B Vitamin Polymorphisms and Behavior: Evidence of Associations

Neuroscience and Biobehavioral Reviews 47 (2014) 307–320

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Review

B vitamin polymorphisms and behavior: Evidence of associations

with neurodevelopment, depression, schizophrenia, bipolar disorder

and cognitive decline

∗

E. Siobhan Mitchell , Nelly Conus, Jim Kaput

Nestle Institute of Health Science, Innovation Park, EPFL Campus, Lausanne 1015, Switzerland

a r t i c l e i n f o a b s t r a c t

Article history: The B vitamins folic acid, vitamin B12 and B6 are essential for neuronal function, and severe deﬁciencies

Received 16 December 2013

have been linked to increased risk of neurodevelopmental disorders, psychiatric disease and dementia.

Received in revised form 11 July 2014

Polymorphisms of genes involved in B vitamin absorption, metabolism and function, such as methylene

Accepted 18 August 2014

tetrahydrofolate reductase (MTHFR), cystathionine ␤ synthase (C␤S), transcobalamin 2 receptor (TCN2)

Available online 27 August 2014

and methionine synthase reductase (MTRR), have also been linked to increased incidence of psychiatric

and cognitive disorders. However, the effects of these polymorphisms are often quite small and many

Keywords:

studies failed to show any meaningful or consistent associations. This review discusses previous ﬁndings

Folate

from clinical studies and highlights gaps in knowledge. Future studies assessing B vitamin-associated

Vitamin B9

polymorphisms must take into account not just traditional demographics, but subjects’ overall diet,

Vitamin B12

Vitamin B6 relevant biomarkers of nutritional status and also analyze related genetic factors that may exacerbate

Dementia behavioral effects or nutritional status.

Geriatric depression Nutrition Genetics Memory Mood

Contents

1. Introduction ...... 308

2. Biochemistry and function of B12, B6, folic acid and related proteins ...... 308

3. Clinical ﬁndings on B vitamin supplementation and cognitive or mood disorders ...... 308

4. Role of genetics in B vitamin deﬁciencies...... 309

5. B vitamin transport genes and deﬁciencies ...... 309

6. Genetic contribution of B vitamin polymorphisms in neurodevelopment ...... 310

6.1. B vitamin deﬁciencies and neurodevelopment ...... 310

6.2. B vitamin polymorphisms and intellectual ability in general populations ...... 310

6.3. B vitamin polymorphisms and Down’s syndrome ...... 313

6.4. B vitamin polymorphisms and autism ...... 314

7. Genetic contribution of B vitamin polymorphisms in depression...... 314

7.1. B vitamin bioavailability and depression...... 314

7.2. General depressive disorders ...... 314

7.3. Geriatric depression ...... 314

7.4. Pregnancy-related depression ...... 315

∗

Corresponding author. Tel.: +41 021 632 6181.

E-mail address: [email protected] (E.S. Mitchell).

http://dx.doi.org/10.1016/j.neubiorev.2014.08.006

308 E.S. Mitchell et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 307–320

8. Genetic contribution of B vitamin polymorphisms in bipolar disorder and schizophrenia...... 315

8.1. Schizophrenia incidence and MTHFR polymorphisms ...... 315

8.2. MTHFR polymorphisms, biomarkers and behavioral phenotypes ...... 315

8.3. Epistatic contribution of COMT to MTHFR ...... 316

8.4. Cystathionine beta-synthase ...... 316

9. Cognitive decline/dementia ...... 316

9.1. MTHFR and cognitive decline ...... 316

9.2. TCN2, MTR, MTHFD1, GCPII ...... 317

10. Discussion ...... 317

Acknowledgements ...... 318

References ...... 318

1. Introduction mitochondrial dysfunction, nuclear disintegration, and apoptosis

of neurons (Kruman et al., 2000). Adequate supplies of SAM are

Vitamin B12, B6 and folic acid play important roles in the devel- crucial for maintenance of neurotransmitters and DNA synthesis

opment, maintenance and function of the brain, and unsurprisingly, (Frankenburg, 2007).

there has been intense activity on elucidating the role of B vita- Vitamin B12 also plays a role in conversion of methylmalonic

min deﬁciency in psychiatric and neurologic diseases. However, the acid-CoA into succinic acid-CoA for use in the tricarboxylic acid

exact relationship between B vitamin status and risk of cognitive or cycle. Speciﬁcally, the mitochondrial enzyme methylmalonyl Co-A

behavioral disorders is unclear. For example, while epidemiological mutase (MUT) requires B12 (in the prosthetic form adenosylcobal-

studies indicate B vitamin deﬁciency as a risk factor for cognition amin) as a co-factor. Very low levels of B12 or mutations in MUT may

problems during normal aging, intervention studies have not pro- lead to methylmalonic acidemia, a disorder associated with severe

duced robust effects (Tangney et al., 2009). One possible reason brain damage, especially during development (Li et al., 2009).

for this lack of clarity may be due to polymorphisms which regu- While the many intersecting pathways of the methyl donor sys-

late B vitamin-associated biochemical pathways, either abrogating tem allow for some imbalance, too high or too low levels of B12, B6,

deﬁciency symptoms, or providing protection in the context of low folate or their co-factors may cause dysregulation of methyl donor

intake (Haggarty, 2007). This review will evaluate genes that reg- activity, and also buildup of toxic intermediates such as homocys-

ulate B vitamin function, which have also been linked to cognitive teine and methylmalonic acid (Fenech, 2010). Moreover, imbalance

dysfunction. of SAM/SAH causes further inhibition of methylation reactions cru-

cial for cognitive function.

2. Biochemistry and function of B12, B6, folic acid and

related proteins 3. Clinical ﬁndings on B vitamin supplementation and

cognitive or mood disorders

Vitamin B9 (folic acid or folate), B6 (pyridoxine and related

vitamers) and B12 (also called cobalamin) play vital roles in A full discussion of the many intervention studies investigating

methyl group donation for synthesis of proteins, lipids, nucleic B vitamin modulation of behavior or cognition is beyond the scope

acids, neurotransmitters, and hormones. In cells, vitamin B12 and of this review. To summarize the ﬁndings thus far: combinations

folic acid are part of the methionine synthase (MS) complex that of B vitamins, especially B6, B12 and folate, are more effective than

reduces homocysteine to methionine, which is then converted into single vitamin treatment and the likelihood of a signiﬁcant effect

S-adenosylmethionine (SAM), a crucial co-factor for 150+ methyl- appears dependent on baseline imbalance of plasma homocysteine

transferases including glycine n-methyltransferase (GNMT) in the and other methyl donor intermediates. However, with these stud-

one carbon pathway (Fig. 1). After methyl group transfer, SAM ies there is a lack of consistency, especially for intervention studies

becomes S-adenosylhomocysteine (SAH), which then becomes in aged populations, in dosage used, length of intervention, exper-

homocysteine, via the enzyme SAH hydrolase (SAHH), thus com- imental population, and assessments such as diet and lifestyle.

pleting a cycle of methyl group transfer. Homocysteine also can Three trials of B12 and folate supplementation (using different

be converted into glutathione, an important antioxidant, via series doses and durations) in patients with dementia revealed no effect

of intermediate steps requiring vitamin B6 as a cofactor and the on cognitive function (Aisen et al., 2008; Vital Trial Collaborative

␤

enzyme cystathionine beta synthase (C S). Group, 2003). Yet another trial using mild cognitive impairment

