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 (<i>n</i> = 33,224) in these associations. Each 1 <i>SD</i> (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 <i>SD</i> (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 <i>SD</i> (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 abstractIncreasing 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.