A paradox of genetic and environmental factors are linked to schizophrenia. For example, cases may be familial or spontaneous. Extensive studies have failed to identify a single gene or small group of genes that accounts for the majority of cases. The complex inheritance pattern suggests a strong environmental component even for those who are predisposed to disease. Environmental factors linked to disease occur early in development. Our goal is to identify common biochemical pathways affected by factors linked to schizophrenia.

Our studies included DNA comparisons between monozygotic twins discordant for schizophrenia, computational evaluations of genomic positions of candidate genes using Genbank resources, and molecular genetic/epigenetic studies on dopamine metabolism in the synaptic cleft.

Twins studies linked schizophrenia to somatic DNA instability (p = <0.01). Genomic studies linked schizophrenia to interspersed fragile site regions (p = 0.001) of the genome that are hot spots for mutation and epigenetics changes. The molecular studies on dopamine metabolism linked schizophrenia to aberrant genetic and epigenetic changes.

These, and other results, point to the confluence of DNA stability (i.e. DNA replication/repair) and epigenetic modification. DNA replication/repair and epigenetic modification are linked at both the macromolecular and biochemical level, require folate, methionine, and cobalamine, and compete for intermediates important for the cellular response to oxidative stress. Mutations in these pathways are linked to schizophrenia, as have deficits in the essential nutrients. The consequences of genetic and/or environmental perturbations to these pathways are complex because many essential pathways and processes are affected.