Restricted accessResearch articleFirst published online 2025-7
Effects of micronutrients on neurodevelopmental disorders through the mediation of brain structure and function: A two-step Mendelian randomization analysis
The physiological functions of micronutrients in neurodevelopment are well documented, but their protective effects on neurodevelopmental disorders remain controversial. We assessed the associations between micronutrients and three main neurodevelopmental disorders, that is, autism spectrum disorder (18,381 cases), attention-deficit/hyperactivity disorder (38,691 cases), and Tourette’s syndrome (4,819 cases), using two-sample Mendelian randomization analyses. In addition, we estimated the mediation role of brain imaging-derived phenotypes (n = 33,224) in these associations. Each 1 SD (0.08 mmol/L) increase in serum magnesium concentration was associated with a 16% reduced risk of autism spectrum disorder (odds ratio 0.84, 95% confidence interval 0.72–0.98). Each 1 SD (65 μmol/L) increase in blood erythrocyte zinc concentration was associated with an 8% reduced risk of attention-deficit/hyperactivity disorder (0.92, 0.86–0.98). Each 1 SD (173 pmol/L) increase in serum vitamin B12 concentration was associated with a 19% reduced risk of Tourette’s syndrome (0.81, 0.68–0.97). These effects were partly mediated by alterations in multiple brain imaging-derived phenotypes, with mediated proportions ranging from 5.84% to 32.66%. Our results suggested that interventions targeting micronutrient deficiencies could be a practical and effective strategy for preventing neurodevelopmental disorders, especially in populations at high risk of malnutrition.
Lay abstract
Increasing evidence highlights the critical role of micronutrients in neurodevelopment. However, the causal relationship between micronutrients and neurodevelopmental disorders remains unclear. Using genetic variants associated with micronutrient levels and neurodevelopmental disorders, our study revealed the protective effects of magnesium on autism spectrum disorders, zinc on attention-deficit/hyperactivity disorder, and vitamin B12 on Tourette’s syndrome. These protective effects were partially mediated through alterations in brain structure, function, and connectivity. Our findings emphasize the importance of adequate micronutrient intake for healthy neurodevelopment and may support the development of intervention strategies aimed at preventing neurodevelopmental disorders by addressing micronutrient deficiencies.
AdamsJ. B.AudhyaT.GeisE.GehnE.FimbresV.PollardE. L.. . .QuigD. W. (2018). Comprehensive nutritional and dietary intervention for autism spectrum disorder—A randomized, controlled 12-month trial. Nutrients, 10, 369.
2.
AlamA. B.ThomasD. S.LutseyP. L.ShresthaS.AlonsoA. (2021). Associations of serum magnesium with brain morphology and subclinical cerebrovascular disease: The atherosclerosis risk in communities-neurocognitive study. Nutrients, 13, 4496.
3.
AlateeqK.WalshE. I.CherbuinN. (2023). Dietary magnesium intake is related to larger brain volumes and lower white matter lesions with notable sex differences. European Journal of Nutrition, 62, 2039–2051.
4.
BakianA. V.BilderD. A.KorgenskiE. K.BonkowskyJ. L. (2018). Autism spectrum disorder and neonatal serum magnesium levels in preterm infants. Child Neurology Open, 5, 2329048x18800566.
5.
BenyaminB.EskoT.RiedJ. S.RadhakrishnanA.VermeulenS. H.TragliaM.. . .WhitfieldJ. B. (2014). Novel loci affecting iron homeostasis and their effects in individuals at risk for hemochromatosis. Nature Communications, 5, 4926.
6.
Bhaya-GrossmanI.ChangE. F. (2022). Speech computations of the human superior temporal gyrus. Annual Review of Psychology, 73, 79–102.
7.
BurgessS. (2014). Sample size and power calculations in Mendelian randomization with a single instrumental variable and a binary outcome. International Journal of Epidemiology, 43, 922–929.
8.
BurgessS.DaveySmith, G.DaviesN. M.DudbridgeF.GillD.GlymourM. M.. . .TheodoratouE. (2019). Guidelines for performing Mendelian randomization investigations: Update for summer 2023. Wellcome Open Research, 4, 186.
9.
CornelisM. C.FornageM.FoyM.XunP.GladyshevV. N.MorrisS.. . .HeK. (2015). Genome-wide association study of selenium concentrations. Human Molecular Genetics, 24, 1469–1477.
10.
