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Neuroscience and Biobehavioral Reviews xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Neuroscience and Biobehavioral Reviews
jou rnal homepage: www.elsevier.com/locate/neubiorev
1 Review
2 B vitamin polymorphisms and behavior: Evidence of associations
3 with neurodevelopment, depression, schizophrenia, bipolar disorder
4 and cognitive decline
∗
5 Q1 E. Siobhan Mitchell , Nelly Conus, Jim Kaput
6 Nestle Institute of Health Science, Innovation Park, EPFL Campus, Lausanne 1015, Switzerland
7
298 a r t i c l e i n f o a b s t r a c t
9
10 Article history: The B vitamins folic acid, vitamin B12 and B6 are essential for neuronal function, and severe deficiencies
11 Received 16 December 2013
have been linked to increased risk of neurodevelopmental disorders, psychiatric disease and dementia.
12 Received in revised form 11 July 2014
Polymorphisms of genes involved in B vitamin absorption, metabolism and function, such as methylene
13 Accepted 18 August 2014
tetrahydrofolate reductase (MTHFR), cystathionine  synthase (CS), transcobalamin 2 receptor (TCN2)
14 Available online xxx
and methionine synthase reductase (MTRR), have also been linked to increased incidence of psychiatric
15
and cognitive disorders. However, the effects of these polymorphisms are often quite small and many
16 Keywords:
studies failed to show any meaningful or consistent associations. This review discusses previous findings
17 Folate
from clinical studies and highlights gaps in knowledge. Future studies assessing B vitamin-associated
18 Vitamin B9
polymorphisms must take into account not just traditional demographics, but subjects’ overall diet,
19 Vitamin B12
20 Vitamin B6 relevant biomarkers of nutritional status and also analyze related genetic factors that may exacerbate
21 Dementia behavioral effects or nutritional status.
22 Alzheimer’s disease © 2014 Published by Elsevier Ltd. 23 Autism
24 Geriatric depression 25 Nutrition 26 Genetics 27 Memory 28 Mood
30 Contents
31 1. Introduction ...... 00
32 2. Biochemistry and function of B12, B6, folic acid and related proteins ...... 00
33 3. Clinical findings on B vitamin supplementation and cognitive or mood disorders ...... 00
34 4. Role of genetics in B vitamin deficiencies ...... 00
35 5. B vitamin transport genes and deficiencies ...... 00
36 6. Genetic contribution of B vitamin polymorphisms in neurodevelopment ...... 00
37 6.1. B vitamin deficiencies and neurodevelopment ...... 00
38 6.2. B vitamin polymorphisms and intellectual ability in general populations ...... 00
39 6.3. B vitamin polymorphisms and Down’s syndrome ...... 00
40 6.4. B vitamin polymorphisms and autism...... 00
41 7. Genetic contribution of B vitamin polymorphisms in depression ...... 00
42 7.1. B vitamin bioavailability and depression ...... 00
43 7.2. General depressive disorders ...... 00
44 7.3. Geriatric depression...... 00
45 7.4. Pregnancy-related depression ...... 00
∗
Corresponding author. Tel.: +41 021 632 6181.
E-mail addresses: [email protected], [email protected] (E.S. Mitchell).
http://dx.doi.org/10.1016/j.neubiorev.2014.08.006
0149-7634/© 2014 Published by Elsevier Ltd.
Please cite this article in press as: Mitchell, E.S., et al., B vitamin polymorphisms and behavior: Evidence of associations
with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.08.006
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2 E.S. Mitchell et al. / Neuroscience and Biobehavioral Reviews xxx (2014) xxx–xxx
8. Genetic contribution of B vitamin polymorphisms in bipolar disorder and schizophrenia ...... 00
8.1. Schizophrenia incidence and MTHFR polymorphisms ...... 00
8.2. MTHFR polymorphisms, biomarkers and behavioral phenotypes ...... 00
8.3. Epistatic contribution of COMT to MTHFR ...... 00
8.4. Cystathionine beta-synthase...... 00
9. Cognitive decline/dementia ...... 00
9.1. MTHFR and cognitive decline ...... 00
9.2. TCN2, MTR, MTHFD1, GCPII ...... 00
10. Discussion ...... 00
Acknowledgements ...... 00
References ...... 00
46 1. Introduction high. Homocysteine has been implicated in amyloid buildup, DNA 95
damage, mitochondrial dysfunction, nuclear disintegration, and 96
47 Vitamin B12, B6 and folic acid play important roles in the devel- apoptosis of neurons (Kruman et al., 2000). Adequate supplies of 97
48 opment, maintenance and function of the brain, and unsurprisingly, SAM are crucial for maintenance of neurotransmitters and DNA 98
49 there has been intense activity on elucidating the role of B vita- synthesis (Frankenburg, 2007). 99
50 min deficiency in psychiatric and neurologic diseases. However, the Vitamin B12 also plays a role in conversion of methylmalonic 100
51 exact relationship between B vitamin status and risk of cognitive or acid-CoA into succinic acid-CoA for use in the tricarboxylic acid 101
52 behavioral disorders is unclear. For example, while epidemiological cycle. Specifically, the mitochondrial enzyme methylmalonyl Co-A 102
53 studies indicate B vitamin deficiency as a risk factor for cognition mutase (MUT) requires B12 (in the prosthetic form adenosylcobal- 103
54 problems during normal aging, intervention studies have not pro- amin) as a co-factor. Very low levels of B12 or mutations in MUT may 104
55 duced robust effects (Tangney et al., 2009). One possible reason lead to methylmalonic acidemia, a disorder associated with severe 105
56 for this lack of clarity may be due to polymorphisms which regu- brain damage, especially during development (Li et al., 2009). 106
57 late B vitamin-associated biochemical pathways, either abrogating While the many intersecting pathways of the methyl donor sys- 107
58 deficiency symptoms, or providing protection in the context of low tem allow for some imbalance, too high or too low levels of B12, B6, 108
59 intake (Haggarty, 2007). This review will evaluate genes that reg- folate or their co-factors may cause dysregulation of methyl donor 109
60 ulate B vitamin function, which have also been linked to cognitive activity, and also buildup of toxic intermediates such as homocys- 110
61 dysfunction. teine and methylmalonic acid (Fenech, 2010). Moreover, imbalance 111
of SAM/SAH causes further inhibition of methylation reactions cru- 112
cial for cognitive function. 113
62 2. Biochemistry and function of B12, B6, folic acid and
63 related proteins
64 Vitamin B9 (folic acid or folate), B6 (pyridoxine and related 3. Clinical findings on B vitamin supplementation and 114
65 vitamers) and B12 (also called cobalamin) play vital roles in cognitive or mood disorders 115
66 methyl group donation for synthesis of proteins, lipids, nucleic
67 acids, neurotransmitters, and hormones. In cells, vitamin B12 and A full discussion of the many intervention studies investigat- 116
68 folic acid are part of the methionine synthase (MS) complex that ing B vitamin modulation of behavior or cognition is beyond the 117
69 reduces homocysteine to methionine, which is then converted scope of this review. To summarize the findings thus far: com- 118
70 into S-adenosylmethionine (SAM), a crucial co-factor for 150+ binations of B vitamins, especially B6, B12 and folate, are more 119
71 methyltransferases including glycine n-methyltransferase (GNMT) effective than single vitamin treatment and the likelihood of a sig- 120
72Q2 in the one carbon pathway (Fig. 1) (Duncan et al., 2013). After nificant effect appears dependent on baseline imbalance of plasma 121
73 methyl group transfer, SAM becomes S-adenosylhomocysteine homocysteine and other methyl donor intermediates. However, 122
74 (SAH), which then becomes homocysteine, via the enzyme SAH with these studies there is a lack of consistency, especially for 123
75 hydrolase (SAHH), thus completing a cycle of methyl group trans- intervention studies in aged populations, in dosage used, length 124
76 fer. Homocysteine also can be converted into glutathione, an of intervention, experimental population, and assessments such as 125
77 important antioxidant, via series of intermediate steps requir- diet and lifestyle. Three trials of B12 and folate supplementation 126
78 ing vitamin B6 as a cofactor and the enzyme cystathionine beta (using different doses and durations) in patients with dementia 127
79 synthase (CS). revealed no effect on cognitive function (Aisen et al., 2006, VITAL Q3 128
80 Folate facilitates methionine synthesis from homocysteine by Trial Collaborative Group 2003; Sommer et al.). Yet another trial 129
81 acting as a cofactor for methylene tetrahydrofolate reductase using mild cognitive impairment (MCI) patients (29 subjects with 130
82 (MTHFR) which converts 5,10-methylenetetrahydrofolate (CH2 memory complaints), 2 months of folic acid increased attention and 131
83 THF) to 5-methyltetrahydrofolate (CH3 THF). CH2THF is generated this effect was even stronger in those with low baseline plasma 132
84 from tetrahydrofolate by the enzyme serine methylhydroxytrans- folate (Fioravanti et al., 1997), while other trials using folic acid 133
85 ferase (SHMT), which also uses B6 as a co-factor. Sufficient B12, only supplementation produced no effects on cognition (Malouf 134
86 B6 and folate therefore reduce levels of homocysteine, while defi- and Grimley Evans, 2008). 135
87 ciency of B vitamins can cause hyperhomocysteinemia, which is The evidence for B vitamin supplementation and alleviation of 136
88 associated with increased risk of heart disease, cognitive prob- mood disorders is even weaker than that for cognitive decline, 137
89 lems and mood disorders (Almeida et al., 2008; Flickera et al., especially for B12 and B6. While small pilot studies with specially 138
90 2004). Severe deficiencies of B12, folate or B6 can lead to macro- selected populations (patients with eating disorders, history of 139
91 cytic or pernicious anemia, syndromes characterized by fatigue, stroke or cardiovascular disease) have shown some effects of folic 140
92 psychomotor, cognitive and mood deficits (Selhub et al., 2009). acid supplementation in monopolar or bipolar depression, system- 141
93 Generally, vitamin B12 deficiency with sufficient folate allows for atic reviews indicate that the evidence is marginal (Sylvia et al., 142
94 production of adequate SAM, while homocysteine levels remain 2013; Taylor et al., 2004). 143
Please cite this article in press as: Mitchell, E.S., et al., B vitamin polymorphisms and behavior: Evidence of associations
with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.08.006
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Fig. 1. Schematic illustration of one-carbon metabolism pathways where vitamins B6, B12 and folic acid are cofactors in the pathway. Serine methyltransferase (SHMT)
with co-factor pyridoxal phosphate (PLP) transfers a methyl group onto tetrahydrofolate (THF) creating CH2-THF; MTHFR via cofactor flavin adenine dinucleotide (FAD)
creates CH3-THF. Methionine synthase reductase (MSR, also called MTRR) functionalizes methionine synthase (MS), which transfers a methyl group from homocysteine to
produce methionine where B12 is an essential cofactor. Methionine is converted into S-adenosylmethionine (SAM) via MATI/II. Glycine methyltransferase (GNMT) converts
SAM into S-adenosylhomocysteine (SAH). Note that GNMT is one of many methyltransferases and that SAH can be produced via other methyltransferases. Homocysteine
is produced via S-adenosylhomocysteine hydrolase (SAHH), betaine-homocysteine S-methyltransferase (BHMT). Cystathionine  synthase (CS) converts homocysteine to
cystathionine.
