title: 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.
authors.affiliation: Dr. John T. Macdonald Foundation Department of Human Genetics, John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, United States of America.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Naj
authors.forename: Gary W
authors.initials: GW
authors.lastname: Beecham
authors.forename: Eden R
authors.initials: ER
authors.lastname: Martin
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Gallins
authors.forename: Eric H
authors.initials: EH
authors.lastname: Powell
authors.forename: Ioanna
authors.initials: I
authors.lastname: Konidari
authors.forename: Patrice L
authors.initials: PL
authors.lastname: Whitehead
authors.forename: Guiqing
authors.initials: G
authors.lastname: Cai
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.forename: William K
authors.initials: WK
authors.lastname: Scott
authors.forename: Jeffery M
authors.initials: JM
authors.lastname: Vance
authors.forename: Michael A
authors.initials: MA
authors.lastname: Slifer
authors.forename: Harry E
authors.initials: HE
authors.lastname: Gwirtsman
authors.forename: John R
authors.initials: JR
authors.lastname: Gilbert
authors.forename: Jonathan L
authors.initials: JL
authors.lastname: Haines
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Margaret A
authors.initials: MA
authors.lastname: Pericak-Vance
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics*; D000619:Aminohydrolases / Q000235:genetics; D020029:Base Pairing / Q000235:genetics; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D030541:Databases, Genetic; D003704:Dementia / Q000235:genetics*; D003710:Demography; D005260:Female; D005492:Folic Acid / Q000378:metabolism*; D005574:Formate-Tetrahydrofolate Ligase / Q000235:genetics; D056426:Genetic Loci / Q000235:genetics*; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D053858:Metabolic Networks and Pathways / Q000235:genetics*; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP) / Q000235:genetics; D009097:Multienzyme Complexes / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D015203:Reproducibility of Results
chemical_list: D009097:Multienzyme Complexes; C021836:formyl-methenyl-methylenetetrahydrofolate synthetase; D005492:Folic Acid; D008754:Methylenetetrahydrofolate Dehydrogenase (NADP); D000619:Aminohydrolases; D005574:Formate-Tetrahydrofolate Ligase