CrowtherC. A.AshwoodP.MiddletonP. F.McPheeA.TranT.HardingJ. E. (2023). Prenatal intravenous magnesium at 30-34 weeks’ gestation and neurodevelopmental outcomes in offspring: The MAGENTA randomized clinical trial. Journal of the American Medical Association, 330, 603–614.
11.
CubilloA.HalariR.SmithA.TaylorE.RubiaK. (2012). A review of fronto-striatal and fronto-cortical brain abnormalities in children and adults with Attention Deficit Hyperactivity Disorder (ADHD) and new evidence for dysfunction in adults with ADHD during motivation and attention. Cortex, 48, 194–215.
12.
DaviesN. M.HolmesM. V.DaveySmith, G. (2018). Reading Mendelian randomisation studies: A guide, glossary, and checklist for clinicians. British Medical Journal, 362, Article k601.
13.
DemontisD.WaltersG. B.AthanasiadisG.WaltersR.TherrienK.NielsenT. T.. . .BørglumA. D. (2023). Genome-wide analyses of ADHD identify 27 risk loci, refine the genetic architecture and implicate several cognitive domains. Nature Genetics, 55, 198–208.
14.
DrudikK.PetridesM. (2024). The superior frontal sulcus in the human brain: Morphology and probability maps. Human Brain Mapping, 45, Article e26635.
15.
EmdinC. A.KheraA. V.KathiresanS. (2017). Mendelian randomization. Journal of the American Medical Association, 318, 1925–1926.
16.
EvansD. M.ZhuG.DyV.HeathA. C.MaddenP. A.KempJ. P.. . .WhitfieldJ. B. (2013). Genome-wide association study identifies loci affecting blood copper, selenium and zinc. Human Molecular Genetics, 22, 3998–4006.
17.
FanselowM. S.DongH. W. (2010). Are the dorsal and ventral hippocampus functionally distinct structures?Neuron, 65, 7–19.
18.
FerrucciL.PerryJ. R.MatteiniA.PerolaM.TanakaT.SilanderK.. . .FraylingT. M. (2009). Common variation in the beta-carotene 15,15’-monooxygenase 1 gene affects circulating levels of carotenoids: A genome-wide association study. American Journal of Human Genetics, 84, 123–133.
19.
FryeR. E.SlatteryJ.DelheyL.FurgersonB.StricklandT.TippettM.. . .QuadrosE. V. (2018). Folinic acid improves verbal communication in children with autism and language impairment: A randomized double-blind placebo-controlled trial. Molecular Psychiatry, 23, 247–256.
20.
GhoreishyS. M.EbrahimiMousavi, S.AsoudehF.MohammadiH. (2021). Zinc status in attention-deficit/hyperactivity disorder: A systematic review and meta-analysis of observational studies. Scientific Reports, 11, 14612.
21.
GrabruckerS.JannettiL.EckertM.GaubS.ChhabraR.PfaenderS.. . .GrabruckerA. M. (2014). Zinc deficiency dysregulates the synaptic ProSAP/Shank scaffold and might contribute to autism spectrum disorders. Brain, 137, 137–152.
22.
GraneroR.Pardo-GarridoA.Carpio-ToroI. L.Ramírez-CoronelA. A.Martínez-SuárezP. C.Reivan-OrtizG. G. (2021). The role of iron and zinc in the treatment of ADHD among children and adolescents: A systematic review of randomized clinical trials. Nutrients, 13, 4059.
23.
GrarupN.SulemP.SandholtC. H.ThorleifssonG.AhluwaliaT. S.SteinthorsdottirV.. . .PedersenO. (2013). Genetic architecture of vitamin B12 and folate levels uncovered applying deeply sequenced large datasets. PLOS Genetics, 9, Article e1003530.
24.
GroveJ.RipkeS.AlsT. D.MattheisenM.WaltersR. K.WonH.. . .BørglumA. D. (2019). Identification of common genetic risk variants for autism spectrum disorder. Nature Genetics, 51, 431–444.
25.
HazraA.KraftP.LazarusR.ChenC.ChanockS. J.JacquesP.. . .HunterD. J. (2009). Genome-wide significant predictors of metabolites in the one-carbon metabolism pathway. Human Molecular Genetics, 18, 4677–4687.
26.
HirotaT.KingB. H. (2023). Autism spectrum disorder: A review. Journal of the American Medical Association, 329, 157–168.
27.