Folate facilitates methionine synthesis from homocysteine by (MCI) patients (29 subjects with memory complaints), 2 months

acting as a cofactor for methylene tetrahydrofolate reductase of folic acid increased attention and this effect was even stronger

(MTHFR) which converts 5,10-methylenetetrahydrofolate (CH2 in those with low baseline plasma folate (Fioravanti et al., 1997),

THF) to 5-methyltetrahydrofolate (CH3 THF). CH2THF is generated while other trials using folic acid only supplementation produced

from tetrahydrofolate by the enzyme serine methylhydroxytrans- no effects on cognition (Malouf and Grimley Evans, 2008).

ferase (SHMT), which also uses B6 as a co-factor. Sufﬁcient B12, The evidence for B vitamin supplementation and alleviation of

B6 and folate therefore reduce levels of homocysteine, while deﬁ- mood disorders is even weaker than that for cognitive decline,

ciency of B vitamins can cause hyperhomocysteinemia, which is especially for B12 and B6. While small pilot studies with specially

associated with increased risk of heart disease, cognitive problems selected populations (patients with eating disorders, history of

and mood disorders (Almeida et al., 2008; Flickera et al., 2004). stroke or cardiovascular disease) have shown some effects of folic

Severe deﬁciencies of B12, folate or B6 can lead to macrocytic or acid supplementation in monopolar or bipolar depression, system-

pernicious anemia, syndromes characterized by fatigue, psychomo- atic reviews indicate that the evidence is marginal (Sylvia et al.,

tor, cognitive and mood deﬁcits (Selhub et al., 2009). Generally, 2013; Taylor et al., 2004).

vitamin B12 deﬁciency with sufﬁcient folate allows for production In terms of physiological status, homocysteine levels are

of adequate SAM, while homocysteine levels remain high. Homo- decreased more by concurrent folic acid, B6 and B12 supplemen-

cysteine has been implicated in amyloid buildup, DNA damage, tation (Vogel et al., 2009), which may partially explain why trials

E.S. Mitchell et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 307–320 309

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 (C␤S) converts homocysteine to

cystathionine.

that supplement only one or the other often do not show posi- ameliorate or intensify neurological disease in carriers of suscepti-

tive results. Furthermore, baseline homocysteine levels in subjects ble genotypes. Not surprisingly, a major challenge for researchers is

appear to be linked to likelihood of cognitive deﬁcit, thus indicat- how to analyze genotype and interactions of genes that affect B vita-

ing a subpopulation (within highly heterogeneous disease groups min bioavailability and function, while simultaneously integrating

such as depression, schizophrenia and dementia) more likely to information on individual nutrient proﬁles and health or patholo-

beneﬁt from supplementation. For example, a recent study supple- gies. Nonetheless, there is a growing view that B12, B6, folic acid

mented 187 mild cognitive impairment (MCI) patients (age 70 or and associated intermediates must be monitored simultaneously

above) with vitamin B12, B6 and folic acid for 24 months showed for appropriate nutrition recommendations in speciﬁc populations

that slower brain atrophy due to treatment was correlated with or individuals.

baseline plasma homocysteine levels (Smith et al., 2010).

In America where folate has been added to cereal grain products

5. B vitamin transport genes and deﬁciencies

for decades, deﬁciency is now very low (<1% of the population)

and B12 is the predominant B vitamin deﬁciency (Selhub and

Vitamin B12 has a complex transport process through the body,

Paul, 2011). Indeed, the ‘masking’ of B12 deﬁciency neurological

beginning with binding to haptocorrin in the stomach, then to

symptoms by an abundance of folate also hinders diagnosis of

intrinsic factor (IF) in the intestines, moving (while bound to IF) into

hyperhomocysteinia, which contributes to higher rates of cognitive

the bloodstream via cubilin receptors. Transcobalamin II (TCN2,

problems.

or holotranscobalamin when bound) transports B12 to peripheral

tissues. Studies in adults with neuropsychiatric disease have also

4. Role of genetics in B vitamin deﬁciencies suggested the presence of an active transport mechanism into the

brain for vitamin B12, implicating the protein amnionless as a

Genetic makeup may play an important role in which popula- possible transporter (Luder et al., 2008). Interestingly, B12 deﬁ-

tions or subgroups will be more sensitive to B vitamin deﬁciency, ciency is frequently linked to poor absorption and metabolism

and thus exhibit increased risk of mental disorders. Genetic dif- rather than low consumption. Moreover, supplementation of B12

ferences may also explain the prevalence of hyperhomocysteinia does not always resolve deﬁciency, pointing to inefﬁcient or low

and methylmalonic acidemia, since most Western diets provide levels of B12-related enzymes or transport proteins. For instance,

adequate supplies of B12, B6 and folic acid. In fact, many cohort in some individuals, B12 plasma levels may be normal but B12

studies have shown that subjects’ genotype predicts cognitive func- intermediates, such as holotranscobalamin, may be reduced due

tion more than plasma B vitamin levels (Wilson et al., 2010). Genetic to polymorphisms in the TCN2 gene. In addition, the TCN2 259R

makeup has been shown to inﬂuence levels of serum metabolites allele is associated with lower holotranscobalamin levels, espe-

in several genome wide association studies. cially in the cerebral spinal ﬂuid of Alzheimer’s patients (Zetterberg

Aside from diet and genetics, plasma B vitamin levels are et al., 2003). Hence, transport proteins such as IF, transcobal-

affected by many factors, such as age and environment, which may amin II, cubilin, and haptocorrin are attractive targets for assessing

310 E.S. Mitchell et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 307–320

Table 1

Genetic polymorphisms in B vitamin-related enzymes.

Gene Enzyme function Mutation effect Disease association

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 (C␤S) 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

cognition–genotype relationships, since these genes are expressed 6. Genetic contribution of B vitamin polymorphisms in

in brain tissues, but to our knowledge only TCN2 has been signiﬁ- neurodevelopment

cant associated to incidence of neuropsychiatric disorders.

While some genetic diseases involving B12 metabolism have 6.1. B vitamin deﬁciencies and neurodevelopment

very severe effects on cognition, such as Immerlund–Grasbeck dis-

order, mutations in this gene pathway appear to be rare and thus During pregnancy, large amounts of vitamin B12, B6 and folic

beyond the scope of this review. Single nucleotide polymorphisms acid are shunted to the fetus. Mothers deﬁcient in these micronu-

(SNPs) that are common (≥1% frequency) in the general popula- trients become more depleted in order to sustain appropriate levels

tion have weak effects on B12 levels. Only about 3% of Western for brain development within the womb. However, infants can

populations have been reported to have plasma B12 deficiency. become B vitamin deficient in the first year of life, where long-

Free plasma B12, however, may not indicate true deﬁciency and term deﬁciencies can cause neurological symptoms such as apathy,

B12 complexed with transholocobalamin or B12-associated inter- tremor and fatigue (Finnell et al., 2008). Apathy and fatigue symp-

mediates (e.g., methylmalonic acid), may be more informative of toms may be due to folate’s role in neurotransmitter production,

bioavailability and functionality. while tremor symptoms appear to be related to the B12’s role

Folate found in food is often bound to glutamate or chains of in myelination of neuronal axons, a prominent and rapid process

glutamic acids. Folate hydrolase (also called N-acetyl-l-aspartyl-l- which occurs during infancy. Some populations in Indian and Latin

glutamate (NAAG) peptidase) cleaves NAAG into N-acetyl aspartate America become deﬁcient due to lack of protein in their diet, and

(NAA), which also releases free folate from glutamate. Folate hydro- coupled with genotypes associated with poor B12 or folic acid

lase plays a vital role in regulating not only brain glutamate, but uptake, infants can show brain atrophy and mental retardation

also free folate availability. The 484C SNP of the folate hydrolase (Black, 2008).

gene, FOLH1, have been implicated in negative symptom severity

and treatment response in schizophrenia (Roffman et al., 2013).