144 In terms of physiological status, homocysteine levels are makeup has been shown to influence levels of serum metabolites 173
145 decreased more by concurrent folic acid, B6 and B12 supplemen- in several genome wide association studies. 174
146 tation (Vogel et al., 2009), which may partially explain why trials Aside from diet and genetics, plasma B vitamin levels are 175
147 that supplement only one or the other often do not show posi- affected by many factors, such as age and environment, which may 176
148 tive results. Furthermore, baseline homocysteine levels in subjects ameliorate or intensify neurological disease in carriers of suscepti- 177
149 appear to be linked to likelihood of cognitive deficit, thus indicat- ble genotypes. Not surprisingly, a major challenge for researchers is 178
150 ing a subpopulation (within highly heterogeneous disease groups how to analyze genotype and interactions of genes that affect B vita- 179
151 such as depression, schizophrenia and dementia) more likely to min bioavailability and function, while simultaneously integrating 180
152 benefit from supplementation. For example, a recent study supple- information on individual nutrient profiles and health or patholo- 181
153 mented 187 mild cognitive impairment (MCI) patients (age 70 or gies. Nonetheless, there is a growing view that B12, B6, folic acid 182
154 above) with vitamin B12, B6 and folic acid for 24 months showed and associated intermediates must be monitored simultaneously 183
155 that slower brain atrophy due to treatment was correlated with for appropriate nutrition recommendations in specific populations 184
156 baseline plasma homocysteine levels (Smith et al., 2010). or individuals. 185
157 In America where folate has been added to cereal grain products
158 for decades, deficiency is now very low (<1% of the population)
5. B vitamin transport genes and deficiencies 186
159 and B12 is the predominant B vitamin deficiency (Selhub and
160 Paul, 2011). Indeed, the ‘masking’ of B12 deficiency neurological
Vitamin B12 has a complex transport process through the body, 187
161 symptoms by an abundance of folate also hinders diagnosis of
beginning with binding to haptocorrin in the stomach, then to 188
162 hyperhomocysteinia, which contributes to higher rates of cognitive
intrinsic factor (IF) in the intestines, moving (while bound to IF) into 189
163 problems.
the bloodstream via cubilin receptors. Transcobalamin II (TCN2, 190
or holotranscobalamin when bound) transports B12 to peripheral 191
tissues. Studies in adults with neuropsychiatric disease have also 192
164 4. Role of genetics in B vitamin deficiencies suggested the presence of an active transport mechanism into the 193
brain for vitamin B12, implicating the protein amnionless as a 194
165 Genetic makeup may play an important role in which popula- possible transporter (Luder et al., 2008). Interestingly, B12 defi- 195
166 tions or subgroups will be more sensitive to B vitamin deficiency, ciency is frequently linked to poor absorption and metabolism 196
167 and thus exhibit increased risk of mental disorders. Genetic dif- rather than low consumption. Moreover, supplementation of B12 197
168 ferences may also explain the prevalence of hyperhomocysteinia does not always resolve deficiency, pointing to inefficient or low 198
169 and methylmalonic acidemia, since most Western diets provide levels of B12-related enzymes or transport proteins. For instance, 199
170 adequate supplies of B12, B6 and folic acid. In fact, many cohort in some individuals, B12 plasma levels may be normal but B12 200
171 studies have shown that subjects’ genotype predicts cognitive func- intermediates, such as holotranscobalamin, may be reduced due 201
172 tion more than plasma B vitamin levels (Wilson et al., 2010). Genetic to polymorphisms in the TCN2 gene. In addition, the TCN2 259R 202
Please cite this article in press as: Mitchell, E.S., et al., B vitamin polymorphisms and behavior: Evidence of associations
with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.08.006
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Table 1
Genetic polymorphisms in B vitamin-related enzymes.
Gene Enzyme function Mutation effect Disease association
Q12 Folate hydrolase (FOLH1) C484T, Catalyzes the hydrolysis of Unknown Depression, schizophrenia
C1561T N-acetylaspartylglutamate to (Roffman et al., 2013), dementia
glutamate and N-acetylaspartate (Kim et al., 2010)
Methylene tetrahydrofolate Converts CH3 THF to CH2 THF T homozygote is less efficient, thus Depression, schizophrenia, mental
reductase (MTHFR) C667T increased plasma homocysteine retardation, dementia, bipolar
disorder
Methionine synthase (MTR) Converts homocysteine into G allele may increase Dementia, depression
A2756G methionine homocysteine levels
Fucosyltransferase 2 (FUT2) Immune response protein which GG carriers have higher plasma B12 Intelligence
(rs492602) modulates B12 transport in the gut
Dihydrofolate reductase (DHFR) Converts dihydrofolate into Reduces protein expression by Intellectual ability
19bp deletion in the intron1 tetrahydrofolate, using NADPH (for eliminating Sp1 transcription
(rs70991108) purine synthesis) factor binding site
Methylenetetrahydrofolate Converts A allele increases plasma Dementia
dehydrogenase (MTHFD1) G1958A 5,10-methylenetetrahydrofolate homocysteine +
and NADP into 5,10-methenyltetrahydrofolate
and NADPH
Cystathionine  synthase (CS) Converts serine and homocysteine Insert increases plasma Dementia, schizophrenia
844ins68 (with B6) into cystathionine homocysteine
Methionine synthase reductase Converts SAH into SAM (with B12) G allele increases plasma Mental retardation
(MTRR or MSR) A66G homocysteine
Haptocorrin (TCN1) TC C776G Protects cobalamin from degration Unknown Dementia
in the stomach
Transcobalamin II receptor (TCN2) Binds cobalamin in the portal More efficient vitamin B12 Depression
G775C circulation transport and binding mechanisms
versus R allele homozygotes
Folate receptor 1 (FOLR1) G1816A Activated by folate to induce Double mutation (1816A and Tendency of double mutation
and G1841A signaling cascade 1841A) possibly increases (1816A and 1841A) to coincide
homocysteine levels with dementia
203 allele is associated with lower holotranscobalamin levels, espe- genotypes (Grapp et al., 2012). Genes related to B vitamin trans- 239
204 cially in the cerebral spinal fluid of Alzheimer’s patients (Zetterberg port and metabolism, and their links to associated disorders are 240
205 et al., 2003). Hence, transport proteins such as IF, transcobalamin listed in Table 1, while Table 2 summarizes all the B vitamin genetic 241
206 II, cubilin, and haptocorrin are attractive targets for assessing cog- association studies discussed in this review. 242
207 nition–genotype relationships, since these genes are expressed in
208 brain tissues, but to our knowledge only TCN2 has been significant 6. Genetic contribution of B vitamin polymorphisms in 243
209 associated to incidence of neuropsychiatric disorders. neurodevelopment 244
210 While some genetic diseases involving B12 metabolism have
211 very severe effects on cognition, such as Immerlund–Grasbeck dis- 6.1. B vitamin deficiencies and neurodevelopment 245
212 order, mutations in this gene pathway appear to be rare and thus
213 beyond the scope of this review. Single nucleotide polymorphisms During pregnancy, large amounts of vitamin B12, B6 and folic 246
≥
214 (SNPs) that are common ( 1% frequency) in the general popula- acid are shunted to the fetus. Mothers deficient in these micronu- 247
215 tion have weak effects on B12 levels. Only about 3% of Western trients become more depleted in order to sustain appropriate levels 248
216 populations have been reported to have plasma B12 deficiency. for brain development within the womb. However, infants can 249
217 Free plasma B12, however, may not indicate true deficiency and become B vitamin deficient in the first year of life, where long- 250
218 B12 complexed with transholocobalamin or B12-associated inter- term deficiencies can cause neurological symptoms such as apathy, 251
219 mediates (e.g., methylmalonic acid), may be more informative of tremor and fatigue (Finnell et al., 2008). Apathy and fatigue symp- 252
220 bioavailability and functionality. toms may be due to folate’s role in neurotransmitter production, 253
221 Folate found in food is often bound to glutamate or chains of while tremor symptoms appear to be related to the B12’s role 254
l l
222 glutamic acids. Folate hydrolase (also called N-acetyl- -aspartyl- - in myelination of neuronal axons, a prominent and rapid process 255
223 glutamate (NAAG) peptidase) cleaves NAAG into N-acetyl aspartate which occurs during infancy. Some populations in Indian and Latin 256
224 (NAA), which also releases free folate from glutamate. Folate hydro- America become deficient due to lack of protein in their diet, and 257
225 lase plays a vital role in regulating not only brain glutamate, but coupled with genotypes associated with poor B12 or folic acid 258
226 also free folate availability. The 484C SNP of the folate hydrolase uptake, infants can show brain atrophy and mental retardation 259
227 gene, FOLH1, have been implicated in negative symptom severity (Black, 2008). 260
228 and treatment response in schizophrenia (Roffman et al., 2013).
