Prenatal nutrition, epigenetics and schizophrenia risk: can we test causal effects?
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.
EpiCentre group, Department of Psychiatry, University of Cambridge, Herchel Smith Building for Brain & Mind Sciences, Forvie Site, Robinson Way, Cambridge, UK. jbk25@cam.ac.uk
James B
JB
Kirkbride
Ezra
E
Susser
Marija
M
Kundakovic
Jacob K
JK
Kresovich
George
G
Davey Smith
Caroline L
CL
Relton
D001921:Brain / Q000378:metabolism / Q000503:physiopathology; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D057890:Epigenomics; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D006801:Humans; D057182:Mendelian Randomization Analysis; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000235:genetics; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects / Q000235:genetics* / Q000378:metabolism; D039401:Prenatal Nutritional Physiological Phenomena / Q000235:genetics*; D000091042:Reelin Protein; D012307:Risk Factors; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D012697:Serine Endopeptidases / Q000235:genetics
D015816:Cell Adhesion Molecules, Neuronal; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; D000091042:Reelin Protein; D005492:Folic Acid; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D012697:Serine Endopeptidases