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.