A Prospective Cohort Study of Genetic and Perinatal Influences in the Etiology of Schizophrenia

Abstract

In this study, we examined whether fetal hypoxia and other obstetric complications (OCs) are related to risk for adult schizophrenia; whether such effects are specific to cases with an early age at onset; and whether the obstetric influences depend on, covary with, or are independent of familial risk. Subjects were 72 patients with schizophrenia or schizoaffective disorder; 63 of their siblings not diagnosed with schizophrenia; and 7,941 nonpsychiatric controls, whose gestations and births were monitored prospectively with standard research protocols as part of the National Collaborative Perinatal Project Adult psychiatric morbidity was ascertained via a longitudinal treatment data base indexing regional public health service utilization, and diagnoses were made by review of all pertinent medical records according to DSM-IV criteria. We found that the odds of schizophrenia increased linearly with increasing number of hypoxia-assodated OCs and that this effect was specific to cases with an early age at onset/first treatment contact There were no relationships between schizophrenia and birth weight or other (prenatal/nonhypoxic) OCs. Siblings of patients with schizophrenia were no more likely to have suffered hypoxia-associated OCs than were nonpsychiatric cohort controls. Because the majority of individuals exposed to fetal hypoxia did not develop schizophrenia, such factors likely are incapable of causing schizophrenia on their own. Together, these findings suggest that hypoxia acts additively or interactively with genetic factors in influencing liability to schizophrenia. We propose a model In which the neurotoxic effects of fetal hypoxia may lead to an earlier onset of psychosis because of premature pruning of cortical synapses.

Serious obstetric complications interact with hypoxia-regulated/vascular-expression genes to influence schizophrenia risk

“…1,5,[7][8][9][10] A recent review by Schmidt-Kastner and colleagues 11 suggested that susceptibility genes for schizophrenia were more likely than randomly selected genes to be regulated by hypoxia/ischemia and/or expressed in the cerebrovasculature. In fact, a substantial fraction of the genes reported to be significantly associated with schizophrenia in at least two published studies fit this description, even though only 1-2% of known genes are involved in hypoxia-induced regulation.…”

Variance in neurocognitive performance is associated with dysbindin-1 in schizophrenia: A preliminary study

“…The heritability of performance deficits on measures of executive function, vigilance, and declarative memory has been demonstrated in twin studies (Cannon et al, 2000;Goldberg et al, 1990) and in studies of first degree relatives Faraone et al, 1995). This has lead to the suggestion that genetic liability for schizophrenia is at least partly mediated by deleterious effects on the brain regions associated with these cognitive functions, including pre-frontal and medial temporal lobe regions (Weinberger et al, 2001 Recent reviews of schizophrenia genetics (Craddock, O'Donovan, & Owen, 2005) have highlighted the potential role of a number of candidate genes in conferring liability to the disorder.…”

Neuroactive Steroids are Altered in Schizophrenia and Bipolar Disorder: Relevance to Pathophysiology and Therapeutics

“…For example, DHEA and DHEAS decrease neuronal death following anoxia (Marx et al, 2000b), and obstetrical complications resulting in hypoxia are associated with increased schizophrenia risk (Dalman et al, 2001;Cannon et al, 1999Cannon et al, , 2000Geddes et al, 1999). Allopregnanolone demonstrates anticonvulsant actions in a number of seizure paradigms (Kokate et al, 1994(Kokate et al, , 1996Devaud et al, 1995;Belelli et al, 1989) and exhibits pronounced protective effects against neurodegeneration in a mouse model of Niemann-Pick type C disease .…”