Dementia revealed: novel chromosome 6 locus for late-onset Alzheimer disease provides genetic evidence for folate-pathway abnormalities

Abstract

Genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) have consistently observed strong evidence of association with polymorphisms in APOE. However, until recently, variants at few other loci with statistically significant associations have replicated across studies. The present study combines data on 483,399 single nucleotide polymorphisms (SNPs) from a previously reported GWAS of 492 LOAD cases and 496 controls and from an independent set of 439 LOAD cases and 608 controls to strengthen power to identify novel genetic association signals. Associations exceeding the experiment-wide significance threshold (alpha=1.03x10(-7)) were replicated in an additional 1,338 cases and 2,003 controls. As expected, these analyses unequivocally confirmed APOE's risk effect (rs2075650, P=1.9x10(-36)). Additionally, the SNP rs11754661 at 151.2 Mb of chromosome 6q25.1 in the gene MTHFD1L (which encodes the methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like protein) was significantly associated with LOAD (P=4.70x10(-8); Bonferroni-corrected P=0.022). Subsequent genotyping of SNPs in high linkage disequilibrium (r2>0.8) with rs11754661 identified statistically significant associations in multiple SNPs (rs803424, P=0.016; rs2073067, P=0.03; rs2072064, P=0.035), reducing the likelihood of association due to genotyping error. In the replication case-control set, we observed an association of rs11754661 in the same direction as the previous association at P=0.002 (P=1.90x10(-10) in combined analysis of discovery and replication sets), with associations of similar statistical significance at several adjacent SNPs (rs17349743, P=0.005; rs803422, P=0.004). In summary, we observed and replicated a novel statistically significant association in MTHFD1L, a gene involved in the tetrahydrofolate synthesis pathway. This finding is noteworthy, as MTHFD1L may play a role in the generation of methionine from homocysteine and influence homocysteine-related pathways and as levels of homocysteine are a significant risk factor for LOAD development.

Figure 1. Quantile-Quantile plots for 483,399 single SNP tests of association.

Plots depict expected versus observed −log10 P-values for 483,399 single SNP tests of association (in 931 LOAD cases and 1,104 cognitive controls, with adjustment for principal components as covariates for population substructure). Plot A includes the most-strongly associated SNPs within the APOE locus, whereas plot B excludes the three most-strongly associated SNPs for clarity.

Figure 2. Manhattan plot of SNP associations in MTHFD1L, on chromosome 6 between 151.2 Mb and 151.3 Mb.

Plot of −log10 P-values for single SNP tests of association with LOAD with adjustment for population substructure for the chromosome 6 region from 151.2Mb to 151.3Mb in MTHFD1L. Blue circles depict results for SNPs examined as part of genomewide association testing, whereas the green circle depicts the genome wide significant association of rs11754661 and the green triangles show the association results of the additional six SNPs proximal to rs11754661 genotyped on the Taqman platform. The orange line below the x-axis depicts the exons (thick line) and introns (thin line) of the MTHFD1L, oriented 5′ to 3′ from left to right.