AMP-AD Open Data and Tools for Target Discovery
Suzana Petanceska PhDDivision of Neuroscience
ALZHEIMER’S DISEASE
ALZHEIMER’S DISEASE - Target Discovery and Preclinical Validation Project
Apply a systems biology approach to discover andvalidate the next generation therapeutic targets using an open science research model:
Generate multi-omics human data from postmortem brain tissue and plasma samples (well phenotypedcohorts and brain banks)
Build network models of targets/pathways
Carry out early target validation in multiple cell-basedand animal models.
Develop a data portal to enable rapid and broad sharingof data and analytical results*.
*Data shared post QC – no publication embargo for secondary use of data
Network Working GroupRNAseq Working Group eQTL Working Group
Deconvolution Working Group Cross-Species Working Group
ALZHEIMER’S DISEASE - Target Discovery and Preclinical Validation Project
Centralized data resource established – AMP-AD Knowledge Portal
Rich genomic, proteomic, metabolomic human data (raw and processed) made available and being widely used
Network models od disease pathways/targets developed
Over 100 novel candidate targets identified and being prioritized in collaboration with industry partners
Animal models phenotyped/evaluated relative to human networks
Web-based interface for sharing target nominations and analytical outputs - AGORA platform - beta version launched
Open source research tools for de-risking dark targets - being developed
Novel biomarker discovery efforts - initiated
Single cell RNAseq profiling (human and mouse) - initiated
ALZHEIMER’S DISEASE - Target Discovery and Preclinical Validation Project
Progress over 5 years
60,000 files contributed by 42 investigators across 22 institutions representing samples from 36 research studies
Over 1800 users with ~55 new users per month
www.synapse.org/ampad
22 model system studies15 genomic data types7043 human samples 15 human studies
Sci Data. 2018 Sep 11;5:180185. doi: 10.1038/sdata.2018.185.
The Mount Sinai cohort of large-scale genomic, transcriptomic and proteomic data in Alzheimer's disease. Wang M et al.
Sci Data. 2018 Aug 7;5:180142. doi: 10.1038/sdata.2018.142.A multi-omic atlas of the human frontal cortex for aging and Alzheimer's disease research.De Jager PL et al.
Sci Data. 2018 Mar 13;5:180036. doi: 10.1038/sdata.2018.36.Global quantitative analysis of the human brain proteome in Alzheimer's and Parkinson's Disease. Ping L et al.
Sci Data. 2017 Oct 17;4:170140. doi: 10.1038/sdata.2017.140.Targeted metabolomics and medication classification data from participants in the ADNI1 cohort.St John-Williams L et al.
Sci Data. 2016 Oct 11;3:160089. doi: 10.1038/sdata.2016.89.Human whole genome genotype and transcriptome data for Alzheimer's and other neurodegenerative diseases.Allen M et al.
ROS/MAP Cohorts
AMP-AD Target
Discovery
AMP-ADKnowledge
Portal M2OVE-AD
NPS-AD
**MICROBIOMEAD
Drug Repurposingand
Combination Therapy Development
Resilience-AD
MODEL-AD
RFA-AG13-013/RFA-AG17-054RFA-AG18-013/RFA-AG18-014
RFA AG15-010RFA AG16-014
RFA AG17-061RFA AG-18-029
PAR 17-032Active FOA
PAR-18-596/NOT AG-18-001
An Open Science Knowledge Network
Common viral species frequently detected in normal, aging brain
Increased HHV-6A and HHV-7 in brains of subjects with AD
Findings were replicated in two additional, independent cohorts
Multiscale networks reveal viral regulation of AD risk, and APP processing genes
Multiscale Analysis of Independent Alzheimer's Cohorts Finds Disruption of Molecular, Genetic, and Clinical Networks by Human Herpesvirus. Redhead et al., Neuron Volume 99, Issue 1, 11 July 2018, Pages 64-82.e7
ALZHEIMER’S DISEASE - Target Discovery and Preclinical Validation Project
agora.ampadportal.org
Beta Version launched at AAIC 2018 - over 100 AMP-AD target nominations released
12
View details about each nominated gene, including the rationale for its selection and druggability information.
http://agora.ampadportal.org/helpHow to Navigate Agora Tutorial
• Access to detailed methods, data, and analyses that led to target nominations
• New widgets to incorporate additional lines of evidence:
– genome explorer (eQTLs, GWAS, transcription factor networks)
– proteomics data
– metabolomic data
– integrative ranking across multiple types of evidence
– single cell RNA-seq
– druggability widget
• New widgets to highlight available tools and resources:
– model systems and other experimental models
• Enabling users to follow, favorite, and give feedback on gene targets of interest
New Features - Coming Soon
Agora Development Timeline (2018/2019)
Fall 2018 Winter 18/19 Spring 19 Summer 19
Now
• Detailed evidence used for nominated targets
• Druggability widget• Improve deployment
infrastructure
Release Agora 1.0 SfN (Nov 4*)
Release Agora 1.5(April 15)
• 2-3 additional widgets
Release Agora 2.0 AAIC 2019 (July 14)
• User interactivity (comment, follow)• 2-3 additional widgets
Agora 1.0 Launch at SFN 2018, San Diego Nov. 4, 6:30p.m. - 8:00p.m.
Hilton Bayfront, Room Indigo 204B
RSVP here
agora.ampadportal.org
- broadcast AMP-AD target predictions- establish confidence in target predictions through unbiased, assessment
across multiple types of evaluations- disseminate tools to encourage independent evaluation
Current services:- Cloud-based File Sharing- Access restrictions and data governance to support human data sharing- Communication services: user profiles, forums- Beta-version of Agora, the knowledge integration platform
Coming in 2019:- Streamlined process for data contribution- Improved query and search for data, people, projects- Active community management: newsletters, customer support- Repository for analytical methods- Cloud-based compute
NOT JUST TARGETS
AMP-AD: Integrative Proteomics for Novel Target and Biomarker Discovery
4.
Fusion-OrbitrapMultiplex (TMT)
QE-OrbitrapLabel-free
“single shot”
~11-12,000 proteinsn=80 tissues
~3,000 proteinsn=1,000 tissues CSF/Plasma
~1800 Cases
Comprehensive and Integrated Analysis of the Human Brain and CSF Proteome in AD
Relate to biological functionand processes
Assess Module-phenotypeRelationships
To CSF
Communitiesof Proteins
Module-BasedBiomarkers
From Brain
From Brain to Plasma: Proteomic Biomarker Discovery and Validation in the US and UK
Simon Lovestone
Allan Levey, Ihab Hajjar& Nick Seyfried
Rima Kaddurah-Daouk
RFA AG18-013 / RFA AG18-014NIA investment: ~$60M over the next 5 years
opportunity to continue and expand the public private partnership
ALZHEIMER’S DISEASE - Target Discovery and Preclinical Validation Project
TARGETSand
BIOMARKERS
OPEN METHODS
OPEN DATA
- AD
ALZHEIMER’S DISEASE - Target Discovery and Preclinical Validation Project