6.2. B vitamin polymorphisms and intellectual ability in general

Free folate is transported into cells via various transporters, includ- populations

ing the reduced folate carrier, an organic anion antiporter that

exchanges 5-methyltetrahydrofolate. Polymorphisms of its encod-

Only a few studies have analyzed B vitamin-related genes and

ing gene, RFC-1, are implicated in homocysteinemia (Lucock and

their association with general neurodevelopment. For example, the

Yates, 2006). Lastly, active folate is transported into the brain via

incidence of neurodevelopmental disorders were higher in subjects

the folate receptor alpha, which is abundantly expressed in the

homozygous for the hypomorphic version of the methionine syn-

choroid plexus. Polymorphisms of the folate receptor alpha gene,

thase reductase (MTRR) A66G allele (Li et al., 2009) which has also

FOLR1, have been reported in severe neurodevelopmental disor-

been linked to high levels of homocysteine in children (Aléssio et al.,

ders and some brain cancers, and also may increase homocysteine

2007). Another gene which has recently been reported to affect

levels, especially in conjunction with other folate-related geno-

neurodevelopment is fucosyltransferase 2 (FUT2). The FUT2 pro-

types (Grapp et al., 2012). Genes related to B vitamin transport and

tein is involved in production of gut antigens during infections, but

metabolism, and their links to associated disorders are listed in

which also affects plasma levels of B12 via modulation of cobalamin

Table 1, while Table 2 summarizes all the B vitamin genetic associ-

transporter expression in the gut (Hazra et al., 2008). Bonilla et al.

ation studies discussed in this review.

(2012) recently reported an association of maternal FUT2 rs492602

E.S. Mitchell et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 307–320 311 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

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

age or

corr.

intellectual

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

disorders

related was

(<400 assoc. any no C667T polymorphisms

pregnancy

depression depressed symptoms

assoc. less

promoter

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

5-HTT

body

with

of genotype

MTHFR

between

syndrome

T or TT genotype C677T negative homocysteine

MTHFR TT

CES-D predicted

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, Genotype thiol citalopram carriers allele MTHFR genotype improve Down’s signiﬁcant neonatal C677T the

acid

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

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

and

mg/d acid

and

110

week subjects

years) case w/1 sample)

folic

Chinese

and 12

63 disability

w/50

with controls

65–90 control

years

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

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

folate

or (2009)

disorder

B6 al.

(2009) B12,

bipolar

(2010) al.

al. et (2005) and

(2008)

(2010) (2010) et

(2003) (2006) (2012) (2006)

(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.

Garcia

al. et

et al.

et et et et

et et investigating et

al.

et 2 et

Río

Development Reference del Shaw Dutta Fintelman-Rodrigues Bosco Pas Lewis Lewis Almeida Lanctt Yuan Gaysina Hong Naumovski Lizer Kim Lewis Ye Devlin Słopien Hill Schizophrenia Depression Studies Table

312 E.S. Mitchell et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 307–320 in

(7 age

to T/T

and than folate

folate

WCST epsilon4

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

in to and

on allele

with worse the total)

667T memory

allele

the

onset, evoked biomarker; showed had homocysteine,

Met/Met

in lower due

of for decreased

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

was found observation patients than

families

of carriers with

and

auditory

stress

performed

folate elevated

speed

assoc.

the and

and at with

T-carriers,

and with homocysteine

C/C other MTHFR

was

greater levels

no genotypes

and

association

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

the

and associated

developing

homozygous in

genotypes 667T 677 677TT C677T interaction subjects not

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 No High MTHFR MTHFR no Patients Gly-carriers folate Effect Lower No 844ins68 sensorimotor with AD assoc. dementia, polymorphisms in Scandinavians. genotype displayed assoc. risk, or 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,

folate

tests; insertion/deletion plasma

B12

plasma

birth

Depression task

age

Negative C667T genotype; MTHFR

and folic

MTHFR Fluency

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; genotype Test His452Tyr; symptoms (ESM); (PANSS), and and cognition incidence and assessments markers; Card MTHFR: factors, (mMMSE), homocysteine; Sort Trails (TICS), Wechsler DRD2: COMTVal158Met performing AD

774 and

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)

al. al. aged (2003) (2008) (2003) (2006) (2007)

(2012) et

al. al. al. al. (2010)

al.

(2012)

et (2011) et in al. al.

al. al. al. et et et et al.

et al.

al.

al. et et et et Continued et

(

et 2

Reference Yoshimi Vares Ozbek Muntjewerff Vehof Roffman Roffman Roffman Roffman Tsutsumi Peerbooms Golimbet Tsai Seripa Religa Durga Flickera Elkins Ford Cognition Table

E.S. Mitchell et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 307–320 313

and offspring IQ in a longitudinal study of parents and children,

regardless of maternal B12 intake. Interestingly, FUT2 rs492602 is differ

also

a key genetic modulator of B12 deﬁciency (approximately 3% of not

Western populations carry the FUT2 allele correlated to low B12) of were

did

(Black, 2008). Lack of B12 to the developing brain may have lifelong

effects in what appear to be intellectually normal children. SNPs cognition

severity

subjects in several genes related to B12 metabolism, i.e., methionine syn- on

thase (MTR), methylene tetrahydrofolate reductase (MTHFR) and incidence

holotranscobalamin

when

␤ ˇ cystathionine synthase (C S) and their association with cognitive carriers function polymorphism

low

w/greater

w/AD ability as measured by IQ tests were also studied. The C S 844ins68

and allele, which decreases efﬁciency of the enzyme, was signiﬁcantly

C677T

increased assoc. IL-1B

polymorphism

under-represented in children with high IQ (Barbaux et al., 2000). cognitive

the

␤ associated any Although brain C S expression is only 20% of that of expression of

poor which of

controls

in the periphery, this ﬁnding suggests that metabolism of homo- to

genotype allele

␤

and cysteine via C S may be an important factor for optimal brain

homocysteine A

GG effects

development. AD

High No MTR Distribution MS relating in APOEepsilon4

dementia,

The MTHFR C677T polymorphism has attracted great interest

since the T variant causes a thermolabile form of MTHFR, which

requires much higher levels of folate than the C variant to stabilize TC

the binding of ﬂavin-adenosine-dinucleotide (FAD). Thus carriers of and

3R,

Scale

the T allele are more susceptible to folic acid deﬁciency, as well as

→

C1420T; A1298C, developmental syndromes and later psychiatric illness. MTHFR has severity

scale

(3MSE)

dementia been analyzed or discussed in over 2500 publications (PubMed) in AD

(TS)

many diverse phenotypes and conditions. For example, one recent C677T,

Depression ratio; and

(SHMT1)

Reisberg study investigated the MTHFR C677T polymorphism by measuring

cognition in 235 Mexican toddlers (via the Bayley’s Scale) and asso- synthase Examination MTHFR

Studies

ciating scores with either nutritional status or genotype. Deﬁciency genotype

battery

holoTC/B12

State

polymorphisms;

of vitamin B12 was negatively associated with mental development

genotypes;

IL-1RN, test

APOE while low dietary intake of folate (<400 mg/day) reduced Bailey’s and

APOE

Scale scores in children of TT genotype carriers only (del Río Garcia Thymidylate and

test;

IL-1B,

A2756G

and et al., 2009).