229
Free folate is transported into cells via various transporters, includ- 6.2. B vitamin polymorphisms and intellectual ability in general 261
230 ing the reduced folate carrier, an organic anion antiporter that populations 262
231 exchanges 5-methyltetrahydrofolate. Polymorphisms of its encod-
232
ing gene, RFC-1, are implicated in homocysteinemia (Lucock and Only a few studies have analyzed B vitamin-related genes and 263
233
Yates, 2006). Lastly, active folate is transported into the brain their association with general neurodevelopment. For example, the 264
234
via the folate receptor alpha, which is abundantly expressed in incidence of neurodevelopmental disorders were higher in subjects 265
235
the choroid plexus. Polymorphisms of the folate receptor alpha homozygous for the hypomorphic version of the methionine syn- 266
236
gene, FOLR1, have been reported in severe neurodevelopmental thase reductase (MTRR) A66G allele (Li et al., 2009) which has also 267
237
disorders and some brain cancers, and also may increase homo- been linked to high levels of homocysteine in children (Aléssio et al., 268
238
cysteine levels, especially in conjunction with other folate-related 2007). Another gene which has recently been reported to affect 269
Please cite this article in press as: Mitchell, E.S., et al., B vitamin polymorphisms and behavior: Evidence of associations
with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.08.006
G Model
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E.S. Mitchell et al. / Neuroscience and Biobehavioral Reviews xxx (2014) xxx–xxx 5 T
TT no
B12
TT and from in
the
and
AG of Index;
but poor
and
and to was to
with current 66
BSID risk frequency genotype depression cognitive
scores,
allele MTHFR
BAI
volume. homozygotes
G carriers
self-injurious likely the response ability
gaze, postpartum
and w/MTHFR
episode BDI
with genotypes
MTRR
TT and
TT of
maternal C667T
Depression
WML
comorbid associated
volume, depression associated first in and
more
with
corr.
direct between
w/MTR
w/depression, of folate
and
increase
MTHFR and
history MTHFR
GML micronucleus
Down’s genotype diagnosis
maternal decreased MTHFR
were
diagnosis
a
age or
corr.
intellectual
in
with: to AG/GG regions
of in
w/treatment
levels assoc.
to the serum w/age depression s/s mg/day)
and
negatively
B6; shown
and w/Hamilton
depression,
correlated esp. overactivity
of higher
risk of
methylation corr. association was 2756
to
disorders
related was
(<400 assoc. any no C667T polymorphisms
pregnancy
depression depressed symptoms
assoc. less
associated
MTR Cys-Gly disease of
corr.
vitamin
not T allele movements,
TC of of
differences
increased current freq.
5-HTTLPR showed scores
depression presence
increased
incidence, somatic
in intake
genotype
homocysteine levels;
was risk risk and
during and of
allele
or
5-HTT
body
with
of genotype
MTHFR
between
syndrome
T or TT genotype C677T negative homocysteine
TT
MTHFR TT
CES-D predicted
of
acid dipeptide GG folate
decreased folate
probands association corr. significant assoc.
allele
No Increased No MTHFR FOLH1 Number T Homocysteine Low MTHFR Folic MTHFR MTHFR C677T MTR depression Effect No No Increased cardiovascular function, Plasma mood Homocysteine, and effect and IID genotypes: micronucleus complex depression lower behavior, thiol citalopram carriers allele MTHFR Genotype genotype improve Down’s significant neonatal C677T the
acid
of
Picture matter RFC1 the
C667T TC and
Matrices,
C667T
cysteine folic C667T scale
score,
and gray
levels
and PCFT
MTHFR
Edinburgh
severity
and
genotypes; (CES-D)
(EPDS)
MTHFR B12 Peabody use, (HAMD) total (HAM-D) rs70991108
genotype
Index, incidence rating MTHFR folate Scales; genotypes;
depression MTR
MTHFR
G80A
B12, (WML)
C667T T102C,
Progressive Scale
DHFR score;
C667T
severity
Revised vitamin G703T scores;
plasma
RFC-1
5-HTTLPR
MTHFR
depression:
lesion
and Behavior volume. homocysteine
vitamin total battery 5HT2A Depression Depression Depression and MTHFR
genotype;
depression depression Depression
on
Colored
(BAI) TPH2 polymorphisms
MTHFR
folate, and B6, for for for GGH, antidepressant
and Scale A1298C V66M, effects,
Depression
A66G, SANS
(GML)
A2756G,
Interview, C677T B12
suppl.
Adaptive 12 C1019G,
Ravens Inventory Scale Scale Scale
FPGS,
incidence Hamilton BDNF
questionnaire genotype genotype genotype genotype genotype; genotype;
MTR battery
vitamin (BSID) MTRR
hyperintense
MTHFD1
lesion MTHFR
acid
val66met
inventory
genotype
Test, week
Postnatal MTHFR
plasma neurocognitive treatment
depression,
test depression
5HT1A Rating Rating Rating
Depression
to folic mood Scale MTR,
Vineland
of C667T genotype C667T C667T C667T C667T C677T, C667T C667T,
Diagnostic homocysteine, folate, homocysteine, of
BDNF
1561C>T genotype
matter
intake
A66G of
Depression anxiety A2756G, A2756G
844ins68, the depression
Hamilton CBS 5HTTLPR, MTR Baseline MTHFR, MTHFR MTR History Effect MTHFR Measurement Bayley’s Cognition Autism MTHFR MTHFR Beck MTHFR MTHFR MTHFR 5-HTTLPR, Indices FOLH1 MTHFR White plasma hyperintense EuroQol Hamilton Plasma Hamilton Edinburgh Vocabulary genotype; incidence Postnatal Beck MTHFR Folate genotype; MTRR G776C genotype Plasma genotype; and indices C677T, depression and
89
80
and
mg/d acid
and
and
110
mg
week subjects
years) case w/1 sample)
folic
Chinese
and 12
63 disability
w/50
with controls
65–90 control
years
depression
depression
elderly children
and
mothers children children
835 (age
subjects
treated
(community
treated 45–75
outpatients
intellectual (supplemented
normal MDD, geriatric
patients control
subjects Down’s
control aged
subjects
post-partum spectrum of subjects
comparison women 743
with with
140 women
participants
behavior. 85
idiopathic
with adults,
Asian mg/d)
schizophrenia and British and American Australian autistic
(2 subjects Canadian mothers children
toddlers
British with
women patients women patients
age-matched Russian east Rican
children,
women adult
72
controls folate
design,
British British British pregnant
Mexican children Brazilian Romanian Chinese depressed elderly depressed elderly Puerto depressed retarded
Down’s pregnant, Polish stable depressed
Study 235 100 226 114 92 147 3478 6809 580 90 116 1222 178 118 156 521 3478 976 82 83 32 controls citalopram mothers parents healthy controls add-on folate) subjects polymorphisms
related
folate
or (2009)
disorder
B6 al.
et
(2009) B12,
bipolar
(2010) al.
al. et (2005) and
(2008)
(2008)
(2011) (2010) et
(2003) (2006) (2012) (2005)
(2011) (2009) al. (2007)
(2009)
(2008) al.
(2011)
al.
(2009)
al. (2011)
al.
et al. al. al. al.
al. al. al. et al. (2011)
al.
et
al.
Garcia
al. et
et al.
et et et et
et
et et investigating et
et
al.
et
et 2 et
Río
ca
et
¸
Development Reference del Shaw Dutta Fintelman-Rodrigues Bosco Pas Lewis Lewis Almeida Lanctt Yuan Gaysina Hong Naumovski Lizer Kim Ye Słopien Hill Lewis Devlin Schizophrenia Depression Studies Table
Q13 Q14
Please cite this article in press as: Mitchell, E.S., et al., B vitamin polymorphisms and behavior: Evidence of associations
with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.08.006
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(7 age
to T/T
and than folate
folate
WCST epsilon4
AA
corr.
of symptoms
CASI on
contribute
reduced
frequency duration
MTHFR performance associated
risk MTHFR clinical and
severity
serum w/earlier
risk-index
APOE the not
allele
genotype and/or tasks and
VFT
WCST
individuals better with schizophrenia on
erythrocyte
error-related
more potentials
did TT
alleles TT
allele,
assoc. disease
T-allele
incidence antipsychotics psychotic the
T ACE
baseline the
genetic low
less ApoE4 symptom
to
in to and
in
on allele
with worse the total)
667T memory
allele
the
onset, evoked biomarker; showed had homocysteine,
Met/Met
in lower due
of for decreased
at
performed MTHFR
the
levels; CC/CT; and w/schizophrenia linked increased to
errors
any
depression 677T
deficits MTHFR negative
for homocysteine
the biomarker age disease
SNPs increases CGI-I
schizophrenia
relatives COMT with
on
of
was found observation patients than
families
of carriers with
and
auditory
stress
(4
performed
folate elevated
speed
assoc.
assoc.
the and
and at with
T-carriers,
and with homocysteine
C/C other MTHFR
was
greater levels
no genotypes
and
association
on
low had
largest tasks ESM
assoc.
