To the Editor: Dr. DeLisi et al. reported the results of a genome-wide scan for linkage in 382 sibling pairs with schizophrenia or schizoaffective disorder. The results of this study emphasized the weakness and fragility of linkage reports on schizophrenia: no linkage appears to be consistently replicable across studies. Thus, the authors questioned whether the genetic contribution to schizophrenia may be epigenetic in nature and whether genetic mapping strategies can detect the underlying genes.

Recently, in fact, I proposed (1, 2) that epimutations (heritable defects in gene expression that do not involve changes in DNA sequence), rather than genetic mutations (heritable changes in DNA sequence of genes), underlie primary (idiopathic) mental disorders such as schizophrenia and that, hence, epigenetic strategies are needed to identify their underlying genes. I gave the following lines of evidence:

1. Among all animals, epigenetic mechanisms in gene expression play the greatest role in humans, and among all organs, they play the greatest role in the development of the brain.

2. Epigenetic mechanisms in gene expression played a major role in the evolution of human mental functions and abilities.

3. Epigenetic mechanisms in gene expression were the link in the transition from genetic inheritance to cultural inheritance (a genetic-based inheritance system involving the storage and transmission of information by the brain through communication, imitation, teaching, and learning) during the evolution of heredity.

Unlike in the case of primary mental disorders, genetic mapping strategies have been successful with regard to the neuropsychiatric disorders: susceptibility genes underlying diseases such as Alzheimer’s disease and Huntington’s disease have been identified. The reasons for this discrepancy that I suggested were that 1) the neuropsychiatric disorders have simpler modes of inheritance (in many, if not all, cases) than the primary mental disorders and, hence, there are likely to be fewer epigenetic mechanisms in the expression of genes underlying neuropsychiatric disorders, and 2) since neuropsychiatric disorders involve fewer psychosocial factors than the primary mental disorders in their pathogenesis, neuropsychiatric disorders are likely to involve fewer epigenetic mechanisms in the expression of their underlying genes (since it is known that epigenetic mechanisms in gene expression involve environmental inputs).