Prenatal nutrition, epigenetics and schizophrenia risk: can we test causal effects?

• Published in: Epigenomics Vol. 4; no. 3; pp. 303 - 315
• Main Authors: Kirkbride, James B, Susser, Ezra, Kundakovic, Marija, Kresovich, Jacob K, Davey Smith, George, Relton, Caroline L
• Format: Journal Article
• Language: English
• Published: England Future Medicine Ltd 01.06.2012
• Subjects: Agouti; Brain; Brain - metabolism; Brain - physiopathology; Cell Adhesion Molecules, Neuronal - genetics; CpG Islands - genetics; DNA Methylation; Epigenesis, Genetic; epigenetic epidemiology; Epigenetic inheritance; Epigenetics; Epigenomics; Extracellular Matrix Proteins - genetics; Female; folate; Folic Acid - metabolism; Genetic aspects; Humans; Management; Mendelian randomization; Mendelian Randomization Analysis; Mental disorders; Metabolism; Methylation; Methylenetetrahydrofolate Reductase (NADPH2) - genetics; Nerve Tissue Proteins - genetics; Nutrition; one-carbon metabolism; Population studies; Pregnancy; Prenatal care; Prenatal experience; Prenatal Exposure Delayed Effects - genetics; Prenatal Exposure Delayed Effects - metabolism; prenatal nutrition; Prenatal Nutritional Physiological Phenomena - genetics; Progeny; psychosis; Reelin; Reelin Protein; Risk Factors; Schizophrenia; Schizophrenia - genetics; Schizophrenia - metabolism; Schizophrenia - physiopathology; Serine Endopeptidases - genetics; United Kingdom
• ISSN: 1750-1911; 1750-192X
• DOI: 10.2217/epi.12.20

We posit that maternal prenatal nutrition can influence offspring schizophrenia risk via epigenetic effects. In this article, we consider evidence that prenatal nutrition is linked to epigenetic outcomes in offspring and schizophrenia in offspring, and that schizophrenia is associated with epigenetic changes. We focus upon one-carbon metabolism as a mediator of the pathway between perturbed prenatal nutrition and the subsequent risk of schizophrenia. Although post-mortem human studies demonstrate DNA methylation changes in brains of people with schizophrenia, such studies cannot establish causality. We suggest a testable hypothesis that utilizes a novel two-step Mendelian randomization approach, to test the component parts of the proposed causal pathway leading from prenatal nutritional exposure to schizophrenia. Applied here to a specific example, such an approach is applicable for wider use to strengthen causal inference of the mediating role of epigenetic factors linking exposures to health outcomes in population-based studies.