Communicated by Christine Van Broeckhoven
Exploratory data from complete genomes of familial alzheimer disease age-at-onset outliers†
Article first published online: 10 AUG 2012
© 2012 Wiley Periodicals, Inc.
Volume 33, Issue 12, pages 1630–1634, December 2012
How to Cite
Lalli, M. A., Garcia, G., Madrigal, L., Arcos-Burgos, M., Arcila, M. L., Kosik, K. S. and Lopera, F. (2012), Exploratory data from complete genomes of familial alzheimer disease age-at-onset outliers. Hum. Mutat., 33: 1630–1634. doi: 10.1002/humu.22167
- Issue published online: 12 NOV 2012
- Article first published online: 10 AUG 2012
- Accepted manuscript online: 24 JUL 2012 09:11AM EST
- Manuscript Accepted: 7 JUL 2012
- Manuscript Received: 13 MAR 2012
- Errett Fisher Foundation and the NIH Fogarty Institute (grants R21 AG024063 and R01 AG029802).
- Alzheimer disease;
- whole-genome sequencing;
- age at onset;
- identity by descent
Identifying genes that modify the age at onset (AAO) of Alzheimer disease and targeting them pharmacologically represent a potential treatment strategy. In this exploratory study, we sequenced the complete genomes of six individuals with familial Alzheimer disease due to the autosomal dominant mutation p.Glu280Ala in PSEN1 (MIM# 104311; NM_000021.3:c.839A>C). The disease and its AAO are highly heritable, motivating our search for genetic variants that modulate AAO. The median AAO of dementia in carriers of the mutant allele is 49 years. Extreme phenotypic outliers for AAO in this genetically isolated population with limited environmental variance are likely to harbor onset modifying genetic variants. A narrow distribution of AAO in this kindred suggests large effect sizes of genetic determinants of AAO in these outliers. Identity by descent (IBD) analysis and a combination of bioinformatics filters have suggested several candidate variants for AAO modifiers. Future work and replication studies on these variants may provide mechanistic insights into the etiopathology of Alzheimer disease. Hum Mutat 33:1630–1634, 2012. © 2012 Wiley Periodicals, Inc.