Emerging gene)cs in schizophrenia: Real challenges for crea)ng animal models

Transcription

1 Emerging gene)cs in schizophrenia: Real challenges for crea)ng animal models Steven A McCarroll, PhD Stanley Center for Psychiatric Research, Broad Ins7tute Department of Gene7cs, Harvard Medical School NASEM Workshop on Therapeu7c Development in the Absence of Preclinical Animal Models of Disease 12 Sept, 2016

2 Summary Real early victories toward revealing gene7c architecture of schizophrenia in humans These results present great challenges for modeling in animals

3 Human gene)cs strategies 7 World Population, Billions Small, ancestral human populations Large, contemporary human populations Rare varia)on Rare/private to individuals and families Ascertainable by sequencing 100,000 10,000 8,000 6,000 4,000 2,000 0 Years Before Present Time Scz has lacked segrega7ng, Mendelian forms analogous to PD or EOAD Common varia)on Present in most/all popula7ons today Rela7onship to phenotypes measured in GWAS

4 Common varia)on Associa7on with schizophrenia (-log10(p)) Chromosome Psychiatric Genomics Consor7um, Nature (going on 150) loci have varia7on that associates with schizophrenia in popula7ons; highly replicated, sta7s7cally strong BUT Polygenicity: exerts risk via many small effects rather than one large, model-able effect Tends to involve mechanisms other than change in protein-coding sequence challenging to iden7fy func7onal alleles and define analogous muta7on in mice

5 Rare varia)on AGCTCAATGGACT... TACCATGGACTGG... GTATTGCCACGAA... TCGAGTCAGACGT... Rare, recurring CNVs (22q, 15q13, others) affec7ng many genes an early hit in GWAS studies As whole-exome and whole-genome sequencing allow scaling to cohorts >10k, fine-scale variants likely to begin to implicate specific genes (e.g. SETD1, Singh et al., Nat Neurosci. 2016) BUT Polygenicity: No one locus explains even 1% of cases (Genovese et al., Nat Neurosci, in press, based on sequence from 5k Scz cases + 50k others) Par)al penetrance: environmental and gene7c modifiers (including common varia7on) s7ll mafer (even the human is an imperfect model for other humans) Constella7ons of phenotypes: typically present in syndromic cases with ID, epilepsy, other neurodevelopmental defects

6 Gene evolu)on can also challenge modeling in animals Example: Complement component 4 (C4) Mouse C4 Mouse Slp Human C4A Human C4B C4A dosage affects Scz risk C4B dosage doesn t affect Scz risk Sekar et al., Nature 2016

7 Moving human C4 genes into mice Jessy Presumey, Allison Bialas, Mike Carroll (ongoing work) Mouse C4 Mouse Slp Hemoly7c ac7vity Engulfment of synapses by microglia Human C4A Human C4B C4-/- C4A Focus is on cellular, physiological (not behavioral) phenotypes

8 Other uses of gene)c results include to nominate poten)al biomarkers for human studies e.g. C4 protein in CSF: ongoing work

9 Summary Real gene7c progress in schizophrenia, but may not lend itself to animal models of disease Most useful levels of analogy in mice etc. may be for phenotypes at molecular/cellular/circuit level (rather than behavior/disease)