From Schizophrenia Genetics to Disease Biology: Harnessing New Concepts and Technologies

Abstract

Schizophrenia (SZ) is a severe mental disorder afflicting around 1% of the population. It is highly heritable but with complex genetics. Recent research has unraveled a plethora of risk loci for SZ. Accordingly, our conceptual understanding of SZ genetics has been rapidly evolving, from oligogenic models towards polygenic or even omnigenic models. A pressing challenge to the field, however, is the translation of the many genetic findings of SZ into disease biology insights leading to more effective treatments. Bridging this gap requires the integration of genetic findings and functional genomics using appropriate cellular models. Harnessing new technologies, such as the development of human induced pluripotent stem cells (hiPSC) and the CRISPR/Cas-based genome/epigenome editing approach are expected to change our understanding of SZ disease biology to a fundamentally higher level. Here, we discuss some new developments.

Multiple genes in a single GWAS risk locus synergistically mediate aberrant synaptic development and function in human neurons

“… 41 , 42 Such seemingly inconsistent cellular phenotypes may be the result of genetic pleiotropy across major psychiatric disorders. 53 Alternatively, given that both neural hyperfunction 12 , 13 , 14 , 41 , 42 and hypofunction 51 , 52 were reported for SZ, our results provide further support for a neuronal homeostatic model of neuropsychiatric disorders where either excess or inadequate synaptic signaling output may contribute to pathophysiology. 54 , 55 The relevance of our observed neurobiological phenotypes to SZ was further corroborated at the molecular level by the fact that the transcriptional changes associated with the SZ risk allele, rs2027349, were strongly enriched for SZ GWAS ( Figure 3 F) and correlated with transcriptomic changes in SZ post-mortem brains ( Figures 3 G, 3H, S5 G, and S5H).…”

“… 49 However, in general, these cellular phenotypes of SZ postulated from studies of human post-mortem brain and animal models were not fully recapitulated by the hiPSC modeling of common or rare risk factors. 50 Our observed increase in neuronal function by the risk allele of rs2027349, although seemingly inconsistent with the documented reduction in dendritic complexities and synaptic function for SZ, 48 , 49 , 51 , 52 is similar to the effect of an SZ GWAS risk variant at the MIR137 locus, 14 as well as the effects of rare SZ-risk variants with high penetrance (e.g., 16p11 duplication, loss-of-function of SHANK3 ). 41 , 42 Such seemingly inconsistent cellular phenotypes may be the result of genetic pleiotropy across major psychiatric disorders.…”