HuoH.LesageE.DongW.VergutsT.SegerC. A.DiaoS.. . .ChenQ. (2023). The neural substrates of how model-based learning affects risk taking: Functional coupling between right cerebellum and left caudate. Brain and Cognition, 172, 106088.
28.
IndikaN. R.FryeR. E.RossignolD. A.OwensS. C.SenarathneU. D.GrabruckerA. M.. . .DeutzN. E. P. (2023). The rationale for vitamin, mineral, and cofactor treatment in the precision medical care of autism spectrum disorder. Journal of Personalized Medicine, 13, 252.
29.
JiangX.O’ReillyP. F.AschardH.HsuY. H.RichardsJ. B.DupuisJ.. . .KielD. P. (2018). Genome-wide association study in 79,366 European-ancestry individuals informs the genetic architecture of 25-hydroxyvitamin D levels. Nature Communications, 9, 260.
30.
JohnsonK. A.WorbeY.FooteK. D.ButsonC. R.GunduzA.OkunM. S. (2023). Tourette syndrome: Clinical features, pathophysiology, and treatment. The Lancet Neurology, 22, 147–158.
31.
KestenbaumB.GlazerN. L.KöttgenA.FelixJ. F.HwangS. J.LiuY.. . .FoxC. S. (2010). Common genetic variants associate with serum phosphorus concentration. Journal of the American Society of Nephrology, 21, 1223–1232.
32.
Ladd-AcostaC.HansenK. D.BriemE.FallinM. D.KaufmannW. E.FeinbergA. P. (2014). Common DNA methylation alterations in multiple brain regions in autism. Molecular Psychiatry, 19, 862–871.
33.
LordC.ElsabbaghM.BairdG.Veenstra-VanderweeleJ. (2018). Autism spectrum disorder. The Lancet, 392, 508–520.
34.
MageeL. A.De SilvaD. A.SawchuckD.SynnesA.von DadelszenP. (2019). No. 376-magnesium sulphate for fetal neuroprotection. Journal of Obstetrics and Gynaecology Canada, 41, 505–522.
35.
MajorJ. M.YuK.WheelerW.ZhangH.CornelisM. C.WrightM. E.. . .AlbanesD. (2011). Genome-wide association study identifies common variants associated with circulating vitamin E levels. Human Molecular Genetics, 20, 3876–3883.
36.
MarshallM. (2020). The hidden links between mental disorders. Nature, 581, 19–21.
37.
MartineauJ.BarthelemyC.GarreauB.LelordG. (1985). Vitamin B6, magnesium, and combined B6-Mg: Therapeutic effects in childhood autism. Biological Psychiatry, 20, 467–478.
38.
MazefskyC. A.HerringtonJ.SiegelM.ScarpaA.MaddoxB. B.ScahillL.WhiteS. W. (2013). The role of emotion regulation in autism spectrum disorder. Journal of the American Academy of Child and Adolescent Psychiatry, 52, 679–688.
39.
MeyerT. E.VerwoertG. C.HwangS. J.GlazerN. L.SmithA. V.van RooijF. J., . . . Meta Analysis of Glucose and Insulin Related Traits Consortium. (2010). Genome-wide association studies of serum magnesium, potassium, and sodium concentrations identify six loci influencing serum magnesium levels. PLOS Genetics, 6, Article e1001045.
40.
MitchellE. S.ConusN.KaputJ. (2014). B vitamin polymorphisms and behavior: Evidence of associations with neurodevelopment, depression, schizophrenia, bipolar disorder and cognitive decline. Neuroscience & Biobehavioral Reviews, 47, 307–320.
41.
MondulA. M.YuK.WheelerW.ZhangH.WeinsteinS. J.MajorJ. M.. . .AlbanesD. (2011). Genome-wide association study of circulating retinol levels. Human Molecular Genetics, 20, 4724–4731.
42.
Müller-VahlK. R.GrosskreutzJ.PrellT.KaufmannJ.BodammerN.PeschelT. (2014). Tics are caused by alterations in prefrontal areas, thalamus and putamen, while changes in the cingulate gyrus reflect secondary compensatory mechanisms. BMC Neuroscience, 15, Article 6.
43.
NoorazarS. G.MalekA.AghaeiS. M.YasaminehN.KalejahiP. (2020). The efficacy of zinc augmentation in children with attention deficit hyperactivity disorder under treatment with methylphenidate: A randomized controlled trial. Asian Journal of Psychiatry, 48, 101868.
