Mental Disease

One model of neuropsychiatric disease is that risk for these illnesses is heavily intertwined with human brain evolution and therefore, at least partially, a consequence of factors that underlie distinct human cognition and behavior.  We know that many of aspects of human cognition and behavior, as well as brain structure are highly heritable, while also subject to major environmental effects, and include factors that may also predispose to common human disorders. Advances in understanding the genetic contributions to neuropsychiatric diseases now permit us to begin to understand how disease risk relates to other human phenotypes and human brain evolution. One particular salient example is the positive correlation between genetic risk for autism spectrum disorder (ASD) and educational attainment (EA), versus an inverse correlation between EA and schizophrenia (SCZ), despite a significant correlation between ASD and SCZ. These findings raise many questions and provide a roadmap for understanding how specific aspects of disease risk overlap, which aspects of brain function they represent, and further, how natural selection may have acted and continues to act on these processes. It has been more than 40 years since the seminal work of King and Wilson highlighted gene regulation rather than protein coding genes as a major source of human evolution. But, it is only recently that we have had the tools, such as the ability to measure gene expression networks across species and genome wide maps of regulatory elements, to study gene regulation. Some of our studies suggest that derived, human-specific gene expression networks may preferentially impact human disease, especially risk for Alzheimer’s disease. More recently, we have started to integrate genetic risk data with the emerging maps of gene regulation to study human specific aspects of gene expression and gene regulation. These analyses indicate that human specific aspects of gene regulation, such as genes regulated by human specific enhancers, are indeed enriched in mutations or common genetic variants that increase risk for ASD and allied neurodevelopmental disorders. This provides strong evidence that genetic elements underlying human brain evolution are particularly susceptible to disruption in disease. With the advent of in vitro systems that permit study of brain development we anticipate that the multitude of specific hypotheses that emerge from these genome-wide studies can be directly studied, and models of the specific mechanisms of human cortical expansion and the relationship to psychiatric illness can be directly tested.