Epidemiological holoTC,

Mini-Mental

With regard to more intellectually disabled children, no associa- recall C667T, C677T

MTR IL-1A,

for

hydroxymethyltransferase

B12,

tion of the MTHFR genotype or degree of impairment in a report that A2756G

examined 100 severely mentally retarded children (i.e., without tri- MTHFR Total APO-E, MS MTHFR C776G, (CES-D) neuropsychological Center Modiﬁed

serine delayed

incidence

somies) compared to 743 normal controls (Shaw et al., 2007). In a

follow up study, 226 children with idiopathic intellectual disability

(IID) were tested, along with their nuclear families, for associations

to B12 and folate cycle gene polymorphisms (Dutta et al., 2011). aged

Speciﬁcally, signiﬁcant differences in genotype frequencies were

observed for the polymorphisms: MTR A2756G, MTRR A66G, and

subjects DHFR rs70991108 in IID subjects as compared to controls.

818

years and AD

6.3. B vitamin polymorphisms and Down’s syndrome controls controls

60–93

24–82,

Due to MTHFR’s role in methyl donation, several studies have 136 166 sporadic

age

examined the relationships between the C677T polymorphism and aged

and and

with

risk of having a Down’s syndrome (DS) child. They have shown that ethnicity

Latinos, having one of the ‘risk’ alleles (C677T or A1298C MTHFR polymor-

phic variants) increases one’s chance of having a Down’s syndrome patients patients Dutch

patients

baby while two risk alleles further increases incidence (Martínez- participants, elderly AD AD

Frías, 2008). Another study using a separate set of polymorphisms: 777 554 152 172 Italian

50–70, ˇ

C S 844ins68, MTR A2756G, reduced folate carrier (RFC-1) G80A

and transcobalamin (TCN) G776C in 114 mothers of Down’s chil-

dren and 110 matched controls found no correlations, indicating

that offspring genotype may be more important than maternal

genotype at these alleles (Fintelman-Rodrigues et al., 2009). A

study examining the interactions of B12-related alleles found that

the MTR AG genotype was a signiﬁcant risk factor for having a

Down’s syndrome child or being a Down’s syndrome case (Bosco

(2011) et al., 2003). In addition, carriers of both the MTR A2756G and the

(2001)

(2010)

al.

MTRR A66G genotypes had even higher risk of having a DS child. (2004) (2003)

al. et al.

al. al.

et Additionally, in a follow up study researchers found that plasma

et et

homocysteine, the MTHFR 677T allele and transcobalamin (TCN)

776G allele were negatively associated with IQ in Down’s syndrome

Schiepers Garrod Bosco Beyer Brunelli

patients (Guéant et al., 2005).

314 E.S. Mitchell et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 307–320

6.4. B vitamin polymorphisms and autism though still debated, evidence has been generated for association

of the MTHFR C677T polymorphism with depression.

Folic acid supplementation has been linked to lower incidence While GWAS studies have failed to signiﬁcantly link any poly-

of autism in a cohort of over 85,000 children (Surén et al., 2013). morphisms to depression, two meta-analyses of 20 and 26 studies

B vitamin-related genes have also been analyzed in subjects with respectively showed a signiﬁcant effect from the MTHFR C677T

autism or autistic spectrum behaviors. In autistic disorder and polymorphism on incidence of depression (López-León et al., 2008;

pervasive development disorder (PDD) groups, plasma levels of Wu et al., 2013). However, there may be ethnicity consideration

methionine, cysteine and total blood glutathione were found to that add complexity to these ﬁndings, since another meta-analysis

be reduced, while plasma homocysteine, vitamin B12, and folate assessed the inﬂuence of the MTHFR C677T polymorphism in 5

were in the normal range (Pas¸ ca et al., 2009). The results of the studies and concluded that the dominant allele (T) had an asso-

MTHFR gene analysis showed a trend of the 677T allele as slightly ciation with depression in Asian but not Caucasian populations

more prevalent in AD patients. Another group, using data from the (Zintzaras, 2006). In contrast a large study of 3478 European

Autism Genetic Resource Exchange (AGRE), analyzed symptomol- women found a strong association between the MTHFR C677T geno-

ogy as deﬁned by the Autism Diagnostic Interview—Revised (ADI-R) type and three indicators of depression (history of depression,

and found that the following four behaviors were positively asso- antidepressant use, or the EuroQoL mood questionnaire). In the

ciated with the MTHFR T allele: poor direct gaze, current complex same article, a meta-analysis of eight studies also indicated a strong

body movements, a history of self-injurious behavior, and current link of the T allele to depression risk (Lewis et al., 2006).

overactivity (Goin-Kochel et al., 2009). In order to clarify the association of MTHFR genotype in depres-

In conclusion, the above ﬁndings point to a meaningful role of sion several groups have used symptom severity or treatment

B vitamin-related genes in select neurodevelopmental syndromes. response as co-variates. A recent study involving 402 depressed

Replicating these associations will be challenging due to the low subjects and 600 controls (Han Chinese ethnicity), found a posi-

frequency of the risk alleles of MTHFR, MTR, MTRR, and DHFR in some tive association between high Hamilton Rating Scale for Depression

populations (Martínez-Frías, 2008). For example, MTHFR C677T (HAMD)-17 scores and TT or CT genotypes (Li et al., 2010). Another

and MTRR A66G polymorphisms are associated with a greater risk study that examined 90 subjects with depression secondary to

of having a child with DS in North America, Ireland, and The traumatic brain injury found that those with MTHFR TT geno-

Netherlands, but not in Sicily or France (Guéant et al., 2003), possi- types predicted greater treatment response with 50 mg citalopram

bly due to the differential incidence of these alleles in the general (Lanctt et al., 2010). However, many individual studies have failed

populations of these regions. Interestingly, a recent pilot interven- to show a MTHFR C677T association with depression incidence. For

tion study of leucovorin (folinic acid) in autistic children displaying instance, Almeida and colleagues reported that for 580 depressed

folate receptor auto-antibodies improved several behavior indices patients the Beck Depression Inventory (BDI) score of TT geno-

(Frye et al., 2013). These results support the notion that bioactive type subjects was unchanged compared to other MTHFR genotypes

folate is deﬁcient in some cases of autism, and may possibly be (Almeida et al., 2005), although plasma homocysteine strongly cor-

inﬂuenced by genes involved in one carbon metabolism. Future related with BDI scores, as well as B12 and folate levels. Two other

studies require multivariate analysis of environmental, physiologi- studies using large cohorts of depressed patients and controls found

cal, nutritional and genetic data of parents and offspring to generate no association of the MTHFR C677T polymorphism to disease inci-

‘risk intersections’ of these factors. dence (Gaysina et al., 2008; Lizer et al., 2011). However, these

studies did not use co-variate data such as symptom severity or

progression to identify more complex interactions of MTHFR alleles

7. Genetic contribution of B vitamin polymorphisms in

and mood. One approach successfully used to discern such interac-

depression

tions demonstrated that childhood trauma and MTHFR TT genotype

predicted depression risk (Lok et al., 2013).

