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 () were replicated in an additional 1,338 cases and 2,003 controls. As expected, these analyses unequivocally confirmed APOE's risk effect (rs2075650, ). 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 (; Bonferroni-corrected P = 0.022). Subsequent genotyping of SNPs in high linkage disequilibrium () 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 ( 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.
Highlights
Alzheimer disease (AD) [MIM 104300] is a neurodegenerative disorder characterized by memory and cognitive impairment affecting more than 13% of individuals aged 65 years and older [1,2] and constitutes the most common form of dementia among older adults
The most significant non-APOE single nucleotide polymorphisms (SNPs) in our previous genome-wide association study (GWAS) [18] (Table S3) was rs11610206 on 12q13 (45.92 Mb) with P~1:43|10{6; in this study, this SNP was still strongly assoFciated with late-onset Alzheimer disease (LOAD) (OR: 0.67 (0.54, 0.85); P~7:70|10{4), but not with experiment-wide statistical significance
Associations with experiment-wide statistical significance have not been observed for MTHFD1L in previous GWAS of LOAD, biological evidence suggests a role for this gene in dementia and AD pathology
Summary
Alzheimer disease (AD) [MIM 104300] is a neurodegenerative disorder characterized by memory and cognitive impairment affecting more than 13% of individuals aged 65 years and older [1,2] and constitutes the most common form of dementia among older adults. While several major genes contributing to risk of Alzheimer Disease have been identified (APP [3], PS1 [4], PS2 [5,6,7]), all but one (APOE [8,9,10]) contributed predominantly to earlyonset forms of AD that cluster within families; other than APOE, few consistent association signals have been observed for late-onset AD (LOAD). Eleven studies have tested association with LOAD on genome-wide panels of single nucleotide polymorphisms (SNPs). Most [13,14,15,16,17,18,19,20,21,22], but not all [23], of these studies indirectly observed associations with APOE on chromosome 19q with strong experiment-wide statistical significance.
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