Systems genetic evidence for a convergence of epilepsy and its co-morbidities on shared molecular pathways

Transcription

1 Systems genetic evidence for a convergence of epilepsy and its co-morbidities on shared molecular pathways Professor Michael Johnson Imperial College London m.johnson@imperial.ac.uk

2 Introduction Epilepsy as a disorder of many symptom domains which are currently called co-morbidities but which are really inherent aspects of the disease Making sense of genetic and phenotypic heterogeneity of epilepsy requires systems-level approaches 23rd May 2018 epixchange Conference

3 Epilepsy is a spectrum disease Familiar with thinking about epilepsy as a syndrome of many causes Less familiar about thinking of it as a spectrum disease of many symptom domains Cf. Parkinsons disease used to thinking about motor and non-motor symptoms Non-motor features of PD are now a major research focus Argue that advances in our understanding of biological underpinnings of epilepsy justify its representation as spectrum disease Important because shifts attention from not just controlling seizures, but to curing the broader cognitive and behavioural consequences of epilepsy 23rd May 2018 epixchange Conference

4 Complex problems require systems-level solutions Tremendous advances in our understanding of epilepsy With increasing molecular complexity the less clear it is which new therapeutic goalposts we should be aiming for E.g., >100 of epilepsy genes and loci Is epilepsy fragmenting into a series of rare diseases? Or will etiological heterogeneity coalesce around common pathways? Making sense of heterogeneity requires systems-level approaches 23rd May 2018 epixchange Conference

5 Network systems framework Common Func)on Pathophysiology 23rd May 2018 epixchange Conference

6 Network systems framework gene expression data from relevant tissue PPI networks TFBS enrichment GWAS/WES enrichment Pathway enrichment 23rd May 2018 epixchange Conference

7 Network systems framework gene expression data from relevant tissue PPI networks TFBS enrichment GWAS/WES enrichment Pathway enrichment 23rd May 2018 epixchange Conference

8 Evidence Imperial College London (Michael Johnson) University of Bonn (Albert Becker) UCB Pharma (Rafal Kaminski) Nat Neurosci 2016;19: rd May 2018 epixchange Conference

9 N=122 N=63 N=100 General fluid cognieve ability Processing speed Crystalized cognieve ability Delayed recall General fluid cognieve ability Processing speed.... Crystalized cognieve ability Delayed recall Epileptic encephalopathy Intellectual Disability Autism Spectrum Disorder Schizophrenia GWAS enrichment Discovery Cognitive traits GS:SFHS n = 6,732 GWAS enrichment Replication Cognitive traits LBC1936 n = 1,003 SNV de novo mutations Neurodevelopmental disease n = 6,871 Combined

10 N=122 N=63 N=100 General fluid cognieve ability Processing speed Crystalized cognieve ability Delayed recall General fluid cognieve ability Processing speed.... Crystalized cognieve ability Delayed recall Epileptic encephalopathy Intellectual Disability Autism Spectrum Disorder Schizophrenia GWAS enrichment Discovery Cognitive traits GS:SFHS n = 6,732 GWAS enrichment Replication Cognitive traits LBC1936 n = 1,003 SNV de novo mutations Neurodevelopmental disease n = 6,871 Combined

11 N=122 N=63 N=100 General fluid cognieve ability Processing speed Crystalized cognieve ability Delayed recall General fluid cognieve ability Processing speed.... Crystalized cognieve ability Delayed recall Epileptic encephalopathy Intellectual Disability Autism Spectrum Disorder Schizophrenia GWAS enrichment Discovery Cognitive traits GS:SFHS n = 6,732 GWAS enrichment Replication Cognitive traits LBC1936 n = 1,003 SNV de novo mutations Neurodevelopmental disease n = 6,871 Combined

12 N=122 N=63 N=100 General fluid cognieve ability Processing speed Crystalized cognieve ability Delayed recall General fluid cognieve ability Processing speed.... Crystalized cognieve ability Delayed recall Epileptic encephalopathy Intellectual Disability Autism Spectrum Disorder Schizophrenia GWAS enrichment Discovery Cognitive traits GS:SFHS n = 6,732 GWAS enrichment Replication Cognitive traits LBC1936 n = 1,003 SNV de novo mutations Neurodevelopmental disease n = 6,871 Combined

13 Gradient of expression of M3 across human life M3# Adolescence adolescence" Fetal development Infancy Child Adulthood fetal"development" infancy" childhood" adulthood" " 4" 5" 6" 7" 8" 9" 10" 12" 13" 14" 15" 16" birth" birth IPC: posterior inferior parietal cortex; VFC: ventrolateral prefrontal cortex STC: superior temporal cortex; S1C: primary somatosensory cortex; OFC: orbital prefrontal cortex; A1C: auditory cortex; ITC: inferior temporal cortex; M1C: primary motor cortex; DFC: dorsolateral prefrontal cortex; MFC: medial pre-frontal cortex; V1C: primary visual cortex; HIP: hippocampus; AMY: amygdala; MD: mediodorsal nucleus of the thalamus; STR: striatum; CBC: cerebellar cortex; IPC VFC STC S1C OFC A1C ITC M1C DFC MFC V1C HIP AMY MD STR CBC Expression data from Kang et al., Nature 2011;478:483-9

14 Beyond seizure control Gene network (functionally related to the post-synaptic density) common to epilepsy, cognition and neurospychiatric disease (ASD, SCZ etc) Systems genetics can reveal pathways of molecular convergence across heterogeneous disorders Perturbation of the epilepsy network genes perhaps explains cognitive & behavioural deficits in epilepsy Networks common to cognitive and behavioural impairments and epilepsy may offer a target for disease modification in epilepsy, beyond seizure control

15 Gene)c suscep)bility Rare de novo varia)on Common Gene)c Varia)on Intermediate Mechanisms Altered Brain Gene Expression Brain Circuit DysfuncEon Epilepsy Symptom Domains Seizures CogniEve disturbance Mood disturbance SUDEP Environment/epigene)cs

16 Thank you! Michael Johnson Nature Neuroscience 2016;19: epixchange is a dissemination activity of the FP7 funded projects DESIRE, EpimiRNA, EPITARGET and EPISTOP. DESIRE, EpimiRNA, EPITARGET and EPISTOP are Collaboration Projects funded by the European Union's 7th Framework Programme under respectively grant agreement n , n , n , n