Incidental neurodevelopmental episodes in the etiology of schizophrenia: an expanded model involving epigenetics and development.
Epidemiological data favors genetic predisposition for schizophrenia, a common and complex mental disorder in most populations. Search for the genes involved using candidate genes, positional cloning, and chromosomal aberrations including triplet repeat expansions have established a number of susceptibility loci and genomic sites but no causal gene(s) with a proven mechanism of action. Recent genome-wide gene expression studies on brains from schizophrenia patients and their matched controls have identified a number of genes that show an alteration in expression in the diseased brains. Although it is not possible to offer a cause and effect association between altered gene expression and disease, such observations support a neurodevelopmental model in schizophrenia. Here, we offer a mechanism of this disease, which takes into account the role of developmental noise and diversions of the neural system. It suggests that the final outcome of a neural developmental process is not fixed and exact. Rather it develops with a variation around the mean. More important, the phenotypic consequence may cross the norm as a result of fortuitous and/or epigenetic events. As a result, a normal genotype may develop as abnormal with a disease phenotype. More important, susceptible genotypes may have reduced penetrance and develop as a normal phenocopy. The incidental episodes in neurodevelopment will explain the frequency of schizophrenia in most populations and high discordance of monozygotic twins.
Singh
S M
SM
Molecular Genetics Unit, Department of Biology and Division of Medical Genetics, University of Western Ontario, London, Ontario, Canada N6A 5B7, USA. ssingh@uwo.ca
McDonald
P
P
Murphy
B
B
O'Reilly
R
R
D001921:Brain / Q000254:growth & development; D044127:Epigenesis, Genetic; D020022:Genetic Predisposition to Disease; D006801:Humans; D008959:Models, Neurological; D012307:Risk Factors; D012559:Schizophrenia / Q000209:etiology* / Q000235:genetics; D014430:Twins, Monozygotic / Q000235:genetics