To the Editor: I read with interest the overview article by Kathleen Ries Merikangas, Ph.D., and Neil Risch, Ph.D. (1), in the special issue of the Journal commemorating the 50th anniversary of the discovery of the DNA double helix. In this article, the authors discussed how the complexities of mental disorders, such as the lack of validity of the classification of these disorders and the complex pattern of their transmission, may have contributed to the difficulties in the identification of their underlying genes by genetic mapping studies such as linkage analysis and association studies. They suggested the use of endophenotypes for the classification of mental disorders and the various tools of genetic epidemiology in future linkage and association studies in order to overcome these sources of complexity in these disorders.

Drs. Merikangas and Risch mentioned epigenetic factors as one of the causes of complex transmission of mental disorders. However, I feel they did not pay due attention to the potential importance of epigenetic factors in mental disorders. Over the past few years, various lines of evidence have been presented that suggest that epigenetic factors, such as epimutations, underlie the primary (idiopathic) mental disorders, such as schizophrenia and bipolar disorder, and that these factors may be the reason for the difficulties that have been encountered in identifying the genes underlying these disorders by genetic mapping studies (2, 3).

Epigenetics refers to the study of nonmutational phenomena, such as DNA methylation and modifications of histones (DNA packaging proteins) in chromatin that modify the expression of genes. Interest in epigenetics has led to the counterpart of genomics: epigenomics, the systematic mapping of epigenetic variation across the genome (4, 5). This is the mission of the Human Epigenome Consortium, which is cataloguing the genomic positions of distinct DNA methylation variants (5).

Recently, I outlined various epigenetic strategies, such as the study of the DNA methylation patterns of genes and the modifications of histones in chromatin in patients with primary mental disorders that may help identify the underlying genes (6). This area of research is being actively pursued, and potentially significant results are beginning to emerge (5). Thus, in the future, epigenomics, in addition to genomics, may prove to be of crucial relevance to psychiatry.