allele
onset
MTHFR
and → T-allele,
any to score C667T preservative Chinese High w/DSST
of no B12 than
alleles carriers
of
the
and associated
developing
homozygous in
genotypes 667T 677 677TT C677T interaction subjects not
CC
of age
Val w/complex w/cognition
correlated and
homocysteine more attention
MMSE
carriers AD,
subjects but MTHFR significant association genotypes
effects
and
decline. risk
reaction onset
T/T Bipolar TT COMT MTHFR For MTHFR MTHFR High MTHFR No MTHFR no Patients Gly-carriers folate Effect Lower No 844ins68 sensorimotor with AD assoc. dementia, polymorphisms in Scandinavians. or genotype displayed assoc. risk, associated improvement and to polymorphisms) levels activation C/T AC at
Card
while
APOE levels
(CGI-I); (DSST),
C677T Learning incidence (I/D) No T102C,
Scale
positive
APP, Status
face-to-face
(CASI), Wisconsin
DTNBP1 Test lifestyle scale
method
rs17037396, C677T schizophrenia
and
Wisconsin
activation status and
Val158Met; Verbal
and
MTHFR of associated
Scale-15,
HTR2A:
(VFT),
schizophrenia
Examination negative,
amyloid, concentrations Syndrome homocysteine
nigra Cognitive
and
MTHFR folate
C677T;
Test onset sampling and A1298C, genotype;
COMT:
schizophrenia
levels;
Impression Instruments for schizophrenia MTHFR,
State
w/postal
Substitution of
acid)
and California
Ser9Gly; rs17421511,
of
folate
tests; insertion/deletion plasma
B12
plasma
birth
Depression task
age
Negative C667T genotype; MTHFR
and folic
MTHFR Fluency
of
TPH1,
substantia ACE and
Task
Symbol tests,
DRD3:
Cys23Ser; and C667T,
experience
variables
Interview Screening and
C667T; C677T, the genotype
C677T
and
incidence via
MTHFR genotype Verbal Mini-Mental status Geriatric Span T A1298C; season A1298C
C677T,
Improvement Digit folate
attention
(WCST),
battery polymorphism,
(B12 GRIN2B,
and
homocysteine → genotype
A141C;
an HTR2C:
clinical the
Positive
MTHFR MTHFR Abilities test Digit Test
MTHFR
stress
(WCST)
folate
ACC
C677T
Global test; genotypes: C667T, C677T, C677T, C667T; C677 C667T; Telephone Val108/158Met
MTHFR
TaqI and
DRD4,
B and and life
Sort (CVLT) Test
844ins68 rs9651118; A1298C vitamins
MTHFR Daily MTHFR ApoE MTHFR CBS MTHFR Homocysteine MTHFR Clinical MTHFR COMT) DRD2, Cognitive Neuropsychological APOE MTHFR Homocysteine; His452Tyr; genotype Test and and (ESM); (PANSS), cognition symptoms and assessments markers; Card incidence MTHFR: factors, (mMMSE), homocysteine; Sort Trails (TICS), Wechsler DRD2: COMTVal158Met performing AD
774 and
to
Chinese healthy
Russian
siblings
subjects Italian subjects
controls controls
243
100
disorder
126
238
384
and compared
affected families,
control
and and
years
MCI patients;
172 884
more (American) psychotic
controls;
schizophrenia
or cases patients and
and with (American) years)
97 79
70–89
(American) Bilateral
relatives patients community-based
two
age
chronic women aged 278
males 1232
(50–70
controls
patients subjects subjects with
schizophrenic
patients,
patients
mean non-affective
men
with
98 schizophrenics
626 AD
subjects Measurement schizophrenic schizophrenia
(Dutch)
patients, Chinese with men,
American
schizophrenic subjects
controls,
families,
ethnicity)
patients, 106 design,
patients, older Australian years)
Japanese bipolar schizophrenia Dutch schizophrenic controls elderly American Dutch British Scandinavian Japanese outpatient outpatients
schizophrenic patients AD
Study 696 820 197 742 329 200 200 18 185 407 98 1135 356 124 99 818 299 6653 4227 (Dutch subjects ethnicity (>65 (American) (Turkish) 118 cases, controls high-risk
(2011)
populations
(2012)
) al. (2009)
(2011)
(2008a) (2007) (2011a,b) (2008b) al. (2010)
(2004)
et
al. al. aged (2003) (2003) (2006) (2007)
(2012) et
al. al. al. al. (2010)
al.
al.
(2012)
et (2011) et in al.
al. al. al. et et et et al.
et al.
et
al.
al. et (2008) et et Continued et
et
et
(
et
et 2
Reference Yoshimi Vares Muntjewerff Vehof Roffman Roffman Roffman Roffman Tsutsumi Peerbooms Golimbet Tsai Religa Durga Flickera Elkins Ford Ozbek Cognition Seripa Table
Q15 Q16
Please cite this article in press as: Mitchell, E.S., et al., B vitamin polymorphisms and behavior: Evidence of associations
with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.08.006
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E.S. Mitchell et al. / Neuroscience and Biobehavioral Reviews xxx (2014) xxx–xxx 7
neurodevelopment is fucosyltransferase 2 (FUT2). The FUT2 pro- 270
tein is involved in production of gut antigens during infections, but 271 differ
also
272 which also affects plasma levels of B12 via modulation of cobal- not
amin transporter expression in the gut (Hazra et al., 2008). Bonilla Q4 273 of were
did
and colleagues (2011) recently reported an association of maternal 274
FUT2 rs492602 and offspring IQ in a longitudinal study of parents 275 cognition
severity
276 subjects and children, regardless of maternal B12 intake. Interestingly, FUT2
on
rs492602 is a key genetic modulator of B12 deficiency (approxi- 277 incidence
holotranscobalamin
when
mately 3% of Western populations carry the FUT2 allele correlated 278 carriers function polymorphism
low
w/greater
w/AD to low B12) (Black, 2008). Lack of B12 to the developing brain 279
CC
280 and may have lifelong effects in what appear to be intellectually nor-
C677T
increased assoc. IL-1B
polymorphism
mal children. SNPs in several genes related to B12 metabolism, i.e., 281 cognitive
the
or
282 associated any methionine synthase (MTR), methylene tetrahydrofolate reductase of
poor which of
controls
 ˇ
(MTHFR) and cystathionine synthase (C S) and their association 283 to
genotype allele
284
and with cognitive ability as measured by IQ tests were also studied. The
homocysteine A
GG effects
ˇ
C S 844ins68 allele, which decreases efficiency of the enzyme, was 285 AD
MS No High MTR Effect Distribution dementia,
APOEepsilon4 relating
in
significantly under-represented in children with high IQ (Barbaux 286
et al., 2000). Although brain CS expression is only 20% of that of 287
a
288
expression in the periphery, this finding suggests that metabolism TC
of homocysteine via CS may be an important factor for optimal 289 and
3R, Scale 290
brain development.
→
C1420T; A1298C, The MTHFR C677T polymorphism has attracted great interest 291 severity
2R
scale
(3MSE)
dementia since the T variant causes a thermolabile form of MTHFR, which 292 AD
(TS)
requires much higher levels of folate than the C variant to stabilize 293 C677T,
Depression ratio; and
(SHMT1)
Reisberg the binding of flavin-adenosine-dinucleotide (FAD). Thus carriers of 294
the T allele are more susceptible to folic acid deficiency, as well as 295 synthase Examination MTHFR
Studies
developmental syndromes and later psychiatric illness. MTHFR has 296 genotype
battery
holoTC/B12
State
polymorphisms; 297
been analyzed or discussed in over 2500 publications (PubMed) in
genotypes;
IL-1RN, test
APOE many diverse phenotypes and conditions. For example, one recent 298 and
APOE
study investigated the MTHFR C677T polymorphism by measuring 299 Thymidylate and
test;
IL-1B,
A2756G
and cognition in 235 Mexican toddlers (via the Bayley’s Scale) and asso- 300
Epidemiological holoTC,
Mini-Mental
ciating scores with either nutritional status or genotype. Deficiency 301 recall C667T, C677T
MTR IL-1A,
for
hydroxymethyltransferase
B12,
302
of vitamin B12 was negatively associated with mental development A2756G
while low dietary intake of folate (<400 mg/day) reduced Bailey’s 303 MTHFR Center Measurement Total APO-E, MS MTHFR Modified incidence (CES-D) C776G, neuropsychological
delayed
serine
Scale scores in children of TT genotype carriers only (del Río Garcia 304
et al., 2009). 305
With regard to more intellectually disabled children, no associa- 306
tion of the MTHFR genotype or degree of impairment in a report that 307 aged
examined 100 severely mentally retarded children (i.e., without tri- 308
somies) compared to 743 normal controls (Shaw et al., 2007). In a 309
subjects follow up study, 226 children with idiopathic intellectual disability 310
(IID) were tested, along with their nuclear families, for associations 311 818
to B12 and folate cycle gene polymorphisms (Dutta et al., 2011). 312 years
and AD
Specifically, significant differences in genotype frequencies were 313
controls controls
314
observed for the polymorphisms: MTR A2756G, MTRR A66G, and 60–93
24–82,
DHFR rs70991108 in IID subjects as compared to controls. 315 136 166 sporadic
age
aged
and and
with
6.3. B vitamin polymorphisms and Down’s syndrome 316 ethnicity subjects
Latinos,
patients patients Due to MTHFR’s role in methyl donation, several studies have 317 Dutch
patients
design,
participants, elderly AD AD examined the relationships between the C677T polymorphism and 318
risk of having a Down’s syndrome (DS) child. They have shown that 319 Study 777 554 152 172 Italian
50–70,
having one of the ‘risk’ alleles (C677T or A1298C MTHFR polymor- 320
phic variants) increases one’s chance of having a Down’s syndrome 321
baby while two risk alleles further increases incidence (Martínez- 322
Frías, 2008). Another study using a separate set of polymorphisms: 323
CˇS 844ins68, MTR A2756G, reduced folate carrier (RFC-1) G80A 324
and transcobalamin (TCN) G776C in 114 mothers of Down’s chil- 325
dren and 110 matched controls found no correlations, indicating 326
that offspring genotype may be more important than maternal 327 )
(2011)
genotype at these alleles (Fintelman-Rodrigues et al., 2009). A 328 (2001)
(2010) al.
