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Common variation in GRB‐associated Binding Protein 2 (GAB2) and increased risk for Alzheimer dementia
Author(s) -
Sleegers Kristel,
Bettens Karolien,
Brouwers Nathalie,
Engelborghs Sebastiaan,
van Miegroet Helen,
De Deyn Peter P,
Van Broeckhoven Christine
Publication year - 2009
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20909
Subject(s) - apolipoprotein e , haplotype , single nucleotide polymorphism , allele , biology , genotype , dementia , genetic association , medicine , genome wide association study , genetics , disease , gene
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 ε4 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 ε4 these associations were present in APOE ε4 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 ε4 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 ε4 + (global p sim 0.02) but not in the APOE ε4 ‐ 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 ε4 carriers. © 2008 Wiley‐Liss, Inc.