The genetic analysis of schizophrenia, autism spectrum disorders (ASDs), and bipolar disorder are identifying rapidly growing lists of disease associated alleles, implicating more than 100 genes even at this early stage. With the exception of rare monogenic forms of ASDs, these disorders are highly polygenic, with risk accruing from both common and rare variants of relatively modest penetrance. If we are to use such information to elucidate disease mechanisms, with the goal of discovering biomarkers and new effective therapeutics, we urgently need convergent genetic information that identifies molecular pathways and implicates particular neural cell types. Thus we at the Stanley Center, working with many collaborators, are collecting large number of samples across diverse global populations, and will perform genetic analyses to a point of diminishing neurobiological returns. We are making efforts to ensure that new cohorts are recontactable to permit recall by genotype for deep phenotyping based on new hypotheses, e.g., concerning candidate biomarkers. The identification of complement-dependent synaptic pruning as a disease mechanism in schizophrenia, illustrates the potential of this approach.
Given the need for model systems with adequate throughput to permit functional interrogation of large numbers of genetic variants, we and others are refining methods to reprogram human fibroblasts and pluripotent cells into diverse neural cell types and experimenting with brain organoid production.Iterating with results from postmortem human brains, these cellular and organoid models will advance the mapping of disease gene expression to specific cell types and possibly circuits. Working with collaborators in Japan and China on Crispr-Cas9 engineered nonhuman primates, will produce evolutionarily close models to investigate circuit function, cognition, and behavior when other approaches are not adequate.