This year we found that schizophrenia risk associated genes interact with obstetrical complications (OC) to increase risk for schizophrenia. Schizophrenia is a complex multifaceted condition, involving both genetic and environmental risk factors. One of the most well validated risk factors is obstetrical complications, especially those related to potential hypoxic/ischemic stress. Obstetrical complications vary in their effects based on genetic background and there had been no prior studies specifically addressing potential interactions of genes and this environmental risk factor. We had collected historical information for genetic study, including various environmental risk factors such as obstetrical complications (OCs). We designed a study aimed at testing this hypothesis and looked in our families at distorted transmission of alleles in candidate genes related to hypoxic stress conditioned on a history of OCs in the offspring. We published the first data showing an interaction of certain putative schizophrenia risk associated genes implicated in hypoxic-ischemic injury and OCs. Specifically, we found that SNPs in AKT1 and in BDNF interacted with a history of serious OCs to increase the odds ratio as much as twelve fold. One of the AKT1 SNPs is a coding SNP that has been linked to AKT1 expression and to risk for schizophrenia. The SNP in BDNF is particularly interesting as it does not show association with schizophrenia in our clinical datasets nor has it been reported to be associated with schizophrenia in the literature. However, it does show strong association with cognitive phenotypes in our normal subject sample and it resides in an untranslated exon that is expressed in the placenta. This remarkable concurrence suggests that a risk factor for early developmental stress related to schizophrenia may involve fetal biology that is external to the fetus. The evidence that patients with schizophrenia have histories of abnormal neurological development is substantial. Developmental delays, including abnormalities in acquisition and refinement of language, gross motor delays in standing and walking, and delayed physical growth, have been detected in infancy and early childhood in numerous studies both in offspring of patients with schizophrenia and 'pre-schizophrenics'. Interestingly, remarkably few studies have explored the relationship between a history of childhood enuresis and schizophrenia. In fact, prior evidence of childhood enuresis in association with adult schizophrenia is very thin and entirely speculative, even though enuresis is objective evidence of neurological dysmaturation and acquisition of nocturnal bladder control is an important and well-established developmental milestone related to prefrontal function that is well characterized in normal populations. We hypothesized, therefore, that enuresis and associated evidence of prefrontal cortical abnormalities would be increased in patients with schizophrenia and we tested this hypothesis in a sample of 211 patients, 234 of their siblings, and 355 controls. Frequency of enuresis was compared across groups and correlated with cognitive and structural MRI measures. Patients with schizophrenia had higher rates of childhood enuresis (21%) compared with siblings (11%) or controls (7%) and relative risk for enuresis was increased in siblings. These effects were found in both sexes. Patients with enuresis performed worse on two frontal lobe cognitive tests Letter Fluency and Category Fluency as compared with non-enuretic patients and similar associations were found in controls. We also discovered gray matter volume reductions in several frontal regions in patients with a history of enuresis as compared with non-enuretic. The high frequency of childhood enuresis associated with schizophrenia and abnormalities in prefrontal function and structure in patients with a childhood history of enuresis suggest that childhood enuresis may be a marker for neurodevelopmental abnormalities related to schizophrenia. These findings add to the evidence implicating prefrontal dysmaturation as a clinical antecedent to the full expression of this disorder, potentially related to genetic risk factors.
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