7.1. B vitamin bioavailability and depression

7.3. Geriatric depression

Low B vitamin status has long been linked to depressive behav-

ior, especially subjects with lethargic, apathetic symptomology

Studies focusing on depressed elderly subjects have found sig-

(Semmes, 2005). S-adenosyl methionine (SAM) has been repeat-

niﬁcant associations with plasma B12 levels, possibly due to a

edly shown as just as effective as many currently prescribed

higher rate of age-related gastritis which decreases intrinsic factor

antidepressants (Coppen and Bolander-Gouaille, 2005). How SAM

(IF) expression causing reduced B12 uptake (Tiemeier et al., 2002).

can function as a neuroactive agent is not clear since a SAM cell

Age-induced B12 deﬁciencies make it more difﬁcult to demonstrate

membrane transporter has not been identiﬁed. SAM could be trans-

genetic linkage to depression in older subjects. In a study of 116

ported across cellular membranes by one of the many members of

patients with geriatric depression plasma homocysteine was signif-

the organic ion and ATP cassette transporter families or via analogs

icantly higher than compared to healthy controls, and there was a

of mitochondrial SAM transporters, but this has not been proven

correlation with the age of ﬁrst episode and comorbid cardiovascu-

in the literature (http://omim.org/entry/611037). More bioavail-

lar disease with homocysteine levels (Yuan et al., 2008). However,

able forms of folate and B12, 5-methyltetrahydrofolate (also called

there were no signiﬁcant differences in the MTHFR C677T polymor-

methylfolate) and methylcobalamin, have also been touted as

phism genotypes and alleles between the patients and the healthy

depression therapies (Coppen and Bolander-Gouaille, 2005).

controls. This ﬁnding was supported by a later study performed

with elderly Chinese depressed patients and age matched controls,

7.2. General depressive disorders where the 677T allele was not more frequent in depressed subjects

or related to cognition or gray matter hyperintensity volume (Hong

Although B vitamin deﬁciency is linked to depression incidence, et al., 2009).

it has proved difﬁcult to show a signiﬁcant association of B vitamin Some studies have found some positive genetic relationships to

polymorphisms. In fact, even highly publicized ‘risk’ alleles such geriatric depression by using novel biomarkers or associated health

as the ‘short’ version of serotonin transporter promoter (5-HTTLPR) conditions as covariates. One of the earliest studies on the associ-

has not been conclusively linked to depression incidence, probably ation of MTHFR and geriatric depression found higher incidence of

because of the heterogeneous nature of the disease. Some strong, the T allele subjects with vascular risk factors (Hickie et al., 2001).

E.S. Mitchell et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 307–320 315

Another geriatric depression study showed that the C677T MTHFR While a majority of single cohort studies have found pos-

T allele was associated with higher scores in the Hamilton Depres- itive polymorphism associations mostly with MTHFR alleles,

sion Index (HADS), while plasma thiol dipeptide Cys-Gly, which is a meta-analyses report contradictory ﬁndings, which may be a con-

product of folate and glutathione metabolism, was negatively asso- sequence of inclusion criteria for subjects and a greater range of

ciated to the T allele (Naumovski et al., 2010). Lastly in 538 elderly ethnicities in recent studies. No signiﬁcant association between

east Asian subjects the MTHFR TT genotype was associated with either allele of the MTHFR C677T polymorphism and the risk

general somatic morbidity and incidence of depression (Kim et al., of developing bipolar disorder, depression or schizophrenia was

2009). found in a meta-analysis of 10 studies (Zintzaras, 2006). In

contrast, a more recent meta-analysis investigated the relative

associations of 20 different polymorphisms previously linked to

7.4. Pregnancy-related depression schizophrenia and found that MTHFR C677T was one of the 6

that showed a signiﬁcant association (Allen et al., 2008). In this

Folic acid supplementation for pregnant women is now a well- same meta-analysis, which used a database of over 1000 genetic

established preventative measure against neural tube defects, but association studies (‘SzGene’), other well-known genes such as

more recently epidemiological data on B vitamin intake and post- apolipoprotein E (APOE), dopamine 2 receptor (D2DR) and catechol-

partum depression has emerged, with some interactions toward O-methyltransferase (COMT) were reported to have no effect on

genotypes (Black, 2008; Lewis et al., 2012; Selhub and Paul, 2011). incidence of schizophrenia (Allen et al., 2008). Lastly, the authors

Folic acid supplementation during the last two trimesters had no remarked that these ﬁndings supported an epigenetic role in these

effect on development of depression 0–8 months after delivery, yet diseases.

did have a slight effect 21 months postpartum, and this effect was The association of MTHFR C677T and schizophrenia is still

intensiﬁed in women with the MTHFR C677T TT genotype (Lewis controversial. In a meta-analysis of studies using east Asian

et al., 2012). The MTHFR C677T allele also was associated with populations, the population attributable risk was only marginally

greater depressed mood during pregnancy and poor mood pre- signiﬁcant for C677T and schizophrenia, as well as bipolar depres-

dicted less methylation in both maternal and neonatal 5-HTTLPR sion (i.e., increased risk for T allele carriers) (Shi et al., 2008).

promoter regions (which regulates expression of the serotonin However, in a genome wide association study (GWAS) of 696

transporter) (Devlin et al., 2010). Surprisingly, few depression asso- Japanese schizophrenic patients compared to 774 controls, impu-

ciation studies have investigated the interaction of polymorphisms tational analysis showed no relationship of MTHFR genes (4 SNPs

related to monoamine function since B vitamins are involved in in total) to risk of developing schizophrenia (Yoshimi et al., 2010).

monoamine metabolism. Lastly, a ‘risk index’ model was used to study whether 384

Few studies have assessed depression linkage to polymorphisms schizophrenic patients exhibited a higher incidence of polymor-

in other B vitamin interacting genes. Ye et al. studied poly- phisms previously associated with schizoid disorders by adding

␥

morphisms in folate polyglutamate synthase (FPGS), -glutamyl together the number of genetic risk factors (methylenetetrahydro-

hydrolase (GGH), methionine synthase (MTR), proton-coupled folate reductase; MTHFR, dopamine 2 receptor; DRD2, dopamine 4

folate transporter (PCFT), and reduced folate carrier 1 (RFC1) genes receptor; DRD4, glutamate receptor ionotropic NMDA subunit 2b;

in 976 Puerto Rican adults, aged 45–75 years, and none of the GRIN2B, tryptophan hydroxyolase; TPH1, and dystrobrevin binding

variants were related to depression (Ye et al., 2011). The folate protein 1; DTNBP1) (Tsutsumi et al., 2011). However, the ‘risk index’

hydrolase (FOLH1) C1561T polymorphism was signiﬁcantly asso- was similar between patients and controls, belying the notion that

ciated with lower CES-D score and TT and TC genotypes were less schizophrenia incidence can be predicted by a limited collection of

likely to report depressive symptoms. A study of 83 Polish women risk genes in the absence of behavioral or biochemical co-variates.

with post-partum depression and 89 controls investigated the asso-

ciation of MTHFR, MTR, and MTHFD1 polymorphisms according to

the severity of depression. After stratiﬁcation of symptoms, the MTR 8.2. MTHFR polymorphisms, biomarkers and behavioral

