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Common folate gene variant, MTHFR C677T, is associated with brain structure in two independent cohorts of people with mild cognitive impairment.

TitleCommon folate gene variant, MTHFR C677T, is associated with brain structure in two independent cohorts of people with mild cognitive impairment.
Publication TypeJournal Article
Year of Publication2012
AuthorsRajagopalan, P, Jahanshad, N, Stein, JL, Hua, X, Madsen, SK, Kohannim, O, Hibar, DP, Toga, AW, Jack, CR, Saykin, AJ, Green, RC, Weiner, MW, Bis, JC, Kuller, LH, Riverol, M, Becker, JT, Lopez, OL, Thompson, PM
Corporate/Institutional AuthorsAlzheimer's Disease Neuroimaging Initiative (ADNI), Cardiovascular Health Study (CHS)
JournalNeuroimage Clin
Volume1
Issue1
Pagination179-87
Date Published2012
ISSN2213-1582
Abstract<p>A commonly carried C677T polymorphism in a folate-related gene, MTHFR, is associated with higher plasma homocysteine, a well-known mediator of neuronal damage and brain atrophy. As homocysteine promotes brain atrophy, we set out to discover whether people carrying the C677T MTHFR polymorphism which increases homocysteine, might also show systematic differences in brain structure. Using tensor-based morphometry, we tested this association in 359 elderly Caucasian subjects with mild cognitive impairment (MCI) (mean age: 75 ± 7.1 years) scanned with brain MRI and genotyped as part of Alzheimer's Disease Neuroimaging Initiative. We carried out a replication study in an independent, non-overlapping sample of 51 elderly Caucasian subjects with MCI (mean age: 76 ± 5.5 years), scanned with brain MRI and genotyped for MTHFR, as part of the Cardiovascular Health Study. At each voxel in the brain, we tested to see where regional volume differences were associated with carrying one or more MTHFR 'T' alleles. In ADNI subjects, carriers of the MTHFR risk allele had detectable brain volume deficits, in the white matter, of up to 2-8% per risk T allele locally at baseline and showed accelerated brain atrophy of 0.5-1.5% per T allele at 1 year follow-up, after adjusting for age and sex. We replicated these brain volume deficits of up to 5-12% per MTHFR T allele in the independent cohort of CHS subjects. As expected, the associations weakened after controlling for homocysteine levels, which the risk gene affects. The MTHFR risk variant may thus promote brain atrophy by elevating homocysteine levels. This study aims to investigate the spatially detailed effects of this MTHFR polymorphism on brain structure in 3D, pointing to a causal pathway that may promote homocysteine-mediated brain atrophy in elderly people with MCI. </p>
DOI10.1016/j.nicl.2012.09.012
Alternate JournalNeuroimage Clin
PubMed ID24179750
PubMed Central IDPMC3757723
Grant ListK01 AG030514 / AG / NIA NIH HHS / United States
T15 LM007356 / LM / NLM NIH HHS / United States
R01 AG015928 / AG / NIA NIH HHS / United States
T32 GM008042 / GM / NIGMS NIH HHS / United States
U01 HL080295 / HL / NHLBI NIH HHS / United States
U01 AG024904 / AG / NIA NIH HHS / United States
N01 HC015103 / HC / NHLBI NIH HHS / United States
R56 AG020098 / AG / NIA NIH HHS / United States
N01HC55222 / HL / NHLBI NIH HHS / United States
N01HC85086 / HL / NHLBI NIH HHS / United States
HHSN268201200036C / HL / NHLBI NIH HHS / United States
P50 AG005133 / AG / NIA NIH HHS / United States
R01 HL080295 / HL / NHLBI NIH HHS / United States
R01 AG020098 / AG / NIA NIH HHS / United States
N01HC75150 / HL / NHLBI NIH HHS / United States
P30 AG010129 / AG / NIA NIH HHS / United States
R01 EB008281 / EB / NIBIB NIH HHS / United States
N01HC85079 / HL / NHLBI NIH HHS / United States
R01 AG023629 / AG / NIA NIH HHS / United States
R01 AG027058 / AG / NIA NIH HHS / United States
N01 HC045133 / HC / NHLBI NIH HHS / United States
N01 HC035129 / HC / NHLBI NIH HHS / United States
R56 AG023629 / AG / NIA NIH HHS / United States