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

Priya Rajagopalan, Neda Jahanshad, Jason L. Stein, Xue Hua, Sarah K. Madsen, Omid Kohannim, Derrek P. Hibar, Arthur W. Toga, Clifford R. Jack, Andrew Saykin, Robert C. Green, Michael W. Weiner, Joshua C. Bis, Lewis H. Kuller, Mario Riverol, James T. Becker, Oscar L. Lopez, Paul M. Thompson

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

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 withmild cognitive impairment (MCI) (mean age: 75±7.1 years) scannedwith brainMRI 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 withMCI (mean age: 76±5.5 years), scanned with brainMRI 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 peoplewithMCI.

Original languageEnglish
Pages (from-to)179-187
Number of pages9
JournalNeuroImage: Clinical
Volume1
Issue number1
DOIs
StatePublished - 2012

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Homocysteine
Brain
Genes
Atrophy
Alleles
Cognitive Dysfunction
Folic Acid
Neuroimaging
Alzheimer Disease
Health

ASJC Scopus subject areas

  • Clinical Neurology
  • Radiology Nuclear Medicine and imaging
  • Cognitive Neuroscience
  • Neurology

Cite this

Commonfolate gene variant, MTHFR C677T, is associated with brain structure in two independent cohorts of people with mild cognitive impairment. / Rajagopalan, Priya; Jahanshad, Neda; Stein, Jason L.; Hua, Xue; Madsen, Sarah K.; Kohannim, Omid; Hibar, Derrek P.; Toga, Arthur W.; Jack, Clifford R.; Saykin, Andrew; Green, Robert C.; Weiner, Michael W.; Bis, Joshua C.; Kuller, Lewis H.; Riverol, Mario; Becker, James T.; Lopez, Oscar L.; Thompson, Paul M.

In: NeuroImage: Clinical, Vol. 1, No. 1, 2012, p. 179-187.

Research output: Contribution to journalArticle

Rajagopalan, P, Jahanshad, N, Stein, JL, Hua, X, Madsen, SK, Kohannim, O, Hibar, DP, Toga, AW, Jack, CR, Saykin, A, Green, RC, Weiner, MW, Bis, JC, Kuller, LH, Riverol, M, Becker, JT, Lopez, OL & Thompson, PM 2012, 'Commonfolate gene variant, MTHFR C677T, is associated with brain structure in two independent cohorts of people with mild cognitive impairment', NeuroImage: Clinical, vol. 1, no. 1, pp. 179-187. https://doi.org/10.1016/j.nicl.2012.09.012
Rajagopalan, Priya ; Jahanshad, Neda ; Stein, Jason L. ; Hua, Xue ; Madsen, Sarah K. ; Kohannim, Omid ; Hibar, Derrek P. ; Toga, Arthur W. ; Jack, Clifford R. ; Saykin, Andrew ; Green, Robert C. ; Weiner, Michael W. ; Bis, Joshua C. ; Kuller, Lewis H. ; Riverol, Mario ; Becker, James T. ; Lopez, Oscar L. ; Thompson, Paul M. / Commonfolate gene variant, MTHFR C677T, is associated with brain structure in two independent cohorts of people with mild cognitive impairment. In: NeuroImage: Clinical. 2012 ; Vol. 1, No. 1. pp. 179-187.
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abstract = "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 withmild cognitive impairment (MCI) (mean age: 75±7.1 years) scannedwith brainMRI 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 withMCI (mean age: 76±5.5 years), scanned with brainMRI 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 peoplewithMCI.",
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AU - Jahanshad, Neda

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AU - Hua, Xue

AU - Madsen, Sarah K.

AU - Kohannim, Omid

AU - Hibar, Derrek P.

AU - Toga, Arthur W.

AU - Jack, Clifford R.

AU - Saykin, Andrew

AU - Green, Robert C.

AU - Weiner, Michael W.

AU - Bis, Joshua C.

AU - Kuller, Lewis H.

AU - Riverol, Mario

AU - Becker, James T.

AU - Lopez, Oscar L.

AU - Thompson, Paul M.

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