GG genotype was shown increase the risk of depression 5-fold, phenotypes

while MTHFR and MTHFD1 genotypes had no inﬂuence (Słopien

et al., 2008). More in-depth analyses of schizophrenia risk and MTHFR have

examined familial genotypes, nutritional status, age of onset and

season of birth as co-variates. The C677T polymorphism signiﬁ-

8. Genetic contribution of B vitamin polymorphisms in cantly affected age at onset of schizophrenia, with lower age of

bipolar disorder and schizophrenia onset coinciding with increased T-allele frequency in 820 Scandina-

vian schizophrenic patients (Vares et al., 2010). In the same study,

8.1. Schizophrenia incidence and MTHFR polymorphisms the MTHFR T allele was associated with earlier age at onset than

siblings homozygous for the C allele in group of high-risk families

Genetic analysis of B vitamin-related genes has been more of Chinese descent (two or more affected siblings, n = 221). Lastly,

prevalent in studies schizophrenia or bipolar disease, where there a study examining season of birth and incidence of schizophrenia

is estimated heritability of 80%, as opposed to unipolar depression, found no association of MTHFR C677T genotypes and schizophrenia

where heritability is estimated to be around 40% (Stringer et al., risk in Dutch subjects (Muntjewerff et al., 2011).

2011). While schizophrenia and bipolar depression are less het- Inclusion of brain imaging and challenging cognition tasks have

erogeneous diseases compared to unipolar depression, the more also been used to increase genetic association robustness. Rothman

robust heritability results may be due to the higher severity of and associates have extensively analyzed the relationship between

cognitive and behavioral problems in the former diseases. Bet- MTHFR, brain activation and cognition in schizophrenic patients. In

ter phenotyping makes it easier to ﬁnd associations and the best an initial study, this team showed that the MTHFR 677T allele was

example is MTHFR C677T. In one recent meta-analysis of MTHFR associated with worse executive function using a Verbal Fluency

C677T (n = 29,502) researchers found a signiﬁcant associations in Test and a Wisconsin Card Sort Test (WCST) (Roffman et al., 2007).

schizophrenic and bipolar but not unipolar depressive patients. Subsequent studies from this group used fMRI to analyze activa-

However, unipolar depression association studies have not been tion of two dopaminergic regions, the bilateral anterior cingulate,

widely performed (Peerbooms et al., 2011). and the substantia nigra in 18 schizophrenic patients performing

316 E.S. Mitchell et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 307–320

attention task. They found that MTHFR 677T allele carriers had less risk of schizophrenia and also to changes in attention and auditory

error-related activation than C/C patients (Roffman et al., 2011a). evoked potentials (Golimbet et al., 2009, 2010). A mouse model

The MTHFR polymorphism C677T also appears to play a of CˇS overexpression was shown to have improved hippocampal

role in reducing positive symptoms via antipsychotic treat- signaling versus wild-type mice, while mice deﬁcient in C␤S

ment. Six polymorphisms were investigated for association to display higher SAHH and Dyrk1A, a kinase involved in methylation

antipsychotic efﬁcacy in 329 Dutch patients using the Clinical with putative roles in Down’s syndrome cognitive dysfunction

Global Impression—Improvement (CGI-I) scale to assess behav- (Becker and Sippl, 2011). Lastly, Roffman et al. recently published

ioral changes. Those individuals with the MTHFR T allele showed a study showing that MTR 2756A and FOLH1 484C contributed

more improvement with atypical antipsychotics such as olanzap- more potently to negative symptom severity than MTFHR C677T

ine, which may be linked to the previous associations of this allele to genotype (Roffman et al., 2011b).

behavioral disturbances (Vehof et al., 2012). However, better treat-

ment response may also couple with other physiological changes,

9. Cognitive decline/dementia

since a separate study revealed that schizophrenic subjects with the

MTHFR T allele had higher risk of metabolic syndrome after antipsy-

Unlike several developmental and psychiatric disorders, no

chotic treatment (Ellingrod et al., 2012). Interestingly, a study with

meta-analysis has been reported for MTHFR or any other B vitamin-

200 schizophrenia patients showed a positive relationship of folic

related SNPs for cognitive decline. While the contribution of B

acid status, MTHFR 677T allele, and reduced negative symptoms

vitamins to brain aging has been demonstrated frequently, asso-

(Roffman et al., 2008c). This 3-way relationship was supported

ciation of polymorphisms in other B vitamin genes with cognitive

by results in 32 schizophrenia patients who received either folic

decline have not been found, perhaps because of confounding of

acid (2 mg/d) or placebo, where a reduction in negative symptoms

age-related decreases in B vitamin absorption and metabolism.

was noted in MTHFR T allele carriers whose folate also rose from

However, in cognitive decline studies there has also been more

treatment (Hill et al., 2011).

attention to not just MTHFR polymorphisms but also other genes

associated with Alzheimer’s incidence, such as APOE.

8.3. Epistatic contribution of COMT to MTHFR

COMT, the enzyme which breaks down dopamine, has long 9.1. MTHFR and cognitive decline

been implicated in schizophrenia and is also a major methyl donor

enzyme. Carriers of both COMT Val alleles and the MTHFR T alleles Recent reports describe the use of several B vitamin biomarkers

showed more preservative errors in the WCST (Roffman et al., and genes to identify possible synergies of the MTHFR polymor-

2008b). In a supporting study with 79 schizophrenia patients and phism with more extensive physiological data. For instance, Religa

80 controls, the T allele was associated with decreased prefrontal and colleagues found that only Alzheimer’s patients with high base-

working memory activation in dopaminergic brain regions, adding line homocysteine and low plasma folate had higher incidence

credence that the MTHFR T allele was associated with decreased of the MTHFR TT genotype (Religa et al., 2003). This same study

dopamine function (Roffman et al., 2008a). Interestingly, the MTHFR also indicated that APOE-epsilon4 alleles were independently dis-

TT and COMT Val/Val genotypes were associated with reduced pre- tributed in such patients (Religa et al., 2003) with no apparent

frontal activation in schizophrenics, and with CC and Met/Met epistatic relation to MTHFR. A found positive association of MTHFR

genotypes in controls. In subjects with MTHFR T and COMT Val TT genotype and ability on a psychomotor task in 818 elderly

alleles, prefrontal cortex dopamine levels were correlated with subjects but not other types of cognition (Durga et al., 2006). In

poor information processing and working memory (Roffman et al., contrast Flickera et al. examined APOE and MTHFR C677T status,

2008a). COMT Val/Met and MTHFR C677T polymorphisms are also and plasma amyloid, APP, APOE and homocysteine in 299 elderly

associated with reactivity due to daily life stress. Anxiety was signif- men, and found no association with MTHFR for any variable. In

icantly increased in 98 schizophrenics homozygous for COMT Met contrast, APOE epsilon4 strongly predicted cognition and depres-

and MTHFR T alleles, while no effects of genes were seen in 100 sion (Flickera et al., 2004). B12 status was positively associated

non-schizophrenic controls (Peerbooms et al., 2012). with cognition as assessed by the MMSE performance the asso-

