Common variation inGRB-associated Binding Protein 2 (GAB2)and increased risk for Alzheimer dementia

Abstract

GRB-associated binding protein 2 (GAB2) was recently reported to be a modifier of late-onsetAlzheimer 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.

Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease

“…Indeed, variants in unlinked modifier genes have been reported to influence penetrance in a variety of different inherited diseases including pancreatitis (Khalid et al 2006), breast cancer (Wolf et al 2010; Wang et al 2010a; Walker et al 2010; Antoniou and Chenevix-Trench 2010; Esteban Cardeñosa et al 2012; Harlid et al 2012), Gaucher disease (Taddei et al 2009; Zhang et al 2012), retinitis pigmentosa (Rio Frio et al 2008; Venturini et al 2012), haemochromatosis (Krayenbuehl et al 2010), hypertrophic cardiomyopathy (Daw et al 2007), frontotemporal lobar degeneration (Finch et al 2011) and amyloid polyneuropathy (Soares et al 2005) among others. In familial late-onset Alzheimer disease, modifying loci may either influence the risk (Sleegers et al 2009; Cruchaga et al 2012) or the age of onset of disease (Wijsman et al 2005; Marchani et al 2010). Importantly, a significant excess of rare coding APP , PSEN1 and PSEN2 variants was noted in probands from late-onset Alzheimer disease families even though these variants did not actually co-segregate with the disease; this suggests that the variants in question may nevertheless serve to modulate the risk of disease (Cruchaga et al 2012).…”

The Gab2 in signal transduction and its potential role in the pathogenesis of Alzheimer’s disease

“…Three similar studies from USA, Netherlands and Belgian in Caucasian population all independently confirm an association between Gab2 and LOAD. Moreover, this association appears to be limited to ApoE ε4 carriers [27][28][29] . And Benedetta et al have found that in Italian population, the involvement of Gab2 polymorphism in the risk of AD is confined to ApoE ε4 non-carriers, suggesting a possible role of Gab2 as an independent risk factor for AD [30] .…”

Association between GAB2 haplotype and higher glucose metabolism in Alzheimer's disease-affected brain regions in cognitively normal APOEε4 carriers

“…Based on the HapMap CEU (Caucasian European) population, consisting of Utah residents with Northern and Western European ancestry from the CEPH (Centre d'Etude du Polymorphisme Humain) collection (http://hapmap.ncbi.nlm.nih.gov/index.html.en), the population frequency for the risk haplotype is 0.836, 0.112 for the protective haplotype, and 0.036 for the neutral haplotype. Several independent groups have confirmed the association between these GAB2 variants in APOEε4 carriers ((Feulner et al, 2009; Ikram et al, 2009; Nacmias et al, 2009; Schjeide et al, 2009; Sleegers et al, 2009), though with lower odds ratios than in the original report, raising the possibility of a common phenomenon in genetic associations studies known as “winners curse” (Nakaoka and Inoue, 2009). Other studies have failed to confirm the association (but have limited power to refute an association with adequate statistical power) (Harold et al, 2009; Li et al, 2008; Lin et al, 2009; Miyashita et al, 2009; Ramirez-Lorca et al, 2009).…”