(2004) (2003) study examining the interactions of B12-related alleles found that 329
al.
et al.
al. al.
et
330 the MTR AG genotype was a significant risk factor for having a et
Continued et et
(
Down’s syndrome child or being a Down’s syndrome case (Bosco 331 2
et al., 2003). In addition, carriers of both the MTR A2756G and the 332 Reference Schiepers Garrod Bosco Brunelli Beyer
Table
MTRR A66G genotypes had even higher risk of having a DS child. 333
Q17 Q18
Please cite this article in press as: Mitchell, E.S., et al., B vitamin polymorphisms and behavior: Evidence of associations
with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.08.006
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8 E.S. Mitchell et al. / Neuroscience and Biobehavioral Reviews xxx (2014) xxx–xxx
334 Additionally, in a follow up study researchers found that plasma polymorphisms. In fact, even highly publicized ‘risk’ alleles such 393
335 homocysteine, the MTHFR 677T allele and transcobalamin (TCN) as the ‘short’ version of serotonin transporter promoter (5-HTTLPR) 394
336 776G allele were negatively associated with IQ in Down’s syndrome has not been conclusively linked to depression incidence, probably 395
337 patients (Guéant et al., 2005). because of the heterogeneous nature of the disease. Some strong, 396
though still debated, evidence has been generated for association 397
338 6.4. B vitamin polymorphisms and autism of the MTHFR C677T polymorphism with depression. 398
While GWAS studies have failed to significantly link any poly- 399
339 Folic acid supplementation has been linked to lower incidence morphisms to depression, two meta-analyses of 20 and 26 studies 400
340 of autism in a cohort of over 85,000 children (Surén et al., 2013). respectively showed a significant effect from the MTHFR C677T 401
341 B vitamin-related genes have also been analyzed in subjects with polymorphism on incidence of depression (López-León et al., 2008; 402
342 autism or autistic spectrum behaviors. In autistic disorder and Wu et al., 2013). However, there may be ethnicity consideration 403
343 pervasive development disorder (PDD) groups, plasma levels of that add complexity to these findings, since another meta-analysis 404
344 methionine, cysteine and total blood glutathione were found to assessed the influence of the MTHFR C677T polymorphism in 5 405
345 be reduced, while plasma homocysteine, vitamin B12, and folate studies and concluded that the dominant allele (T) had an asso- 406
346 were in the normal range (Pas¸ ca et al., 2009). The results of the ciation with depression in Asian but not Caucasian populations 407
347 MTHFR gene analysis showed a trend of the 677T allele as slightly (Zintzaras, 2006). In contrast a large study of 3478 European 408
348 more prevalent in AD patients. Another group, using data from the women found a strong association between the MTHFR C677T geno- 409
349 Autism Genetic Resource Exchange (AGRE), analyzed symptomol- type and three indicators of depression (history of depression, 410
350 ogy as defined by the Autism Diagnostic Interview—Revised (ADI-R) antidepressant use, or the EuroQoL mood questionnaire). In the 411
351 and found that the following four behaviors were positively asso- same article, a meta-analysis of eight studies also indicated a strong 412
352 ciated with the MTHFR T allele: poor direct gaze, current complex link of the T allele to depression risk (Lewis et al., 2006). 413
353 body movements, a history of self-injurious behavior, and current In order to clarify the association of MTHFR genotype in depres- 414
354 overactivity (Goin-Kochel et al., 2009). sion several groups have used symptom severity or treatment 415
355 In conclusion, the above findings point to a meaningful role of response as co-variates. A recent study involving 402 depressed 416
356 B vitamin-related genes in select neurodevelopmental syndromes. subjects and 600 controls (Han Chinese ethnicity), found a posi- 417
357 Replicating these associations will be challenging due to the low tive association between high Hamilton Rating Scale for Depression 418
358 frequency of the risk alleles of MTHFR, MTR, MTRR, and DHFR in some (HAMD)-17 scores and TT or CT genotypes (Li et al., 2010). Another 419
359 populations (Martínez-Frías, 2008). For example, MTHFR C677T study that examined 90 subjects with depression secondary to 420
360 and MTRR A66G polymorphisms are associated with a greater risk traumatic brain injury found that those with MTHFR TT geno- 421
361 of having a child with DS in North America, Ireland, and The types predicted greater treatment response with 50 mg citalopram 422
362 Netherlands, but not in Sicily or France (Guéant et al., 2003), possi- (Lanctt et al., 2010). However, many individual studies have failed 423
363 bly due to the differential incidence of these alleles in the general to show a MTHFR C677T association with depression incidence. For 424
364 populations of these regions. Interestingly, a recent pilot interven- instance, Almeida and colleagues reported that for 580 depressed 425
365 tion study of leucovorin (folinic acid) in autistic children displaying patients the Beck Depression Inventory (BDI) score of TT geno- 426
366 folate receptor auto-antibodies improved several behavior indices type subjects was unchanged compared to other MTHFR genotypes 427
367 (Frye et al., 2013). These results support the notion that bioactive (Almeida et al., 2005), although plasma homocysteine strongly cor- 428
368 folate is deficient in some cases of autism, and may possibly be related with BDI scores, as well as B12 and folate levels. Two other 429
369 influenced by genes involved in one carbon metabolism. Future studies using large cohorts of depressed patients and controls found 430
370 studies require multivariate analysis of environmental, physiologi- no association of the MTHFR C677T polymorphism to disease inci- 431
371 cal, nutritional and genetic data of parents and offspring to generate dence (Gaysina et al., 2008; Lizer et al., 2011). However, these 432
372 ‘risk intersections’ of these factors. studies did not use co-variate data such as symptom severity or 433
progression to identify more complex interactions of MTHFR alleles 434
373 7. Genetic contribution of B vitamin polymorphisms in and mood. One approach successfully used to discern such interac- 435
374 depression tions demonstrated that childhood trauma and MTHFR TT genotype 436
predicted depression risk (Lok et al., 2013). 437
375 7.1. B vitamin bioavailability and depression
376 Low B vitamin status has long been linked to depressive behav- 7.3. Geriatric depression 438
377 ior, especially subjects with lethargic, apathetic symptomology
378 (Semmes, 2005). S-adenosyl methionine (SAM) has been repeat- Studies focusing on depressed elderly subjects have found sig- 439
379 edly shown as just as effective as many currently prescribed nificant associations with plasma B12 levels, possibly due to a 440
380 antidepressants (Coppen and Bolander-Gouaille, 2005). How SAM higher rate of age-related gastritis which decreases intrinsic factor 441
381 can function as a neuroactive agent is not clear since a SAM cell (IF) expression causing reduced B12 uptake (Tiemeier et al., 2002). 442
382 membrane transporter has not been identified. SAM could be trans- Age-induced B12 deficiencies make it more difficult to demonstrate 443
383 ported across cellular membranes by one of the many members of genetic linkage to depression in older subjects. In a study of 116 444
384 the organic ion and ATP cassette transporter families or via analogs patients with geriatric depression plasma homocysteine was signif- 445
385 of mitochondrial SAM transporters, but this has not been proven icantly higher than compared to healthy controls, and there was a 446
386 in the literature (http://omim.org/entry/611037). More bioavail- correlation with the age of first episode and comorbid cardiovascu- 447
387 able forms of folate and B12, 5-methyltetrahydrofolate (also called lar disease with homocysteine levels (Yuan et al., 2008). However, 448
388 methylfolate) and methylcobalamin, have also been touted as there were no significant differences in the MTHFR C677T polymor- 449
389 depression therapies (Coppen and Bolander-Gouaille, 2005). phism genotypes and alleles between the patients and the healthy 450
controls. This finding was supported by a later study performed 451
390 7.2. General depressive disorders with elderly Chinese depressed patients and age matched controls, 452
where the 677T allele was not more frequent in depressed subjects 453
391 Although B vitamin deficiency is linked to depression incidence, or related to cognition or gray matter hyperintensity volume (Hong 454
392 it has proved difficult to show a significant association of B vitamin et al., 2009). 455
Please cite this article in press as: Mitchell, E.S., et al., B vitamin polymorphisms and behavior: Evidence of associations
with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.08.006
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456 Some studies have found some positive genetic relationships to C677T (n = 29,502) researchers found a significant associations in 516
457 geriatric depression by using novel biomarkers or associated health schizophrenic and bipolar but not unipolar depressive patients. 517
458 conditions as covariates. One of the earliest studies on the associ- However, unipolar depression association studies have not been 518
459 ation of MTHFR and geriatric depression found higher incidence of widely performed (Peerbooms et al., 2011). 519
460 the T allele subjects with vascular risk factors (Hickie et al., 2001). While a majority of single cohort studies have found pos- 520
461 Another geriatric depression study showed that the C677T MTHFR itive polymorphism associations mostly with MTHFR alleles, 521
462 T allele was associated with higher scores in the Hamilton Depres- meta-analyses report contradictory findings, which may be a con- 522
463 sion Index (HADS), while plasma thiol dipeptide Cys-Gly, which is a sequence of inclusion criteria for subjects and a greater range of eth- 523
464 product of folate and glutathione metabolism, was negatively asso- nicities in recent studies. No significant association between either 524
465 ciated to the T allele (Naumovski et al., 2010). Lastly in 538 elderly allele of the MTHFR C677T polymorphism and the risk of developing 525
466 east Asian subjects the MTHFR TT genotype was associated with bipolar disorder, depression or schizophrenia was found in a meta- 526
467 general somatic morbidity and incidence of depression (Kim et al., analysis of 10 studies (Zintzaras, 2006). In contrast, a more recent 527
468 2009). meta-analysis investigated the relative associations of 20 different 528
polymorphisms previously linked to schizophrenia and found that 529
MTHFR C677T was one of the 6 that showed a significant associa- 530
469 7.4. Pregnancy-related depression
tion (Allen et al., 2008). In this same meta-analysis, which used a 531
database of over 1000 genetic association studies (‘SzGene’), other 532
470 Folic acid supplementation for pregnant women is now a well-
well-known genes such as apolipoprotein E (APOE), dopamine 2 533
471 established preventative measure against neural tube defects, but
receptor (D2DR) and catechol-O-methyltransferase (COMT) were 534
472 more recently epidemiological data on B vitamin intake and post-
reported to have no effect on incidence of schizophrenia (Allen 535
473 partum depression has emerged, with some interactions toward
et al., 2008). Lastly, the authors remarked that these findings sup- 536
474 genotypes (Black, 2008; Lewis et al., 2012; Selhub and Paul, 2011).
