Common Variation in GRB-associated Binding Protein 2 (GAB2) and Increased Risk for Alzheimer Dementia

GRB-associated binding protein 2 (GAB2) was recently reported to be a modifier of late-onset Alzheimer dementia (AD) risk in carriers of the APOE epsilon 4 allele in a genome-wide association analysis. We aimed to investigate this association in a well-characterized Belgian late-onset AD patient/control group: 528 Belgian AD patients (mean onset age 79.0 +/- 5.2 years, 70.2% females) and 601 ethnically matched control individuals (mean age 61.9 +/- 15.3 years, 57.1% females) were genotyped for 10 SNPs across the GAB2 locus. For 2 SNPs the most common genotype was associated with risk for AD, with the most significant result for rs4945261 [OR 1.49 (95% CI 1.04-2.15)]. After stratification by presence or absence of APOE epsilon 4 these associations were present in APOE epsilon 4 carriers only. When assessing the effect of APOE and rs4945261 in one model, rs4945261 did not show a main effect, but the joint risk effect of rs4945261-GG and APOE epsilon 4 on AD was significant (OR 3.87, 95% CI 2.66-5.63; p=1.0E-12), with a deviation of 1.87 from the multiplicative model of interaction. Haplotype analyses showed evidence of association in the total (global p(sim) 0.04) and APOE epsilon 4+ (global p(sim) 0.02) but not in the APOE epsilon 4-group (global p(sim) 0.6). The association was driven by a higher frequency of the major haplotype in patients. Our data independently replicate an association between GAB2 and late-onset AD, which appears to be limited to APOE epsilon 4 carriers. (C) 2008 Wiley-Liss, Inc.