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families. In: PLoS One. 2012 ; Vol. 7, No. 2.
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