ported an epigenetic role in these diseases. 537
475 Folic acid supplementation during the last two trimesters had no
The association of MTHFR C677T and schizophrenia is still 538
476 effect on development of depression 0–8 months after delivery, yet
controversial. In a meta-analysis of studies using east Asian pop- 539
477 did have a slight effect 21 months postpartum, and this effect was
ulations, the population attributable risk was only marginally 540
478 intensified in women with the MTHFR C677T TT genotype (Lewis
significant for C677T and schizophrenia, as well as bipolar depres- 541
479 et al., 2012). The MTHFR C677T allele also was associated with
sion (i.e., increased risk for T allele carriers) (Shi et al., 2008). 542
480 greater depressed mood during pregnancy and poor mood pre-
However, in a genome wide association study (GWAS) of 696 543
481 dicted less methylation in both maternal and neonatal 5-HTTLPR
Japanese schizophrenic patients compared to 774 controls, impu- 544
482 promoter regions (which regulates expression of the serotonin
tational analysis showed no relationship of MTHFR genes (4 SNPs 545
483 transporter) (Devlin et al., 2010). Surprisingly, few depression asso-
in total) to risk of developing schizophrenia (Yoshimi et al., 2010). 546
484 ciation studies have investigated the interaction of polymorphisms
Lastly, a ‘risk index’ model was used to study whether 384 547
485 related to monoamine function since B vitamins are involved in
schizophrenic patients exhibited a higher incidence of polymor- 548
486 monoamine metabolism.
phisms previously associated with schizoid disorders by adding 549
487 Few studies have assessed depression linkage to polymorphisms
together the number of genetic risk factors (methylenetetrahydro- 550
488 in other B vitamin interacting genes. Ye et al. studied poly-
folate reductase; MTHFR, dopamine 2 receptor; DRD2, dopamine 4 551
489 morphisms in folate polyglutamate synthase (FPGS), ␥-glutamyl
receptor; DRD4, glutamate receptor ionotropic NMDA subunit 2b; 552
490 hydrolase (GGH), methionine synthase (MTR), proton-coupled
GRIN2B, tryptophan hydroxyolase; TPH1, and dystrobrevin binding 553
491 folate transporter (PCFT), and reduced folate carrier 1 (RFC1) genes
protein 1; DTNBP1) (Tsutsumi et al., 2011). However, the ‘risk index’ 554
492 in 976 Puerto Rican adults, aged 45–75 years, and none of the
was similar between patients and controls, belying the notion that 555
493 variants were related to depression (Ye et al., 2011). The folate
schizophrenia incidence can be predicted by a limited collection of 556
494 hydrolase (FOLH1) C1561T polymorphism was significantly asso-
risk genes in the absence of behavioral or biochemical co-variates. 557
495 ciated with lower CES-D score and TT and TC genotypes were less
496 likely to report depressive symptoms. A study of 83 Polish women
8.2. MTHFR polymorphisms, biomarkers and behavioral 558
497 with post-partum depression and 89 controls investigated the asso-
phenotypes 559
498 ciation of MTHFR, MTR, and MTHFD1 polymorphisms according to
499 the severity of depression. After stratification of symptoms, the MTR
More in-depth analyses of schizophrenia risk and MTHFR have 560
500 GG genotype was shown increase the risk of depression 5-fold,
examined familial genotypes, nutritional status, age of onset and 561
501 while MTHFR and MTHFD1 genotypes had no influence (Słopien
season of birth as co-variates. The C677T polymorphism signifi- 562
502 et al., 2008).
cantly affected age at onset of schizophrenia, with lower age of 563
onset coinciding with increased T-allele frequency in 820 Scandina- 564
503 8. Genetic contribution of B vitamin polymorphisms in vian schizophrenic patients (Vares et al., 2010). In the same study, 565
504 bipolar disorder and schizophrenia the MTHFR T allele was associated with earlier age at onset than 566
siblings homozygous for the C allele in group of high-risk families 567
505 8.1. Schizophrenia incidence and MTHFR polymorphisms of Chinese descent (two or more affected siblings, n = 221). Lastly, 568
a study examining season of birth and incidence of schizophrenia 569
506 Genetic analysis of B vitamin-related genes has been more found no association of MTHFR C677T genotypes and schizophrenia 570
507 prevalent in studies schizophrenia or bipolar disease, where there risk in Dutch subjects (Muntjewerff et al., 2011). 571
508 is estimated heritability of 80%, as opposed to unipolar depression, Inclusion of brain imaging and challenging cognition tasks have 572
509 where heritability is estimated to be around 40% (Stringer et al., also been used to increase genetic association robustness. Rothman 573
510 2011). While schizophrenia and bipolar depression are less het- and associates have extensively analyzed the relationship between 574
511 erogeneous diseases compared to unipolar depression, the more MTHFR, brain activation and cognition in schizophrenic patients. In 575
512 robust heritability results may be due to the higher severity of an initial study, this team showed that the MTHFR 677T allele was 576
513 cognitive and behavioral problems in the former diseases. Bet- associated with worse executive function using a Verbal Fluency 577
514 ter phenotyping makes it easier to find associations and the best Test and a Wisconsin Card Sort Test (WCST) (Roffman et al., 2007). 578
515 example is MTHFR C677T. In one recent meta-analysis of MTHFR Subsequent studies from this group used fMRI to analyze activation 579
Please cite this article in press as: Mitchell, E.S., et al., B vitamin polymorphisms and behavior: Evidence of associations
with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.08.006
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10 E.S. Mitchell et al. / Neuroscience and Biobehavioral Reviews xxx (2014) xxx–xxx
580 of two dopaminergic regions, the bilateral anterior cingulate, and associated genes. The 844ins68 polymorphism of the cystathionine 642
581 the substantia nigra in 18 schizophrenic patients performing atten- beta-synthase (CˇS) was associated to increased risk of schizophre- 643
582 tion task. They found that MTHFR 677T allele carriers had less nia and also to changes in attention and auditory evoked potentials 644
583 error-related activation than C/C patients (Roffman et al., 2011a). (Golimbet et al., 2009, 2010). A mouse model of CˇS overexpres- 645
584 The MTHFR polymorphism C677T also appears to play a role sion was shown to have improved hippocampal signaling versus 646
585 in reducing positive symptoms via antipsychotic treatment. Six wild-type mice, while mice deficient in CS display higher SAHH 647
586 polymorphisms were investigated for association to antipsychotic and Dyrk1A, a kinase involved in methylation with putative roles in 648
587 efficacy in 329 Dutch patients using the Clinical Global Impres- Down’s syndrome cognitive dysfunction (Becker and Sippl, 2011). 649
588 sion—Improvement (CGI-I) scale to assess behavioral changes. Lastly, Roffman et al. recently published a study showing that MTR 650
589 Those individuals with the MTHFR T allele showed more improve- 2756A and FOLH1 484C contributed more potently to negative 651
590 ment with atypical antipsychotics such as olanzapine, which may symptom severity than MTFHR C677T genotype (Roffman et al., 652
591 be linked to the previous associations of this allele to behav- 2011b). 653
592 ioral disturbances (Vehof et al., 2012). However, better treatment
593 response may also couple with other physiological changes, since
9. Cognitive decline/dementia 654
594 a separate study revealed that schizophrenic subjects with the
595 MTHFR T allele had higher risk of metabolic syndrome after antipsy-
Unlike several developmental and psychiatric disorders, no 655
596 chotic treatment (Ellingrod et al., 2012). Interestingly, a study with
meta-analysis has been reported for MTHFR or any other B vitamin- 656
597 200 schizophrenia patients showed a positive relationship of folic
related SNPs for cognitive decline. While the contribution of B 657
598 acid status, MTHFR 677T allele, and reduced negative symptoms
vitamins to brain aging has been demonstrated frequently, asso- 658
599 (Roffman et al., 2008c). This 3-way relationship was supported
ciation of polymorphisms in other B vitamin genes with cognitive 659
600 by results in 32 schizophrenia patients who received either folic
decline have not been found, perhaps because of confounding of 660
601 acid (2 mg/d) or placebo, where a reduction in negative symptoms
age-related decreases in B vitamin absorption and metabolism. 661
602 was noted in MTHFR T allele carriers whose folate also rose from
However, in cognitive decline studies there has also been more 662
603 treatment (Hill et al., 2011).
