Took me a few days but I read it. Here is the portion on schizophrenia.
Developing Gene-Targeted Therapies of
Psychiatric and Neurodevelopmental Disorders
Although scientists have begun to tackle complex polygenic disorderswith gene therapy, they have not yet begun to apply this therapeutic approach to psychiatric disorders, said Hyman. He asserted that the time has come to think about this challenge while recognizing that clinical applications are a long way off. Although neuropsychiatric disorders are highly heritable, all common neuropsychiatric disorders are highly polygenic, with phenotypes resulting from myriad small genetic nudges rather than a large genetic shove, said Hyman. He noted that this complicates efforts to identify which genes could be targeted. Moreover, he said, highly penetrant alleles that substantially elevate risk for early-onset behavioral disorders are quickly selected out of the gene pool because these highly disabling illnesses reduce the likelihood that an affected person will have children (Power et al., 2013). Large-effect alleles can occur de novo, but are rarely transmitted, while common and rare variants with low effect sizes can be readily transmitted, said Hyman.
Nonetheless, scientists have created animal models that replicate the human phenotype and have been able to reverse the phenotype by targeting specific genes, suggesting that gene therapy may be feasible. For example, Hyman cited the work of Adrian Bird and colleagues, who were able to reverse neurological defects in a mouse model of Rett syndrome (Guy et al., 2007).
Schizophrenia, however, is far more complex, said Hyman, with hundreds of genome-wide significant loci identified and extreme phenotypic heterogeneity (Huckins et al., 2019). He described a tool that could help scientists roughly stratify affected individuals at a genetic level by creating, for each individual, a weighted sum of risk alleles across the entire genome to produce a polygenic risk score (PRS). The PRS enables stratification of subjects by severity of genetic loading and permits identification of shared common variant risk across phenotypes, said Hyman. It can also help identify important genetic pathways and potentially identify targets for gene therapy interventions, he said. For example, about 70 percent of genome-wide association study (GWAS) hits in AD studies are expressed in microglia and are thought to be involved in inappropriate synapse elimination, said Hyman. He speculated that in schizophrenia, although none of the GWAS hits are expressed in microglia, there may be similar biological processes reached through different pathways such as genes encoding synaptic proteins and complement proteins that signal to microglia, adding that useful target selection can sometimes emerge from analysis of these pathways. What is important, he said, is to understand the biology. Transgenic animal models would require vastly improved methods of multiplexing using gene editing technologies.