DNA polymorphism-diet-cofactor-development hypothesis and the gene-teratogen model for schizophrenia and other developmental disorders

Abstract

Three problems in identifying genes causing schizophrenia and other developmental disorders may be locus heterogeneity, high disease allele frequency, and unknown mode of inheritance. The DNA polymorphism-diet-cofactor-development (DDCD) hypothesis addresses the first two. The gene-teratogen model addresses the third. The DDCD hypothesis is that schizophrenia results in part from brain abnormality in utero from the aggregate effect of multiple mutations of small effect of genes related to important cofactors (e.g., folate, cobalamin, or pyridoxine) potentiated by maternal dietary deficiency of these cofactors and by pregnancy. The effect results from insufficiency of the cofactors and from resulting effects such as impaired DNA synthesis, immune deficiency, effects on niacin and serotonin metabolism, and teratogens, e.g., hyperhomocysteinemia. The hypothesis addresses all of the unusual features of schizophrenia: e.g., decreased brain gray matter, birth-month effect, geographical differences, socioeconomic predilection, association with obstetrical abnormalities, decreased incidence of rheumatoid arthritis, and association with famine and viral epidemics. In the gene-teratogen model, a teratogenic effect in utero produces a developmental disorder through a teratogenic locus and a modifying or specificity locus, as well as through environmental factors. An example is the major intrauterine effect seen in offspring of phenylketonuric mothers. Thus, the mode of inheritance of genes acting prenatally may in some cases be fundamentally different from that of genes acting postnatally. The model is interesting because it is simple and because teratogenic loci will be difficult to locate by conventional linkage mapping techniques due to misspecification of the affection status of both mother and affected children. A new study design is suggested for identifying teratogenic loci.

Genetic liability to schizophrenia in Oceanic Palau: a search in the affected and maternal generation

“…The PAH STR is roughly 50 Kb from PAH, and its alleles are in LD with variants in PAH, at least in those populations examined (Goltsov et al 1993). There is some literature tying maternal PAH levels, especially phenylketonuria, to liability to Scz in offspring (see Johnson 1999 for review); there is also some evidence, however, for association in the affected generation with PAH STR alleles (Wilcox et al 2002) and PAH variants themselves (Richardson et al 2003). The clustering of association results in 17q23.2-23.3 occurs for the same loci that show two-point linkage to narrow and broad (true) diagnosis in these pedigrees (Klei et al 2005), as well as moderate associations with diagnosis.…”

Do Maternal Folate and Homocysteine Levels Play a Role in Neurodevelopmental Processes That Increase Risk for Schizophrenia?

“…[38][39][40][41][42][43][44][45] These factors also appear to have an association with low folate. 38,41,46 With respect to the late winter/early spring births, the low folate intake, secondary to decreased supplies of folate-rich foods commencing in the autumn, would occur during the second trimester of the pregnancy. 46 This period is also implicated in a study by Opler and colleagues, 47 which suggested an association between schizophrenia and high second-trimester maternal δ-aminolevulinic acid (δ-ALA) levels.…”

“…38,41,46 With respect to the late winter/early spring births, the low folate intake, secondary to decreased supplies of folate-rich foods commencing in the autumn, would occur during the second trimester of the pregnancy. 46 This period is also implicated in a study by Opler and colleagues, 47 which suggested an association between schizophrenia and high second-trimester maternal δ-aminolevulinic acid (δ-ALA) levels. δ-ALA is a marker for lead exposure, which, like folate, is also associated with poor urban settings, 48 though not with many of the other factors listed above.…”

“…Indeed, this maternal factor may largely account for the absence of the homocysteine-metabolizing cystathionine β-synthase (CBS) enzyme in fetal brain, as compared to the relatively high levels found in adults. 63 That the maternal genotype can directly influence fetus development is well described, 46 and maternal genetic regulation of homocysteine has also previously been associated with teratogenesis for NTDs 64 and trisomy 21. 65 Consequently, genetic studies for homocysteineelevating alleles that focus on the patient's genotype may be comparatively unimportant if the schizophrenogenic neurodevelopmental potential is maternally derived.…”

“…62 Investigations into the genetic component of schizophrenia, at least with respect to early developmental factors, may therefore require analysis of the maternal genotype as well as that of the patient, as suggested in the gene-teratogen model of disease. 46 Decreased MTHFR activity probably exerts this teratogenic effect by hindering the remethylation of homocysteine to methionine. This process results in elevated homocysteine, which appears to be the direct teratogen.…”