GAB2 as an Alzheimer disease susceptibility gene: follow-up of genomewide association results.
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.


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


METHODS
Academic research.


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


METHODS
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.
Schjeide
Brit-Maren M
BM
Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, 114 16th St, Charlestown, MA 02129, USA.
Hooli
Basavaraj
B
Parkinson
Michele
M
Hogan
Meghan F
MF
DiVito
Jason
J
Mullin
Kristina
K
Blacker
Deborah
D
Tanzi
Rudolph E
RE
Bertram
Lars
L
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism* / Q000503:physiopathology; D001921:Brain / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D004252:DNA Mutational Analysis; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D005819:Genetic Markers / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; C490895:GAB2 protein, human; D005819:Genetic Markers