Ready for Danny Weinberger’s guest lecture #BAP2018 
Many features of human temperament are present in early life - also true of mental illness? #BAP2018
Schizophrenia may not be a disease but rather a state of brain development #BAP2018
Developmental milestones are delayed in people who subsequently experience schizophrenia #BAP2018
Do genetic studies support this? Pattern of relative risk scales with polygenic risk scores. Rare copy number variants 2.0%. 97% due to accumulation of common variants which we all have whether or not we suffer mental illness
What role do these variants have in development? Are they preferentially expressed in Fetal development? #BAP2018
Yes. Compared to post natal life. Also true of autism and intellectual disability #BAP2018
RNA sequencing - in 36 brains - looking for differentially expressed regions of transcriptome - found 50,000 some of which are preferentially expressed in development #BAP2018
40% are in regions of the genome that are not expressed #BAP2018
CREB transcripts switch across development #BAP2018
He same gene is associated with expression of different isoforms at different times in development. Enriched in loci that confer SZ risk
Manhattan plots: like a road map but no idea of what happens in the building #BAP2018
Lots of mechanisms through non-coding variants change gene function - what is their biology? Has to read out in the RNA. That is how we’ll find out how these variants influence illness #BAP2018
Gene x environment = sequence x epigenetics #BAP2018
Is DNA methylation different in PFC in risk genes across development? And age 15-25 (time of SZ onset)? Former rather than latter enriched #BAP2018
This is true in post Mortem brains. Markers of illness in epigenetics from 45 years earlier, rather than the impact of psychosis itself
What’s missing? Most genes affect risk through highly connected cellular networks. And the environment. #BAP2018
The intrauterine environment may be relevant. Do genomic risk and difficult pregnancy interact? #BAP2018
Without an early life complication, genomic risk did not change, replicated across 4 cohorts #BAP2018
How? Does interaction scale with the severity of early life complication? Has to be serious #BAP2018
What is going on the placenta? #BAP2018
Fetal compartments most of the genome. The interacting risk loci are much more abundantly expressed #BAP2018
They are about cellular and oxidative stress #BAP2018
This initiates an immune response #BAP2018
Increased prevalence in males? Seems to be relevant too - placental risk effects higher in males #BAP2018
Preserving prenatal health in males at high placental genetic risk #BAP2018
@beckyneuro taken out of context, and with typo, it seems I am calling out the placenta :-) that might be a fair summary of the talk too :-)
