Psychiatric genetics: contextual cumulative combinatorics of gene variants and environment

Classic genetics research in psychiatric disorders has provided an abundance of data but a paucity of insight. Things will only get worse in terms of this ratio, as massive sequencing of genomes becomes routine.

The reasons are four-fold. First, psychiatric disorders are genetically complex, with many (hundreds, if not thousands) genes involved. We first proposed that over a decade ago, based on our pioneering gene expression work cross-matched with human genetic data (Convergent Functional Genomics). Second, psychiatric disorders are genetically heterogeneous, with different mutations in the same gene present in different individuals. Many of these mutations are in fact common variants present in non-psychiatrically ill individuals as well. Third, psychiatric disorders as currently defined by DSM are overlapping and interdependent, with genes and biological pathways shared among disorders. Fourth, the environment plays a major role in modulating gene expression and the development or not of illness.

The key to progress is to acknowledge reality in the four areas mentioned above. Illness or lack of illness are the result of cumulative combinatorics of common gene variants and environmental stressors (or favorable factors). Genetic context and environmental context are important to whether a mutation contributes or not to the illness.  Gene expression studies are more informative than classic genetics, as they reflect the actual results of the interaction between genes and environment, and underlie the subsequent patho-physiological outcomes. Biological pathways and mechanistic-level analyses will show more commonality and reproducibility across individuals, and from study to study. A dimensional approach to psychiatric profiling of individuals will eliminate the confusion and overlap of DSM, as well as permit a better mapping and tracking of biological reality. Our group has provided comprehensive proof and solutions over the years in all these areas, and we will continue to do our bit.

 
Alexander B. Niculescu, III, MD, PhD

Clock Genes and Mood

"There can be no transforming of darkness into light and of apathy into movement without emotion"
      - Carl Jung     

      After more than a decade of work on understanding mood, using the magnifying glass of severe mood dysregulation disorders such as bipolar disorder, our group has proposed and provided evidence for mood being related to levels of activity, energy and growth, in response to internal and external environment cues. When the environment is favorable, levels of activity and growth are (or should be) high. When the environment is unfavorable, levels of activity are (or should be) low. When there is a discongruence between levels of activity of the organism and the environment, we are dealing with a mood disorder, manifested as depression or (hypo)mania.

      Following early hypotheses from W. Bunney and R. Lennox, our group has provided over the last decade cumulative empirical evidence that supports a model where circadian clock genes are the core mechanism of mood regulation and dysregulation. They serve as a thermostat, increasing or decreasing the level of activity of cells, brain and of the whole organism. Some key circadian clock genes we have identified and provided evidence for involvement in mood are ARNTL, RORB, and DBP. DBP, first identified by us as a candidate gene for bipolar disorder over a decade ago, has provided a basis for us developing the first broad-spectrum genetic mouse model of bipolar disorder, which mimics both phases of the illness, depression and mania, as well as mimics the sensitivity to stress and the propensity to substance abuse.

      Due to the genetic overlap and biological interdependence between mood, anxiety and cognition, circadian clock genes have also appeared in screens conducted by us and others for genes involved in other disorders, such as anxiety disorders and schizophrenia. It is understandable how levels of energy (mood) can influence signal transduction reactivity (anxiety) or brain connectivity (cognition).

      Clock genes are present in every cell in the body, regulating the expression of thousands of other genes. They are likely going to become key targets for therapeutic intervention and new drug development, and provide a biological rationale for circadian medicine, circadian psychiatry, and other subspecialties of the future.

Alexander B. Niculescu, III, MD, PhD