A protective-compensatory model may reconcile the genetic and the developmental findings in schizophrenia

The neurodevelopmental, the multifactorial-oligogenic and the gene-environment diathesis models have provoked advances in schizophrenia research, yet the exact pathophysiology remains indefinable. We broadened our analysis of 20years of findings in adults and children descending from densely affected families in the Québec population with a founder effect. The goal was to inspect the link between these family-genetic and developmental findings.

48 multigenerational families affected by schizophrenia or bipolar disorder represented a quasi-total sample of affected kindreds in the Eastern-Quebec catchment area. Among the 1274 adult family members with lifetime best-estimate diagnoses, 341 had DSM-IV schizophrenia or bipolar disorder. Young offspring of an affected parent were studied with the same clinical, physiological and cognitive measures as the adults.

Four new observations emerged: 1. A striking resemblance between the clinical, neuropsychological and genetic findings in these densely affected families and those reported in sporadic samples; 2. A high degree of heterogeneity despite the origin from a founder-effect population; 3. Cognitive deficits in some non-affected adult relatives as severe as those in patients; 4. Children descending from kindreds displayed neurodevelopmental endophenotypic anomalies comparable to those of adult patients.

These four observations could be reconciled under the hypothesis that highly familial and sporadic cases share mechanisms based on defective protective genes, a model to an extent similar to cancer findings. These defective protective genes running in families would longitudinally disturb the compensatory mechanisms in children inheriting them and might be at the core of the schizophrenia process.