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Follow-up of Genomewide Association Results

Brit-Maren M. Schjeide, BS; Basavaraj Hooli, MS; Michele Parkinson, BS; Meghan F. Hogan, BS; Jason DiVito, BS; Kristina Mullin, BS; Deborah Blacker, MD, ScD; Rudolph E. Tanzi, PhD; Lars Bertram, MD

Arch Neurol. 2009;66(2):250-254. doi:10.1001/archneurol.2008.552

Background  Genomewide association (GWA) studies have recently implicated 4 novel Alzheimer disease (AD) susceptibility loci (GAB2, GOLM1, and 2 uncharacterized loci to date on chromosomes 9p and 15q). To our knowledge, these findings have not been independently replicated.

Objective  To assess these GWA findings in 4 large data sets of families affected by AD.

Design  Follow-up of genetic association findings in previous studies.

Setting  Academic research.

Participants  More than 4000 DNA samples from almost 1300 families affected with AD.

Main Outcome Measures  Genetic association analysis testing of 4 GWA signals (rs7101429 [GAB2], rs7019241 [GOLM1], rs10519262 [chromosome 15q], and rs9886784 [chromosome 9p]) using family-based methods.

Results  In the combined analyses, only rs7101429 in GAB2 yielded significant evidence of association with the same allele as in the original GWA study (P =.002). The results are in agreement with recent meta-analyses of this and other GAB2 polymorphisms suggesting approximately a 30% decrease in risk for AD among carriers of the minor alleles. None of the other 3 tested loci showed consistent evidence for association with AD across the investigated data sets.

Conclusions  GAB2 contains genetic variants that may lead to a modest change in the risk for AD. Despite these promising results, more data from independent samples are needed to better evaluate the potential contribution of GAB2 to AD risk in the general population.

Author Affiliations: Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology (Mss Schjeide, Parkinson, Hogan, and Mullin, Messrs Hooli and DiVito, and Drs Tanzi and Bertram), and Gerontology Research Unit, Department of Psychiatry (Dr Blacker), Massachusetts General Hospital, Harvard Medical School, Charlestown, and Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts (Dr Blacker).

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