Genome-wide haplotype association study identifies the FRMD4A gene as a risk locus for Alzheimer's disease

Abstract

Recently, several genome-wide association studies (GWASs) have led to the discovery of nine new loci of genetic susceptibility in Alzheimer's disease (AD). However, the landscape of the AD genetic susceptibility is far away to be complete and in addition to single-SNP (single-nucleotide polymorphism) analyses as performed in conventional GWAS, complementary strategies need to be applied to overcome limitations inherent to this type of approaches. We performed a genome-wide haplotype association (GWHA) study in the EADI1 study (n=2025 AD cases and 5328 controls) by applying a sliding-windows approach. After exclusion of loci already known to be involved in AD (APOE, BIN1 and CR1), 91 regions with suggestive haplotype effects were identified. In a second step, we attempted to replicate the best suggestive haplotype associations in the GERAD1 consortium (2820 AD cases and 6356 controls) and observed that 9 of them showed nominal association. In a third step, we tested relevant haplotype associations in a combined analysis of five additional case-control studies (5093 AD cases and 4061 controls). We consistently replicated the association of a haplotype within FRMD4A on Chr.10p13 in all the data set analyzed (OR: 1.68; 95% CI: (1.43-1.96); P=1.1 × 10(-10)). We finally searched for association between SNPs within the FRMD4A locus and Aβ plasma concentrations in three independent non-demented populations (n=2579). We reported that polymorphisms were associated with plasma Aβ42/Aβ40 ratio (best signal, P=5.4 × 10(-7)). In conclusion, combining both GWHA study and a conservative three-stage replication approach, we characterised FRMD4A as a new genetic risk factor of AD.

Figure 1

Haplotypic Odd ratios (ORs) for Alzheimer's disease (AD) risk with the AAC haplotype derived from rs7081208, rs2446581, rs17314229 at Chromosome 10p13 in seven independent European populations.

Figure 2

Linkage disequilibrium map in the FRMD4A locus and localization of the region defined by the rs7081208, rs2446581 and rs17314229 at this locus (in bold).

Figure 3

Association of single-nucleotide polymorphism (SNP) in the FRMD4A locus with plasma Aβ₁₋₄₂/Aβ₁₋₄₀ level following meta-analyses of z-score β coefficients under an additive model adjusted for age and gender using three independent healthy populations. SNPs in red are nominally associated with Aβ peptide levels. SNPs in are the three markers defining the AAC haplotype assocated with Alzheimer's disease (AD) risk.