attention to not just MTHFR polymorphisms but also other genes 663
associated with Alzheimer’s incidence, such as APOE. 664
604 8.3. Epistatic contribution of COMT to MTHFR
605 COMT, the enzyme which breaks down dopamine, has long 9.1. MTHFR and cognitive decline 665
606 been implicated in schizophrenia and is also a major methyl donor
607 enzyme. Carriers of both COMT Val alleles and the MTHFR T alle- Recent reports describe the use of several B vitamin biomarkers 666
608 les showed more preservative errors in the WCST (Roffman et al., and genes to identify possible synergies of the MTHFR polymor- 667
609 2008b). In a supporting study with 79 schizophrenia patients and phism with more extensive physiological data. For instance, Religa 668
610 80 controls, the T allele was associated with decreased prefrontal and colleagues found that only Alzheimer’s patients with high base- 669
611 working memory activation in dopaminergic brain regions, adding line homocysteine and low plasma folate had higher incidence 670
612 credence that the MTHFR T allele was associated with decreased of the MTHFR TT genotype (Religa et al., 2003). This same study 671
613 dopamine function (Roffman et al., 2008a). Interestingly, the MTHFR also indicated that APOE-epsilon4 alleles were independently dis- 672
614 TT and COMT Val/Val genotypes were associated with reduced pre- tributed in such patients (Religa et al., 2003) with no apparent 673
615 frontal activation in schizophrenics, and with CC and Met/Met epistatic relation to MTHFR. A found positive association of MTHFR 674
616 genotypes in controls. In subjects with MTHFR T and COMT Val TT genotype and ability on a psychomotor task in 818 elderly 675
617 alleles, prefrontal cortex dopamine levels were correlated with subjects but not other types of cognition (Durga et al., 2006). In 676
618 poor information processing and working memory (Roffman et al., contrast Flickera et al. examined APOE and MTHFR C677T status, 677
619 2008a). COMT Val/Met and MTHFR C677T polymorphisms are also and plasma amyloid, APP, APOE and homocysteine in 299 elderly 678
620 associated with reactivity due to daily life stress. Anxiety was signif- men, and found no association with MTHFR for any variable. In 679
621 icantly increased in 98 schizophrenics homozygous for COMT Met contrast, APOE epsilon4 strongly predicted cognition and depres- 680
622 and MTHFR T alleles, while no effects of genes were seen in 100 sion (Flickera et al., 2004). B12 status was positively associated 681
623 non-schizophrenic controls (Peerbooms et al., 2012). with cognition as assessed by the MMSE performance the asso- 682
624 A recent review addressed the COMT Val/Met allele polymor- ciation was stronger in those with APOE epsilon 4 genotype (Feng 683
625 phism and concluded that optimal functioning of dopamine may et al., 2009). Conversely, Abello showed that Italian AD patients had 684
626 have a U-shaped curve where too little or too much causes dys- higher than average homocysteine levels which were potentiated 685
627 function. MTHFR may exacerbate a COMT-mediated imbalance of by MTHFR T and APOE epsilon 4 status (Anello et al., 2004). In a study 686
628 dopaminergic signaling (Witte and Flöel, 2012). The above fam- conducted in China, 356 elderly males with no major neurological 687
629 ily of association studies point to a more mechanistic exploration disorders were assessed by the Cognitive Abilities Screening Instru- 688
630 of MTHFR C677T cognitive roles by revealing epistatic interactions ments (CASI) and the Wechsler Digit Span Task tests and tested for 689
631 which may be modifiable via carefully controlled supplementation. MTHFR C677T genotype; TT and CC homozygotes did worse on the 690
632 Analysing COMT polymorphisms in combination with other B vita- CASI compared to C/T carriers, suggesting that a median level of 691
633 min pathways may be efficacious since the methyl transfer function MTHFR activity may be most beneficial for cognition (Tsai et al., 692
634 of this enzyme is so tightly linked to B vitamin sufficiency. Other 2011). High homocysteine and MTHFR 677T were associated with 693
635 genes shown to have epistatic relationships with COMT are DISC1, intima-media thickness, a physiology indicative of microvascular 694
636 RGS4 and BDNF (Nicodemus et al., 2007; Witte and Flöel, 2012), damage (Gorgone et al., 2009). 695
637 where cognitive ability is enhanced or impaired via particular gene Two longitudinal studies showed nominal association of MTHFR 696
638 combinations. TT genotype status with measures of decline. Positive correlations 697
of the TT genotype were associated with lower scores on the Digit 698
639 8.4. Cystathionine beta-synthase Symbol Substitution Test, Trails B test and with annual decline on 699
the Mini-Mental State Examination (MMSE) (Elkins et al., 2007). 700
640 Compared to the extensive analyses of MTHFR interactions with Baseline homocysteine predicted risk of dementia over a 10 year 701
641 schizophrenia, very few studies have examined other B-vitamin period in 4337 healthy aged men (Ford et al., 2012). However, the 702
Please cite this article in press as: Mitchell, E.S., et al., B vitamin polymorphisms and behavior: Evidence of associations
with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.08.006
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703 study was underpowered for conclusive understanding of MTHFR subjects with imbalances in active or downstream components of 764
704 polymorphisms on development of dementia. the methyl donor pathways, like SAM/SAH. 765
705 On the whole it appears that effects of MTHFR on age-related Even with some successes in showing genotype contributions, 766
706 cognition are subtle and inconsistent. the value of assessing genetic analysis of behavioral diseases can be 767
questioned even for those conditions with strong hereditary con- 768
tributions. In fact, most available studies show negligible effects of 769
707 9.2. TCN2, MTR, MTHFD1, GCPII
single genes such as MTHFR, MTR and CˇS polymorphisms. While 770
the MTHFR C677T polymorphism may mediate significant effects 771
708 Garrod and colleagues (2008) found a relationship of high
on populations of schizophrenics, it contributes 1–3% to the inci- 772
709 homocysteine and low holotranscobalamin to poor cognitive func-
dence and 1–3% to the risk of severity. General practitioners, clinical 773
710 tion. TCN2 776 GG polymorphisms were associated with low
trial researchers, or health policy analysts would not likely consider 774
711 plasma holotranscobalamin and high homocysteine in elderly
genetic testing or treatment for most psychiatric disease because 775
712 Latino patients. Unfortunately, the effect of genotypes on cogni-
of the limited evidence. 776
713 tion was not directly tested (Garrod et al., 2010, 2008). The T776C
A more promising experimental design would be based on 777
714 polymorphism may affect the folding of the transcobalamin pro-
systems biology approaches to map the synergies of multiple 778
715 tein, possibly reducing affinity for B12, although this proposal has
genotypes in subjects, combined with improved assessments of 779
716 not been conclusively tested (Riedel et al., 2011). TCN2 status also
nutritional intakes, more exhaustive physiological analyses, and 780
717 affects homocysteine levels but it has not been analyzed as exten-
standardized psychiatric or cognitive testing. Since one carbon 781
718 sively as MTHFR.
metabolism is involved in many basic processes, the systems 782
719 The methionine reductase (MTR) A2756G polymorphism was
approach might include assessing ‘omics’ or customized panels 783
720 analyzed in 152 patients with Alzheimer’s disease and 136 con-
relating to nutritional pathways. For instance epigenetic modifi- 784
721 trols. Homozygosity for the A allele was associated with greater
cations of many neurodevelopmental genes have been shown to 785
722 severity of dementia, which increased when subjects were also
be attenuated by folic acid and B12 deficiencies (Schaevitz and 786
723 APOE4 or IL-6 CC carriers (Bosco et al., 2004). This potential gene-
Berger-Sweeney, 2012). Similarly, MTRR or MTHFR genotypes are 787
724 gene interaction may be due to homocysteine’s neurotoxicity via
also associated with methylation status of genes involved in neu- 788
725 oxidative stress and amyloid beta generation. APOE4 has been
rodevelopment such as IGFBP3 and IGF2 (McKay et al., 2012). Q5 789
726 shown to increase amyloid beta levels by reducing brain clearance
Methyl donor deficiency may strongly impact epigenetic 790
727 compared to epsilon 2 and 3 (Brown et al., 2011). Other stud-
remodeling during key periods of development, and these epi- 791
728 ies have shown no effects of B12 related polymorphisms such as
genetic changes are likely intensifying the genetic influence of 792
729 MTR A2756G genotypes, thymidylate synthase (TS) 2R→3R and ser-
B vitamin genotypes. Indeed, Burghardt and associates reported 793
730 ine hydroxymethyltransferase (SHMT1) 1420C→T on cognition in
that female schizophrenics with MTHFR 677TT genotypes had 794
731 elderly subjects (Bathum et al., 2007; Schiepers et al., 2011).
the lowest levels of DNA methylation in blood cells, indicating a 795
732 The glutamate carboxypeptidase (GCPII) C1561T polymorphism
possible role of epigenetic contribution to mental illness as well 796
733 appears to increase plasma folate and decrease homocysteine, as
as comorbidities such as metabolic syndrome (Burghardt et al., 797
734 well as scores in the Symbol Digit Modalities Test (SDMT) in aged
2012). ‘Hypomethylating’ B vitamin genotypes may be contribut- 798
735 Norwegians (Halsted et al., 2007). However, no effects of GCPII or
ing to the notable diversity of neurological and psychiatric diseases 799
736 FOLH1 genotypes were found for indices of depression or alco-
linked to one carbon pathway polymorphisms. Depending on com- 800
737 hol use in this population. Finally, a study in Chinese Alzheimer’s
plex interactions of environment, diet and genetics, deficiencies 801
738 patients found a very weak association of the MTHFD1 G1958A
in methylation capacity may give rise to differential changes in 802
739 A allele for early onset AD, but found no association of the CˇS
sets of proteins involved in schizophrenia, depression or demen- 803
740 844ins68 polymorphism (Bi et al., 2010).
