G Model NBR 2010 1–14 ARTICLE IN PRESS 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 (C␤S), 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 G Model NBR 2010 1–14 ARTICLE IN PRESS 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.