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

TitleDementia revealed: novel chromosome 6 locus for late-onset Alzheimer disease provides genetic evidence for folate-pathway abnormalities.
Publication TypeJournal Article
Year of Publication2010
AuthorsNaj AC, Beecham GW, Martin ER, Gallins PJ, Powell EH, Konidari I, Whitehead PL, Cai G, Haroutunian V, Scott WK, Vance JM, Slifer MA, Gwirtsman HE, Gilbert JR, Haines JL, Buxbaum JD, Pericak-Vance MA
JournalPLoS Genet
Volume6
Issue9
Paginatione1001130
Date Published2010 Sep 23
ISSN1553-7404
KeywordsAged, Alzheimer Disease, Aminohydrolases, Base Pairing, Chromosomes, Human, Pair 6, Databases, Genetic, Dementia, Demography, Female, Folic Acid, Formate-Tetrahydrofolate Ligase, Genetic Loci, Genome-Wide Association Study, Humans, Male, Metabolic Networks and Pathways, Methylenetetrahydrofolate Dehydrogenase (NADP), Multienzyme Complexes, Polymorphism, Single Nucleotide, Reproducibility of Results
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.

DOI10.1371/journal.pgen.1001130
Alternate JournalPLoS Genet.
PubMed ID20885792
PubMed Central IDPMC2944795
Grant ListAG19757 / AG / NIA NIH HHS / United States
U24 AG021886 / AG / NIA NIH HHS / United States
R01 NS031153 / NS / NINDS NIH HHS / United States
P50 NS039764 / NS / NINDS NIH HHS / United States
AG010491 / AG / NIA NIH HHS / United States
AG002219 / AG / NIA NIH HHS / United States
AG027944 / AG / NIA NIH HHS / United States
P01 AG002219 / AG / NIA NIH HHS / United States
NS31153 / NS / NINDS NIH HHS / United States
P01 AG010491 / AG / NIA NIH HHS / United States
R01 AG020135 / AG / NIA NIH HHS / United States
P50 AG005138 / AG / NIA NIH HHS / United States
R01 AG019757 / AG / NIA NIH HHS / United States
R01 AG027944 / AG / NIA NIH HHS / United States
U24 AG21886 / AG / NIA NIH HHS / United States
AG20135 / AG / NIA NIH HHS / United States
NS039764 / NS / NINDS NIH HHS / United States
AG005138 / AG / NIA NIH HHS / United States