Genetics of Psychiatric Disorders: Where Have We Been and Where Are We Going?

Three papers in this month’s issue of the Journal provide an indication of shifts in psychiatric genetics and an indication of what the future may bring. The article by Ross and colleagues is an excellent example of the ongoing use of family genetic studies to improve our understanding of which elements of psychiatric disorders are heritable and which are not. Since family studies have already demonstrated an increased risk for schizophrenia in first-degree relatives of probands with schizophrenia, the emphasis has appropriately shifted to identifying the elements of the phenotype that are heritable. This is an important, but not completely necessary, first step before setting forth a clinical symptom as a subgrouping variable for finding genes in more homogenous clinical samples. Subgrouping implies a categorical rather than dimensional approach to genetics. However, one must also recognize that a category may also be an approach to studying a quantitative trait locus. A quantitative trait locus is typically one of many genes that contribute to shifting a phenotype (e.g., blood pressure or deficit symptoms) in one direction. A classic example of a quantitative trait locus is the serotonin transporter and, more specifically, the length variant in the serotonin transporter gene (SLC 6A4). This gene has been shown to lead to a shift in the distribution of expression of the serotonin transporter gene in all tissues in which it is expressed (1, 2). However, as seen in quantitative trait loci for blood pressure, this single gene does not fully determine the level of serotonin transporter. Single major genes typically drive phenotypes from continuous traits to categorical traits, such as the category of early-onset dementia with presenillin mutations.

The article by Tsuang and colleagues in this issue provides a courageous attempt to redefine schizophrenia nosology by emphasizing that it is time to establish and empirically test new concepts of diagnosis, such as schizotaxia. An intriguing quantitative trait locus to study would be the one that increases the “risk” that someone will attempt to shift a dominant paradigm. To their credit, Tsuang and colleagues seem to be on the vital, novelty-seeking side of the scientific equation. Although time does not permit a fuller discussion, one suspects that such creativity is another example of the ongoing conspiracy between nature and nurture.

Concerning the nature side of the equation, one needs to consider what a dimension of schizotaxia implies from a genetic perspective. Throughout the series of articles on psychiatric genetics in this issue, one does not see the courageous logical next step, implied by a quantitative trait locus approach to genetic contributions to mental development. Genetic counseling is mentioned only in a negative context. If we are to fully abandon one gene/one disorder concepts of psychiatric illness, we must confront the meaning of multiple genes that lead to psychiatric illness. In this model, the sum or product of genetic and environmental susceptibility and protective factors overwhelms the dynamic mental equilibrium of an individual to lead to schizotaxia or schizophrenia. However, for at least one of the quantitative trait loci it is likely that many more people benefit from the same locus in some manner. In some cases the advantage of such a risk gene is not related to the risk (e.g., protection from malaria with one copy of the beta hemoglobin S variant). However, it is also possible that several of the genetic variants contributing to schizotaxia provide susceptibility to questioning authoritative texts such as DSM-IV. When one looks to the people who have shaped the field in the Journal’s “Images in Psychiatry” section, it is likely that almost all of them were pushed slightly toward original thinking by one of the multiple “susceptibility” genes for schizotaxia. As far as genetic counseling is concerned, what do we say to the creative parents who are concerned that the absence of all schizotaxia genes may increase the risk of having a child who does not have their sense of creativity?

The paper by McMahon and colleagues is an example of the current explosion of molecular genetic studies of complex genetic disorders, ranging from diabetes to bipolar mood disorder. Following their observation of an increase in maternal inheritance of bipolar mood disorder, they investigated a specific etiological mechanism. Although their etiological hypothesis of mitochondrial mutations was not confirmed, it is exciting that they were able to test a hypothesis that would have changed psychiatric diagnosis considerably. Higher levels of schizotaxia protection might have protected the senior author from moving away from the crowd studying nuclear genetic variants to establishing the mitochondrial genome as an important cause of metabolic, epileptic, and psychiatric syndromes (3).

It is important for authors to reveal their conflicts of interest. This editorial is written by someone who will enjoy the movement of psychiatric genetics into the future when a full genome screen will include complete sequencing of the nuclear (including Y chromosome) and mitochondrial genomes, study of methylation patterns contributing to control of gene expression (perhaps requiring imaging of DNA and RNA in specific neurons and glia), measurement of expansions of DNA in specific cell populations, and the pattern of histone acetylation contributing to gene expression.

The next milestone in the Human Genome Project will be completion of sequencing of most of the genes and surrounding regions before or soon after the publication of these articles. However, scientists with no or little concern for schizophrenia are following their love of originality by changing our concepts of nature and nurture by unraveling layer upon layer of the knowledge of how experience modifies the physical structure of genes. The most significant psychiatric genetic finding of 1999 was arguably the discovery that the MECP2 gene causes Rett syndrome, a pervasive developmental disorder included in the DSM-IV classification (4). It should not come as a surprise that a disorder involving complex cognitive and behavioral symptoms can be understood only by considering how MECP2 is involved in developmental regulation of gene expression.

Reduced risk for schizophrenia is consolation for those with so few schizotaxia genes to enjoy disruption of conventional thinking about static and deterministic genes unfolding in current molecular genetic research.