30 October 2007. Schizophrenia is a complex disease that stems from both genetic and environmental risk factors. If scientists thirst for associations to explain the former, they hunger for rationales to the latter. Environmental exposures that happen prior to, during, or shortly after birth, are particularly hard to reconcile with a disease that has an onset much later in life. One perinatal risk factor that begs for an explanation is inadequate nutrition. It is not clear why children born during times of famine are at increased risk for schizophrenia later, but a paper in this week’s PNAS whets our appetite.
Researchers led by Bastiaan Heijmans at Leiden University, The Netherlands, and L. H. Lumey at Columbia University, New York, report that people conceived around the time of the Dutch Hunger Winter of 1944-1945 have epigenetic changes that can be recorded 60 years later. The findings support the developmental origins hypothesis, which suggests that adverse conditions experienced in the womb can give rise to disease, such as schizophrenia, later in life.
The 1944-1945 Dutch Hunger Winter and the Chinese famine of 1959-1961 are the two most notable examples of increased schizophrenia risk among people conceived during a time of famine (see Susser et al., 1996 and St Clair et al., 2005). It has long been hypothesized that such environmental stress can cause epigenetic change—alterations that affect the structure but not the sequence of the human genome. Environmentally induced epigenetic changes, such as modification of DNA by methylation, can influence the activity of genes and are well documented in animal models (see Sinclair et al., 2007) but not in people. “The current study presents a first example of an association between a periconceptional exposure and DNA methylation in humans,” write the authors.
First author Heijmans and colleagues focused on methylation of the insulin-like growth factor 2 (IGF2) gene, a known site of methylation in the human genome. IGF2 is maternally imprinted, meaning that the copy of the gene inherited from the mother is chemically silenced. This silencing is achieved by methylation of a specific region in the gene called the differentially methylated region, or DMR. Failure to methylate the DMR can lead to activation of the maternally inherited gene, with potentially disastrous consequences, including development of colon and other cancers (see Cui, 2007). Using the IGF2 gene as a marker of methylation, the researchers examined the DMRs from 60 individuals born around the Dutch Hunger Winter.
The researchers compared methylation patterns in people born around the famine with those in same-sex siblings who were not exposed to or affected by that hard winter during gestation. Examining five different methylation targets in the DMR, Heijmans and colleagues found that four of them were significantly undermethylated in people who had been conceived during the height of the famine, when daily caloric intake was rationed to about 667 kcal per person. In contrast, siblings conceived before the famine and born during or shortly after it had normal methylation patterns, suggesting that exposure to famine conditions later in gestation had little effect on epigenetic changes in the IGF2 gene. This was true even though babies exposed to the famine later in gestation had much lower birth weights (average of 3,126 g) than those conceived during the famine but born afterwards (average birth weights 3,612 g). The results suggest that irrespective of final birth weight, malnutrition only very early in development causes epigenetic changes in the IGF2 gene that can be measured years later.
By showing that poor nutrition around conception can alter the epigenome, the study provides a molecular rationale for the developmental origins theory. “Our findings are a key element in elaborating this hypothesis,” write the authors. The authors also suggest that low birth weight, often used as a proxy for compromised development, may not be all that pertinent to epigenetics, though it must be kept in mind that they are only looking at one small part of the genome.
How famine influences methylation is not entirely clear, though the authors suggest that it could be related to a deficiency in methyl donor molecules, such as the amino acid methionine. It is also not clear how such epigenetic changes might relate mechanistically to schizophrenia or other diseases, such as coronary heart disease (see Painter et al., 2006), but the authors suggest that it will be important to explore the consequences of epigenetic change in future studies. Given that the periconceptional exposure to famine reduced IGF2 methylation by only 5 percent and in only 72 percent of affected individuals, the impact of such environmental exposure on schizophrenia may not be big. “Analogous to current studies in genetic epidemiology, such epigenetic epidemiologic studies may need to be large and to include replication,” suggest the authors.—Tom Fagan.
Heijmans BT, Tobi EW, Stein AD, Putter H, Blauw GJ, Susser ES, Slagboom PE, Lumey LH. Persistent epigenetic differences associated with prenatal exposure to famine in humans. PNAS early edition, October 27 2008. Abstract