Dementia Revealed: Novel Chromosome 6 Locus for Late-Onset Alzheimer Disease Provides Genetic Evidence for Folate-Pathway Abnormalities

• DOI: 10.1371/journal.pgen.1001130
• Publication Date: 2010-09-23T19:38:19Z
• Authors: Adam C. Naj; Gary W. Beecham; Eden R. Martin; Paul J. Gallins; Eric H. Powell; Ioanna Konidari; Patrice L. Whitehead; Guiqing Cai; Vahram Haroutunian; William K. Scott; Jeffery M. Vance; Michael A. Slifer; Harry E. Gwirtsman; John R. Gilbert; Jonathan L. Haines; Joseph D. Buxbaum; Margaret A. Peric...
• Keywords: Genome-wide Association Study; Linkage Disequilibrium; Genetic Association; SNP; Bonferroni correction

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