Genome-wide association analysis reveals putative Alzheimer's disease susceptibility loci in addition to APOE

Abstract

Alzheimer's disease (AD) is a genetically complex and heterogeneous disorder. To date four genes have been established to either cause early-onset autosomal-dominant AD (APP, PSEN1, and PSEN2(1-4)) or to increase susceptibility for late-onset AD (APOE5). However, the heritability of late-onset AD is as high as 80%, (6) and much of the phenotypic variance remains unexplained to date. We performed a genome-wide association (GWA) analysis using 484,522 single-nucleotide polymorphisms (SNPs) on a large (1,376 samples from 410 families) sample of AD families of self-reported European descent. We identified five SNPs showing either significant or marginally significant genome-wide association with a multivariate phenotype combining affection status and onset age. One of these signals (p = 5.7 x 10(-14)) was elicited by SNP rs4420638 and probably reflects APOE-epsilon4, which maps 11 kb proximal (r2 = 0.78). The other four signals were tested in three additional independent AD family samples composed of nearly 2700 individuals from almost 900 families. Two of these SNPs showed significant association in the replication samples (combined p values 0.007 and 0.00002). The SNP (rs11159647, on chromosome 14q31) with the strongest association signal also showed evidence of association with the same allele in GWA data generated in an independent sample of approximately 1,400 AD cases and controls (p = 0.04). Although the precise identity of the underlying locus(i) remains elusive, our study provides compelling evidence for the existence of at least one previously undescribed AD gene that, like APOE-epsilon4, primarily acts as a modifier of onset age.

Figure 1

Q-Q Plot of Markers Tested in the GWA Screening Phase Distribution of FBAT-GEE p values for all 404,604 SNPs on the 500K array with ≥20 informative families as Q-Q plot depicting observed versus expected p values.

Figure 2

Kaplan-Meier Survival Curves for rs11159647 in 500K Screening Sample and Combined Follow-Up Data Set Dotted lines represent carriers of the A/A genotype, broken lines are A/G-carriers, solid lines are G/G-carriers. (A) shows the NIMH sample used in the 500K screen. (B) shows the sample after combining all follow-up samples (NIA, NCRAD, and CAG).

Figure 3

Genomic Context of the Chromosome 14q31 Association Signal Linkage disequilibrium structure and location of Genscan Gene predictions (NTSs) in a 500 kb interval encompassing rs11159647 on chromosome 14q31.2.

Figure 4

Association Results of Markers within 500 kb of the Chromosome 14q31 Association Signal Distribution of association results of SNPs on the 500K array within ±250 kb of SNP rs11159647 on chromosome 14q31 showing genome-wide significance in the NIMH-CAU sample (FBAT-GEE statistic, additive model).