IEPA 11

Unbiased, large-scale genetics is providing significant new insights into disease mechanisms of schizophrenia and other psychiatric disorders.  However, the highly polygenic nature of these disorders poses daunting challenges for follow-up biological studies.  While in aggregate the genetic component of risk for schizophrenia is large, it arises in populations from thousands of alleles affecting many hundreds of genes, with each disease-associated allele exerting a small additive increment of risk.  The genetic loading of individuals affected by schizophrenia represents a subset of the risk alleles segregating in populations—consistent with the clinical heterogeneity of the disorder. While such polygenicity obviates the many widely used experimental paradigms in neurobiology that have been optimized to study single genetic perturbations of large effect, it also brings scientific benefits:  the ability to use aggregate genetic signals for risk prediction in populations, to identify shared mechanisms across disorders, and to exploit the convergence of risk alleles to identify relevant neural cell types and molecular pathways.   However, the ultimate utility of aggregate measures, such as polygenic risk scores, for epidemiology, clinical studies, and prevention, requires, requires concerted efforts to extend human genetic studies of schizophrenia and other psychiatric disorders across diverse global populations.