A recent review addressed the COMT Val/Met allele polymor- ciation was stronger in those with APOE epsilon 4 genotype (Feng

phism and concluded that optimal functioning of dopamine may et al., 2009). Conversely, Abello showed that Italian AD patients had

have a U-shaped curve where too little or too much causes dys- higher than average homocysteine levels which were potentiated

function. MTHFR may exacerbate a COMT-mediated imbalance of by MTHFR T and APOE epsilon 4 status (Anello et al., 2004). In a study

dopaminergic signaling (Witte and Flöel, 2012). The above fam- conducted in China, 356 elderly males with no major neurological

ily of association studies point to a more mechanistic exploration disorders were assessed by the Cognitive Abilities Screening Instru-

of MTHFR C677T cognitive roles by revealing epistatic interactions ments (CASI) and the Wechsler Digit Span Task tests and tested for

which may be modiﬁable via carefully controlled supplementation. MTHFR C677T genotype; TT and CC homozygotes did worse on the

Analysing COMT polymorphisms in combination with other B vita- CASI compared to C/T carriers, suggesting that a median level of

min pathways may be efﬁcacious since the methyl transfer function MTHFR activity may be most beneﬁcial for cognition (Tsai et al.,

of this enzyme is so tightly linked to B vitamin sufﬁciency. Other 2011). High homocysteine and MTHFR 677T were associated with

genes shown to have epistatic relationships with COMT are DISC1, intima-media thickness, a physiology indicative of microvascular

RGS4 and BDNF (Nicodemus et al., 2007; Witte and Flöel, 2012), damage (Gorgone et al., 2009).

where cognitive ability is enhanced or impaired via particular gene Two longitudinal studies showed nominal association of MTHFR

combinations. TT genotype status with measures of decline. Positive correlations

of the TT genotype were associated with lower scores on the Digit

8.4. Cystathionine beta-synthase Symbol Substitution Test, Trails B test and with annual decline on

the Mini-Mental State Examination (MMSE) (Elkins et al., 2007).

Compared to the extensive analyses of MTHFR interactions Baseline homocysteine predicted risk of dementia over a 10 year

with schizophrenia, very few studies have examined other B- period in 4337 healthy aged men (Ford et al., 2012). However, the

vitamin associated genes. The 844ins68 polymorphism of the study was underpowered for conclusive understanding of MTHFR

cystathionine beta-synthase (CˇS) was associated to increased polymorphisms on development of dementia.

E.S. Mitchell et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 307–320 317

On the whole it appears that effects of MTHFR on age-related Even with some successes in showing genotype contributions,

cognition are subtle and inconsistent. the value of assessing genetic analysis of behavioral diseases can be

questioned even for those conditions with strong hereditary con-

tributions. In fact, most available studies show negligible effects of

9.2. TCN2, MTR, MTHFD1, GCPII

single genes such as MTHFR, MTR and CˇS polymorphisms. While

the MTHFR C677T polymorphism may mediate signiﬁcant effects

Garrod and colleagues (2008) found a relationship of high

on populations of schizophrenics, it contributes 1–3% to the inci-

homocysteine and low holotranscobalamin to poor cognitive func-

dence and 1–3% to the risk of severity. General practitioners, clinical

tion. TCN2 776 GG polymorphisms were associated with low

trial researchers, or health policy analysts would not likely consider

plasma holotranscobalamin and high homocysteine in elderly

genetic testing or treatment for most psychiatric disease because

Latino patients. Unfortunately, the effect of genotypes on cogni-

of the limited evidence.

tion was not directly tested (Garrod et al., 2010, 2008). The T776C

A more promising experimental design would be based on

polymorphism may affect the folding of the transcobalamin pro-

systems biology approaches to map the synergies of multiple

tein, possibly reducing afﬁnity for B12, although this proposal has

genotypes in subjects, combined with improved assessments of

not been conclusively tested (Riedel et al., 2011). TCN2 status also

nutritional intakes, more exhaustive physiological analyses, and

affects homocysteine levels but it has not been analyzed as exten-

standardized psychiatric or cognitive testing. Since one carbon

sively as MTHFR.

metabolism is involved in many basic processes, the systems

The methionine reductase (MTR) A2756G polymorphism was

approach might include assessing ‘omics’ or customized panels

analyzed in 152 patients with Alzheimer’s disease and 136 con-

relating to nutritional pathways. For instance epigenetic modiﬁ-

trols. Homozygosity for the A allele was associated with greater

cations of many neurodevelopmental genes have been shown to

severity of dementia, which increased when subjects were also

be attenuated by folic acid and B12 deﬁciencies (Schaevitz and

APOE4 or IL-6 CC carriers (Bosco et al., 2004). This potential gene-

Berger-Sweeney, 2012). Similarly, MTRR or MTHFR genotypes are

gene interaction may be due to homocysteine’s neurotoxicity via

also associated with methylation status of genes involved in neu-

oxidative stress and amyloid beta generation. APOE4 has been

rodevelopment such as IGFBP3 and IGF2 (McKay et al., 2012).

shown to increase amyloid beta levels by reducing brain clearance

Methyl donor deﬁciency may strongly impact epigenetic

compared to epsilon 2 and 3 (Brown et al., 2011). Other stud-

remodeling during key periods of development, and these epi-

ies have shown no effects of B12 related polymorphisms such as

genetic changes are likely intensifying the genetic inﬂuence of

MTR A2756G genotypes, thymidylate synthase (TS) 2R→3R and ser-

B vitamin genotypes. Indeed, Burghardt and associates reported

ine hydroxymethyltransferase (SHMT1) 1420C→T on cognition in

that female schizophrenics with MTHFR 677TT genotypes had

elderly subjects (Bathum et al., 2007; Schiepers et al., 2011).

the lowest levels of DNA methylation in blood cells, indicating a

The glutamate carboxypeptidase (GCPII) C1561T polymorphism

possible role of epigenetic contribution to mental illness as well

appears to increase plasma folate and decrease homocysteine, as

as comorbidities such as metabolic syndrome (Burghardt et al.,

well as scores in the Symbol Digit Modalities Test (SDMT) in aged

2012). ‘Hypomethylating’ B vitamin genotypes may be contribut-

Norwegians (Halsted et al., 2007). However, no effects of GCPII or

ing to the notable diversity of neurological and psychiatric diseases

FOLH1 genotypes were found for indices of depression or alco-

linked to one carbon pathway polymorphisms. Depending on com-

hol use in this population. Finally, a study in Chinese Alzheimer’s

plex interactions of environment, diet and genetics, deﬁciencies

patients found a very weak association of the MTHFD1 G1958A

in methylation capacity may give rise to differential changes in

A allele for early onset AD, but found no association of the CˇS

sets of proteins involved in schizophrenia, depression or demen-

844ins68 polymorphism (Bi et al., 2010).

tia pathology. However, it must be noted that DNA methylation

status of brain versus peripheral tissue is not consistent, and thus

10. Discussion it will be important to validate mechanisms of nutritional and

epigenetic interactions using animal models. These models could

While many epidemiological studies have shown that B vita- also incorporate analysis of other epigenetic mechanisms such as

min deﬁciency is associated with various psychiatric and cognitive microRNA expression and histone deacetylation (Roth and Sweatt,

issues, B vitamin supplementation has had little effect on its own. 2011; Stone et al., 2011).