44.
O’SeaghdhaC. M.WuH.YangQ.KapurK.GuessousI.ZuberA. M.. . .BochudM. (2013). Meta-analysis of genome-wide association studies identifies six new Loci for serum calcium concentrations. PLOS Genetics, 9, Article e1003796.
45.
PosnerJ.PolanczykG. V.Sonuga-BarkeE. (2020). Attention-deficit hyperactivity disorder. The Lancet, 395, 450–462.
46.
ReynoldsE. (2006). Vitamin B12, folic acid, and the nervous system. The Lancet Neurology, 5, 949–960.
47.
RichiardiL.BelloccoR.ZugnaD. (2013). Mediation analysis in epidemiology: Methods, interpretation and bias. International Journal of Epidemiology, 42, 1511–1519.
48.
SchoenM.AsogluH.BauerH. F.MüllerH. P.AbaeiA.SauerA. K.. . .BoeckersT. M. (2019). Shank3 transgenic and prenatal zinc-deficient autism mouse models show convergent and individual alterations of brain structures in MRI. Frontiers in Neural Circuits, 13, Article 6.
49.
ShenkinA. (2006). Micronutrients in health and disease. Postgraduate Medical Journal, 82, 559–567.
50.
ShennanA.SuffN.JacobssonB.SimpsonJ. L.NormanJ.GrobmanW. A.. . .MolB. W. (2021). FIGO good practice recommendations on magnesium sulfate administration for preterm fetal neuroprotection. International Journal of Gynecology & Obstetrics, 155, 31–33.
51.
SmithS. M.DouaudG.ChenW.HanayikT.Alfaro-AlmagroF.SharpK.ElliottL. T. (2021). An expanded set of genome-wide association studies of brain imaging phenotypes in UK Biobank. Nature Neuroscience, 24, 737–745.
52.
TangneyC. C.AggarwalN. T.LiH.WilsonR. S.DecarliC.EvansD. A.MorriaM. C. (2011). Vitamin B12, cognition, and brain MRI measures: A cross-sectional examination. Neurology, 77, 1276–1282.
53.
VoganV. M.MorganB. R.SmithM. L.TaylorM. J. (2019). Functional changes during visuo-spatial working memory in autism spectrum disorder: 2-year longitudinal functional magnetic resonance imaging study. Autism, 23, 639–652.
54.
VolkL.ChiuS. L.SharmaK.HuganirR. L. (2015). Glutamate synapses in human cognitive disorders. Annual Review of Neuroscience, 38, 127–149.
55.
WillekensJ.RunnelsL. W. (2022). Impact of zinc transport mechanisms on embryonic and brain development. Nutrients, 14, 2526.
56.
YaoS.ZhangM.DongS. S.WangJ. H.ZhangK.GuoJ.. . .YangT.-L. (2022). Bidirectional two-sample Mendelian randomization analysis identifies causal associations between relative carbohydrate intake and depression. Nature Human Behaviour, 6, 1569–1576.
57.
YuD.SulJ. H.TsetsosF.NawazM. S.HuangA. Y.ZelayaI., . . . the Psychiatric Genomics Consortium Tourette Syndrome Working Group. (2019). Interrogating the genetic determinants of Tourette’s syndrome and other tic disorders through genome-wide association studies. The American Journal of Psychiatry, 176, 217–227.
58.
ZhangC.WeiG.ZhouH.LiuL. (2024). Causal relationships of familial hypercholesterolemia with the risk of multiple vitamin deficiencies: A Mendelian randomization study. Frontiers in Endocrinology, 15, Article 1401260.
59.
ZhaoB.LiT.YangY.WangX.LuoT.ShanY.. . .ZhuH. (2021). Common genetic variation influencing human white matter microstructure. Science, 372, Article eabf3736.
60.
ZhengJ. S.LuanJ.SofianopoulouE.ImamuraF.StewartI. D.DayF. R.. . .WarehamN. J. (2021). Plasma vitamin C and type 2 diabetes: Genome-wide association study and Mendelian randomization analysis in European populations. Diabetes Care, 44, 98–106.
61.
ZhouW.NielsenJ. B.FritscheL. G.DeyR.GabrielsenM. E.WolfordB. N.. . .LeeS. (2018). Efficiently controlling for case-control imbalance and sample relatedness in large-scale genetic association studies. Nature Genetics, 50, 1335–1341.
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