Thread by @therealRYC

How do the hundreds of genetic risk-factors for #Schizophrenia actually lead to disease? New work medrxiv.org/content/10.110… from @manoliskellis illuminates the #SingleCell landscape of #Brains from patients with #Schizophrenia and their healthy counterparts🔬🧠🧵1/10

Combining single-nuclear RNA-Seq @10xGenomics, barcode #ing, and multi-level cell-state decomposition, first author Brad Ruzicka et al. identify 20 cell types in the prefrontal cortex of 24 patients with #Schizophrenia and 24 controls 2/10

While most of these #cells have been described before, what's powerful about the approach is that we can now ask: are there specific cell-types that are increased or decreased in numbers in #Schizophrenia patients compared to healthy individuals (great study design) 3/10

Intriguingly, the authors discover a new neuronal state that is higher in numbers in #Schizophrenia patients. These #neurons are found closer to the surface of the brain and highly express many genes related to #synaptic plasticity, even when compared to other neurons 4/10

When these #Schizophrenia-associated #neurons are present, the rest of the #brain seems paradoxically to be transcriptionally more similar to healthy patients, indicating a transcriptional "resilience" that may be an adaptive response to disease 5/10

While many genes that have altered expression in Schizophrenia patients are known, this study could resolve the specific cells these genes are altered in (HUGE)! Most of them appear to be in #Neurons, providing mechanistic insight at the cellular level 6/10

These genes not only converge on #GWAS hits, but also share upstream #transcriptionfactor regulators that also impact genes related to neurodevelopment, bridging two long-standing, time-separated hypotheses about #Schizophrenia pathogenesis 7/10

Elegantly designed, beautifully analyzed, and most importantly - deeply insightful. Remarkable integration of multiple datatypes and existing datasets to bring new knowledge about the cellular origins of #Schizophrenia 8/10

Several nuances about the underlying methodology I won't go into here that rely on the BEST best practices to reduce artifacts will really impress people in the field. Great example of how rigorous we should be when designing/executing single-cell experiments 9/10

I wonder how the genetics of each of the 24 patients could be used to decipher how specific SNPs impact cell-type expression of key #Schizophrenia genes, old and and new (may require larger "n"). Congratulations @manoliskellis and team! @lexfridman discussion round 4?😉10/10🧵