Since ‘vulnerability’ genotypes such as MTHFR 677TT have low Translating animal model results to humans may not require

frequencies in many populations and its effects are subtle, the num- large numbers of participants using systems analyses and n-of-1

bers of subjects needed for a B vitamin intervention study, with experimental approaches (Lillie et al., 2011). These types of studies

sufﬁcient groups of homozygotes, is unfeasible. Yet observational require longitudinal analyses with more exhaustive phenotyping

studies using cohorts are not appropriate to test whether psychi- of the participant, but also better analysis of metadata: socioeco-

atric and cognition issues are reversible or even caused by changes nomic, psychological history, and other lifestyle measures. The

in B vitamin intake. Although analyses of variants in several B combination of ‘phenotyping’ data with new strategies such as

vitamin metabolic pathways seem promising in genetic associa- middle out analysis methods may provide a means to better under-

tion studies, the contribution of a single gene or small subset of stand complex phenotypes (Majumder and Mukherjee, 2011; de

genes is not likely to show reproducible effects, due to different Graaf et al., 2009). The use of middle out methods can ultimately

genetic populations or different diets. More consistent intervention focus analysis on an expanded subsystem of genes contributing

study outcomes were observed in subjects with baseline homo- to the phenotype studied. For instance, SAM-dependent methyl-

cysteinuria or other markers of imbalanced methyl donor status, transferases are a large family of enzymes that are unconnected to

where genotype status contributes to an imbalance and thus is each other except for the need of adequate SAMe supplies to func-

amenable to correcting levels of nutrients. However, as stated tion. COMT is the best known of this genes family and its variants

earlier, selection or stratiﬁcation of subjects based on self-report have been shown to be associated with psychiatric diseases. Poly-

questionnaires or even plasma B vitamins may not indicate levels morphisms in other SAM-dependent enzymatic genes would be

of active forms such as methylcobalamin or methylenetetrahydro- expected to have much more severe effects in individuals with B12

folate. Thus future studies would be well served by selection of or folic acid-related polymorphisms. Besides methyltransferases,

subjects with imbalances in active or downstream components of SAM transporters have also not been well-studied for associations

the methyl donor pathways, like SAM/SAH. to mental health, thus further research is needed to identify other

318 E.S. Mitchell et al. / Neuroscience and Biobehavioral Reviews 47 (2014) 307–320

genes which affect SAM bioavailability as well as metabolism, and Bi, X.-H., Zhao, H.-L., Zhang, Z.-X., Liu, Q., Zhang, J.-W., 2010. Association analysis of

C␤S 844ins68 and MTHFD1 G1958A polymorphisms with Alzheimer’s disease

apply these sets of genes to clinical outcomes. Although few tri-

in Chinese. J. Neural Transm. 117, 499–503.

als have applied focused genotyping panels based on particular

Black, M.M., 2008. Effects of vitamin B12 and folate deﬁciency on brain development

pathways or families of enzymes, with the pace of technological in children. Food Nutr. Bull. 29, S126–S131.

Bosco, P., Guéant-Rodriguez, R.M., Anello, G., Barone, C., Namour, F., Caraci,

advances in sequencing, even small n studies may beneﬁts from

F., Romano, A., Romano, C., Guéant, J.L., 2003. Methionine synthase (MTR)

these practices.

→

2756 (A G) polymorphism, double heterozygosity methionine synthase 2756

One of the difﬁculties of measuring a micronutrient deﬁciency’s AG/methionine synthase reductase (MTRR) 66 AG, and elevated homocysteine-

mia are three risk factors for having a child with down syndrome. Am. J. Med.

effect on behavior is the lack of consistent methods for assessing an

Genet. 121A, 219–224.

individual’s needs and responses, since optimal nutrient status will

Bosco, P., Guéant-Rodríguez, R.M., Anello, G., Romano, A., Namour, B., Spada, R.S.,

be different depending on genotype. Genes involved in transport, Caraci, F., Tringali, G., Ferri, R., Guéant, J.L., 2004. Association of IL-1 RN*2 allele

such as transcobalamin 2 (TCN2) may contribute to less efﬁcient and methionine synthase 2756 AA genotype with dementia severity of sporadic

Alzheimer’s disease. J. Neurol. Neurosurg. Psychiatry 75, 1036–1038.

uptake of vitamin B12, yet standard measures of B12 in plasma may

Bonilla, C., Lawlor, D.A., Taylor, A.E., Gunnell, D.J., Ben-Shlomo, Y., Ness, A.R., Timp-

not show this deﬁcit, thereby overlooking ‘sufﬁcient’ psychiatric

son, N.J., St Pourcain, B., Ring, S.M., Emmett, P.M., Smith, A.D., Refsum, H., Pennell,

patients who may beneﬁt from nutritional therapy. A recent study C.E., Brion, M.J., Smith, G.D., Lewis, S.J., 2012. Vitamin B-12 status during preg-

nancy and child’s IQ at age 8: a Mendelian randomization study in the Avon

demonstrated that serum holoTC, but not plasma vitamin B12,

longitudinal study of parents and children. PLoS One 7, e51084.

MMA, or tHcy, varied according to TCN2 67A→G genotype (Riedel

Brown, B., Huang, M., Karlamangla, A., Seeman, T., Kado, D., 2011. Do the effects

et al., 2011). The contribution of this gene to deﬁciency would not be of APOE- E4 on cognitive function and decline depend upon vitamin status?

Macarthur studies of successful aging. J. Nutr. Health Aging 15, 196–201.

found by focusing on free vitamin B12 levels alone. Another inter-

Brunelli, T., Bagnoli, S., Giusti, B., Nacmias, B., Pepe, G., Sorbi, S., Abbate, R., 2001. The

esting development in nutritional research is the development of

C677T methylenetetrahydrofolate reductase mutation is not associated with

computational models that may shed more light on how ﬂuxes of Alzheimer’s disease. Neurosci. Lett. 315, 103–105.

Burghardt, K.J., Pilsner, J.R., Bly, M.J., Ellingrod, V.L., 2012. DNA methylation in

B vitamin bioavailability proteins will alter propensity for mental

schizophrenia subjects: gender and MTHFR 677C/T genotype differences. Epige-

illness risk.

nomics 4, 261–268.

In conclusion, diverse clinical studies have revealed weak Coppen, A., Bolander-Gouaille, C., 2005. Treatment of depression: time to consider

folic acid and vitamin B12. J. Psychopharmacol. (Oxf.) 19, 59–65.

and in some cases inconsistent associations of cognition,

de Graaf, A.A., Freidig, A.P., De Roos, B., Jamshidi, N., Heinemann, M., Rullmann,

mood and neurodevelopment disorders to genes involved in

J.A., Hall, K.D., Adiels, M., van Ommen, B., 2009. Nutritional Systems Biology

B vitamin metabolism. Use of new experimental models and Modeling: From Molecular Mechanisms to Physiology. PLoS Comput. Biol. 5,

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del Río Garcia, C., Torres-Sánchez, L., Chen, J., Schnaas, L., Hernández, C., Osorio, E.,

standing of an individual’s exposures to stress, diet, and

Portillo, M.G., López-Carrillo, L., 2009. Maternal MTHFR 677C>T genotype and

lifestyle will likely improve the consistency and reliability of

dietary intake of folate and vitamin B12: their impact on child neurodevelop-

genotype–nutrient–behavior interaction data. ment. Nutr. Neurosci. 12, 13–20.

Devlin, A.M., Brain, U., Austin, J., Oberlander, T.F., 2010. Prenatal exposure to mater-

nal depressed mood and the MTHFR C677T variant affect SLC6A4 methylation

Acknowledgements in infants at birth. PLoS ONE 5, e12201.

Durga, J., van Boxtel, M.P.J., Schouten, E.G., Bots, M.L., Kok, F.J., Verhoef, P., 2006.

Folate and the methylenetetrahydrofolate reductase 677C→T mutation corre-

We thank David Kronlage and Jane Durga for their editorial com-

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