A genetic variant near the gene for MTHFD1L on chromosome 6 likely doubles a person’s risk of late-onset Alzheimer disease, according to research presented today at the American Academy of Neurology meeting in Toronto, Canada. The discovery, from a large genomewide association screen, jibes well with what is known about the protein’s role in metabolizing homocysteine, a known risk factor for Alzheimer’s. First author Adam Naj and principal investigator Margaret Pericak-Vance, both of the University of Miami, Florida, outlined the finding in a poster session.
The study authors hunted for AD-linked genes in a genomewide association study encompassing nearly 500,000 SNPs and including more than 2,000 AD subjects, and over 3,000 controls in the combined discovery and confirmation datasets. They found that SNPs in and around the MTHFD1L gene were linked to AD risk, with the disease-associated variants doubling risk. In comparison, the ApoE4 allele increases AD risk by a factor of 3.68. However, the presenters noted that the odds ratio of two is likely to go down a bit with further study.
MTHFD1L encodes a protein, methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like, that may help convert homocysteine into methionine, so problems with this gene might lead to elevated homocysteine levels. Increased plasma homocysteine is a well-known AD risk factor (see ARF related news story on Seshadri et al., 2002). In addition, MTHFD1L variants have been linked to coronary disease (Coronary Artery Disease Consortium, 2009) and dementia can be caused by reduced blood flow to the brain, so the link among MTHFD1L, Alzheimer’s, and coronary disease is compelling, Pericak-Vance said.
Other studies have not found a significant association between SNPs near MTHFD1L AD (see AlzGene), although some GWAS have come close. Pericak-Vance and Naj suggested that their study met stringent statistical GWAS thresholds because of the particular SNPs they analyzed, and the size of the cohort.
The authors speculated that carriers of the MTHFD1L disease-linked variant are unable to properly convert homocysteine to methionine, allowing homocysteine to build up. This molecule could then cause disease by altering vasculature, increasing oxidative stress, or poisoning cortical neurons. However, Naj noted that it is too soon to be sure what happens in people with different MTHFD1L variants. “We have no evidence to go on as to what it actually does,” he told ARF. As with any GWAS, it will be necessary to look for the significance of this gene in other datasets to confirm its importance. The researchers are currently sequencing MTHFD1L and testing plasma homocysteine levels in control and AD samples.—Amber Dance.
- Seshadri S, Beiser A, Selhub J, Jacques PF, Rosenberg IH, D'Agostino RB, Wilson PW, Wolf PA. Plasma homocysteine as a risk factor for dementia and Alzheimer's disease. N Engl J Med. 2002 Feb 14;346(7):476-83. PubMed.
- , Samani NJ, Deloukas P, Erdmann J, Hengstenberg C, Kuulasmaa K, McGinnis R, Schunkert H, Soranzo N, Thompson J, Tiret L, Ziegler A. Large scale association analysis of novel genetic loci for coronary artery disease. Arterioscler Thromb Vasc Biol. 2009 May;29(5):774-80. PubMed.
- Olson JM, Goddard KA, Dudek DM. A second locus for very-late-onset Alzheimer disease: a genome scan reveals linkage to 20p and epistasis between 20p and the amyloid precursor protein region. Am J Hum Genet. 2002 Jul;71(1):154-61. PubMed.
- Figgins JA, Minster RL, Demirci FY, Dekosky ST, Kamboh MI. Association studies of 22 candidate SNPs with late-onset Alzheimer's disease. Am J Med Genet B Neuropsychiatr Genet. 2009 Jun 5;150B(4):520-6. PubMed.
- Li H, Wetten S, Li L, St Jean PL, Upmanyu R, Surh L, Hosford D, Barnes MR, Briley JD, Borrie M, Coletta N, Delisle R, Dhalla D, Ehm MG, Feldman HH, Fornazzari L, Gauthier S, Goodgame N, Guzman D, Hammond S, Hollingworth P, Hsiung GY, Johnson J, Kelly DD, Keren R, Kertesz A, King KS, Lovestone S, Loy-English I, Matthews PM, Owen MJ, Plumpton M, Pryse-Phillips W, Prinjha RK, Richardson JC, Saunders A, Slater AJ, St George-Hyslop PH, Stinnett SW, Swartz JE, Taylor RL, Wherrett J, Williams J, Yarnall DP, Gibson RA, Irizarry MC, Middleton LT, Roses AD. Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol. 2008 Jan;65(1):45-53. PubMed.
- Dorszewska J, Florczak J, Rozycka A, Kempisty B, Jaroszewska-Kolecka J, Chojnacka K, Trzeciak WH, Kozubski W. Oxidative DNA damage and level of thiols as related to polymorphisms of MTHFR, MTR, MTHFD1 in Alzheimer's and Parkinson's diseases. Acta Neurobiol Exp (Wars). 2007;67(2):113-29. PubMed.
- Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T, Zismann VL, Joshipura KD, Pearson JV, Hu-Lince D, Huentelman MJ, Craig DW, Coon KD, Liang WS, Herbert RH, Beach T, Rohrer KC, Zhao AS, Leung D, Bryden L, Marlowe L, Kaleem M, Mastroeni D, Grover A, Heward CB, Ravid R, Rogers J, Hutton ML, Melquist S, Petersen RC, Alexander GE, Caselli RJ, Kukull W, Papassotiropoulos A, Stephan DA. GAB2 alleles modify Alzheimer's risk in APOE epsilon4 carriers. Neuron. 2007 Jun 7;54(5):713-20. PubMed.
- Blacker D, Bertram L, Saunders AJ, Moscarillo TJ, Albert MS, Wiener H, Perry RT, Collins JS, Harrell LE, Go RC, Mahoney A, Beaty T, Fallin MD, Avramopoulos D, Chase GA, Folstein MF, McInnis MG, Bassett SS, Doheny KJ, Pugh EW, Tanzi RE, . Results of a high-resolution genome screen of 437 Alzheimer's disease families. Hum Mol Genet. 2003 Jan 1;12(1):23-32. PubMed.
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