Growing complexity of SZ genetics
Flint & Munafò, Nature. 2014
Start of post-doc
@Gage lab
Start of lab
@ISMMS
Today
Up to 1000
SZ genes?
Modeling SZ with hiPSC neural cellspredisposition to
^
Schizophrenia
Brennand et al, Molecular Psychiatry. 2015
miR-9 is decreased in a subset of SZ NPCs
Topol, Zhu et al, Cell Reports. 2016
Gang Fang
• All SZ NPCs have miR-9
levels less than median
value of control NPCs
• Signal driven by 50% of SZ
NPCs with values less
than bottom quartile of
controls
miR-9 targets are associated with common genetic risk for SZ
Hauberg et al, JAMA Psych, 2016.
Fromer et al, Nat. Neuro. 2016
Post-mortem (and hiPSC) case-control studies of SZ remain underpowered
“With 25 cases and 25 controls, we find that even null data will lead to estimates of differential expression > 2 (... or < 0.25), ... by chance for a large number of genes (0-26%).”
“Genomewide, the median number of subjects with SCZ and controls needed to obtain 80% power assuming 10,000 genes is ~28,500, well beyond any available data set.”
258 SZ; 279 control
• Poor replication of findings from previous (smaller) post-mortem studies
• No case-control signature in genes at the 108 SZ loci
Summary
• Post-mortem and hiPSC-based studies will be underpowered for the foreseeable future.
• eQTLs and differential expression signals between post-mortem and hiPSC-based studies show significant overlap.
• hiPSC-based isogenic approaches will power meaningful analyses to verify causal variants identified by GWAS and eQTL studies.