GAB2 as an Alzheimer Disease Susceptibility Gene: Follow-up of Genomewide Association Results

Although the heritability of late-onset Alzheimer disease (AD) is high,1,2 our knowledge of the underlying putative susceptibility genes remains incomplete. The only unequivocally established late-onset AD gene is APOE (OMIM 107741) (encoding apolipoprotein E), whose e4 allele increases the risk for AD by 4- to 15-fold in a dose-dependent manner.3,4 APOE and most other genetic association findings in AD originate from candidate gene approaches (ie, studies that investigate certain genes based on a prior hypothesis regarding their potential involvement in pathogenesis).5 An alternative to this approach is afforded by recent advances in large-scale genotyping technologies enabling researchers to perform comprehensive unbiased genomewide association (GWA) analyses.6 To date, 3 groups have reported the results of AD GWA analyses.7–9 The first group used a low-density design testing roughly 17 000 single-nucleotide polymorphisms (SNPs) in or near genetic coding regions in almost 4000 combined cases and controls, including several confirmed by autopsy.7 The only SNPs consistently associated with AD risk across different samples were located within or in proximity to APOE and most likely reflect linkage disequilibrium (LD) with the e4 allele. Although several additional loci were highlighted as potential AD genes by the authors, none showed the same consistency of effect or level of statistical significance as the e4-related variants. The second group tested approximately 500 000 SNPs in roughly 1100 unrelated AD cases (all with neuropathologically confirmed diagnoses) and controls.8 Again, except for a single SNP in strong LD with APOE e4, no other genomewide significant signals were observed. In a follow-up article,10 the same group reported evidence of an association between variants in GRB2-associated binding protein 2 (Gab2 [gene abbreviation, GAB2]) (OMIM 606203) on chromosome 11q14 and AD risk in the same 1100 neuropathologically confirmed persons and in approximately 360 clinically diagnosed AD cases and controls, but this was noted only in carriers of APOE e4. The association was observed with 10 different SNPs in GAB2, all displaying high degrees of LD, indicating that they likely point to the same underlying signal. Finally, the third group tested almost 500 000 markers in approximately 1500 clinically diagnosed AD cases and controls from Canada (replicated in approximately 670 AD cases and controls from the United Kingdom). They reported an association between variants in Golgi membrane protein 1 (encoded by GOLM1 [OMIM 606804], also known as GOLPH2) on chromosome 9q22 and 2 uncharacterized loci on chromosomes 9p and 15q.9 The findings from the 2 high-density GWA screens are summarized in Table 1. Table 1 Summary of Findings in High-Density Genomewide Association (GWA) Screens in Alzheimer Disease (AD) In the present study, we assessed the 4 putative AD loci that emerged from 2 high-density 500000 GWA screens.