Brain Connectivity and Gyrification as Endophenotypes for Schizophrenia: Weight of the Evidence

The tremendous heterogeneity in the clinical symptoms and cognitive/emotional deficits seen in patients with schizophrenia has made it challenging to determine the underlying pathogenesis of the illness. One leading hypothesis that has come to the forefront over the past several decades is that schizophrenia is caused by aberrant connectivity between brain regions. In fact, a new field of connectomics has emerged to study the effects of brain connectivity in health and illness. It is known that schizophrenia is highly heritable, although in the search for the underlying genetic factors we have only scratched the tips of the omics icebergs. One technique to help identify underlying genetic factors is the use of heritable intermediate phenotypes, or endophenotypes. Endophenotypes provide mechanisms to study the genetic underpinnings of the disorder by focusing on measureable traits that are more proximal to gene regulation and expression than are symptoms. Thus, the goal of this paper is to conduct a critical review of the evidence linking both structural and functional connectivity as an endophenotype for schizophrenia.