tia pathology. However, it must be noted that DNA methylation 804
status of brain versus peripheral tissue is not consistent, and thus 805
741 10. Discussion it will be important to validate mechanisms of nutritional and 806
epigenetic interactions using animal models. These models could 807
742 While many epidemiological studies have shown that B vita- also incorporate analysis of other epigenetic mechanisms such as 808
743 min deficiency is associated with various psychiatric and cognitive microRNA expression and histone deacetylation (Roth and Sweatt, 809
744 issues, B vitamin supplementation has had little effect on its own. 2011; Stone et al., 2011). 810
745 Since ‘vulnerability’ genotypes such as MTHFR 677TT have low Translating animal model results to humans may not require 811
746 frequencies in many populations and its effects are subtle, the num- large numbers of participants using systems analyses and n-of- 812
747 bers of subjects needed for a B vitamin intervention study, with 1 experimental approaches (Nikles et al., 2011). These types of Q6 813
748 sufficient groups of homozygotes, is unfeasible. Yet observational studies require longitudinal analyses with more exhaustive phe- 814
749 studies using cohorts are not appropriate to test whether psychi- notyping of the participant, but also better analysis of metadata: 815
750 atric and cognition issues are reversible or even caused by changes socioeconomic, psychological history, and other lifestyle measures. 816
751 in B vitamin intake. Although analyses of variants in several B The combination of ‘phenotyping’ data with new strategies such as 817
752 vitamin metabolic pathways seem promising in genetic associa- middle out analysis methods may provide a means to better under- 818
753 tion studies, the contribution of a single gene or small subset of stand complex phenotypes (Majumder et al., 2011; deGraaf et al., Q7 819
754 genes is not likely to show reproducible effects, due to different 2011). The use of middle out methods can ultimately focus analysis 820
755 genetic populations or different diets. More consistent intervention on an expanded subsystem of genes contributing to the pheno- 821
756 study outcomes were observed in subjects with baseline homo- type studied. For instance, SAM-dependent methyltransferases are 822
757 cysteinuria or other markers of imbalanced methyl donor status, a large family of enzymes that are unconnected to each other except 823
758 where genotype status contributes to an imbalance and thus is for the need of adequate SAMe supplies to function. COMT is the best 824
759 amenable to correcting levels of nutrients. However, as stated known of this genes family and its variants have been shown to be 825
760 earlier, selection or stratification of subjects based on self-report associated with psychiatric diseases. Polymorphisms in other SAM- 826
761 questionnaires or even plasma B vitamins may not indicate levels dependent enzymatic genes would be expected to have much more 827
762 of active forms such as methylcobalamin or methylenetetrahydro- severe effects in individuals with B12 or folic acid-related poly- 828
763 folate. Thus future studies would be well served by selection of morphisms. Besides methyltransferases, SAM transporters have 829
Please cite this article in press as: Mitchell, E.S., et al., B vitamin polymorphisms and behavior: Evidence of associations
with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neurosci. Biobehav. Rev. (2014), http://dx.doi.org/10.1016/j.neubiorev.2014.08.006
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12 E.S. Mitchell et al. / Neuroscience and Biobehavioral Reviews xxx (2014) xxx–xxx
830 also not been well-studied for associations to mental health, thus Bi, X.-H., Zhao, H.-L., Zhang, Z.-X., Liu, Q., Zhang, J.-W., 2010. Association analysis of 896
CS 844ins68 and MTHFD1 G1958A polymorphisms with Alzheimer’s disease 897
831 further research is needed to identify other genes which affect
in Chinese. J. Neural Transm. 117, 499–503. 898
832 SAM bioavailability as well as metabolism, and apply these sets
Black, M.M., 2008. Effects of vitamin B12 and folate deficiency on brain development 899
833 of genes to clinical outcomes. Although few trials have applied in children. Food Nutr. Bull. 29, S126–S131. 900
Bosco, P., Guéant-Rodriguez, R.M., Anello, G., Barone, C., Namour, F., Caraci, 901
834 focused genotyping panels based on particular pathways or families
F., Romano, A., Romano, C., Guéant, J.L., 2003. Methionine synthase (MTR) 902
835 of enzymes, with the pace of technological advances in sequencing,
→
2756 (A G) polymorphism, double heterozygosity methionine synthase 2756 903
836 even small n studies may benefits from these practices. AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteine- 904
mia are three risk factors for having a child with down syndrome. Am. J. Med. 905
837 One of the difficulties of measuring a micronutrient deficiency’s
Genet. 121A, 219–224. 906
838 effect on behavior is the lack of consistent methods for assessing an
Bosco, P., Guéant-Rodríguez, R.M., Anello, G., Romano, A., Namour, B., Spada, R.S., 907
839 individual’s needs and responses, since optimal nutrient status will Caraci, F., Tringali, G., Ferri, R., Guéant, J.L., 2004. Association of IL-1 RN*2 allele 908
and methionine synthase 2756 AA genotype with dementia severity of sporadic 909
840 be different depending on genotype. Genes involved in transport,
Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 75, 1036–1038. 910
841 such as transcobalamin 2 (TCN2) may contribute to less efficient
Brown, B., Huang, M., Karlamangla, A., Seeman, T., Kado, D., 2011. Do the effects 911
842 uptake of vitamin B12, yet standard measures of B12 in plasma may of APOE- E4 on cognitive function and decline depend upon vitamin status? 912
Macarthur studies of successful aging. J. Nutr. Health Aging 15, 196–201. 913
843 not show this deficit, thereby overlooking ‘sufficient’ psychiatric
Burghardt, K.J., Pilsner, J.R., Bly, M.J., Ellingrod, V.L., 2012. DNA methylation in 914
844 patients who may benefit from nutritional therapy. A recent study
schizophrenia subjects: gender and MTHFR 677C/T genotype differences. Epige- 915
845
demonstrated that serum holoTC, but not plasma vitamin B12, nomics 4, 261–268. 916
846 MMA, or tHcy, varied according to TCN2 67A→G genotype (Riedel Coppen, A., Bolander-Gouaille, C., 2005. Treatment of depression: time to consider 917
folic acid and vitamin B12. J. Psychopharmacol. (Oxf.) 19, 59–65. 918
847 et al., 2011). The contribution of this gene to deficiency would not be
del Río Garcia, C., Torres-Sánchez, L., Chen, J., Schnaas, L., Hernández, C., Osorio, E., 919
848 found by focusing on free vitamin B12 levels alone. Another inter-
Portillo, M.G., López-Carrillo, L., 2009. Maternal MTHFR 677C>T genotype and 920
849 esting development in nutritional research is the development of dietary intake of folate and vitamin B12: their impact on child neurodevelop- 921
ment. Nutr. Neurosci. 12, 13–20. 922
850 computational models that may shed more light on how fluxes of
Devlin, A.M., Brain, U., Austin, J., Oberlander, T.F., 2010. Prenatal exposure to mater- Q9 923
851 B vitamin bioavailability proteins will alter propensity for mental
nal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation 924
852 illness risk. in infants at birth. PLoS ONE, 5. 925
Durga, J., van Boxtel, M.P.J., Schouten, E.G., Bots, M.L., Kok, F.J., Verhoef, P., 2006. 926
853 In conclusion, diverse clinical studies have revealed weak
Folate and the methylenetetrahydrofolate reductase 677C→T mutation corre- 927
854 and in some cases inconsistent associations of cognition, mood
late with cognitive performance. Neurobiol. Aging 27, 334–343. 928
855 and neurodevelopment disorders to genes involved in B vita- Dutta, S., Shaw, J., Chatterjee, A., Sarkar, K., Usha, R., Chatterjee, A., Sinha, S., 929
Mukhopadhyay, K., 2011. Importance of gene variants and co-factors of folate 930
856 min metabolism. Use of new experimental models and designs,
metabolic pathway in the etiology of idiopathic intellectual disability. Nutr. 931
857 more extensive phenotyping, and more detailed understand-
Neurosci. 14, 202–209. 932
858 ing of an individual’s exposures to stress, diet, and lifestyle Elkins, J.S., Johnston, S.C., Ziv, E., Kado, D., Cauley, J.A., Yaffe, K., 2007. Methylenete- 933
trahydrofolate reductase C677T polymorphism and cognitive function in older 934
859 will likely improve the consistency and reliability of geno-
women. Am. J. Epidemiol. 166, 672–678. 935
860 type–nutrient–behavior interaction data.
Ellingrod, V.L., Taylor, S.F., Dalack, G., Grove, T.B., Bly, M.J., Brook, R.D., Zöllner, S.K., 936
Pop-Busui, R., 2012. Risk factors associated with metabolic syndrome in bipo- 937
lar and schizophrenia subjects treated with antipsychotics: the role of folate 938
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Fenech, M., 2010. Folate, DNA damage and the aging brain. Mech. Ageing Dev. 131, 940
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862 Kevere et al. (2014).
Feng, L., Li, J., Yap, K.-B., Kua, E.-H., Ng, T.-P., 2009. Vitamin B-12, apolipoprotein 942
E genotype, and cognitive performance in community-living older adults: evi- 943
863 Acknowledgements dence of a gene-micronutrient interaction. Am. J. Clin. Nutr. 89, 1263–1268. 944
Finnell, R.H., Shaw, G.M., Lammer, E.J., Rosenquist, T.H., 2008. Gene–nutrient inter- 945
actions: importance of folk acid and vitamin B12 during early embryogenesis. 946
864 We thank David Kronlage and Jane Durga for their editorial com- Food Nutr. Bull. 29, S86–S98. 947
865 ments. Fintelman-Rodrigues, N., Corrêa, J.C., Santos, J.M., Pimentel, M.M.G., Santos- 948
Rebouc¸ as, C.B., 2009. Investigation of CBS, MTR, RFC-1 and TC polymorphisms 949
as maternal risk factors for Down syndrome. Dis. Markers 26, 155–161. 950
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