1 A quick introduction to two open multi-omic datasets BrainHack 2017, TorontoLeon French Computational Neurobiology lab Campbell Family Mental Health Research Institute Centre for Addiction and Mental Health

2 Hackathon Theme: Advances and Challenges in Neuroscience Data Integration (multi-centre, multimodal, & multi-species)

3 Hackathon challenges:Data access

4 Hackathon challenges:Data access Integration

5 Outline Allen Human Brain Atlas MyConnectome Allen Mouse Brain AtlasesMulti-omic: transciptome, connectome (DTI images) Open MyConnectome Multi-omic: connectome, transcriptome, metabolome Multi-center Allen Mouse Brain Atlases Multi-omic: transcriptome, connectome Know of others? Let me know

6 Allen Human Brain AtlasComprehensive study of gene expression 6 human postmortem brains 3702 brain samples 58,692 measurements of gene expression over 200 million gene expression values! Hawrylycz, et al. (2012) An anatomically comprehensive atlas of the adult human brain transcriptome, Nature 489:

7 Outline Epigenetic signals of brain plasticityIntegration of molecular data in postmortem brain Integration of molecular and imaging data FreeSurfer view of the cortical transcriptome Integration for cortical regions Cannabis receptor 1 example use case Slide from 2012_Hackathon_Mike_Hawrylycz_Human_Microarray_Gene_Expression_Data.pdf.

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10 Integration By genes - easiestMNI coordinates have been annotated for the 3,702 locations T1 and T2 MRI images for all six brains DTI images for 2 individuals Refined MNI Coordinates from Chris Filo Gorgolewski: https://github.com/chrisfilo/alleninf/blob/master/alleninf/data/corrected_mni_coordinates.csv

11 Things to know Donor brains were normalSome MRI images obtained in cranio, others ex-cranio Both hemispheres assayed first two brains only The six donors vary in age, sex and ethnicity Best used to study molecular neuroanatomy In general, differences in gene expression: Across regions > species > individuals

12 Open tools Allen Institute API and website ABAEnrichment MENGADifferential expression, single gene views ABAEnrichment R package for differential expression MENGA To compare expression of single genes with MRI based data LinkRbrain (BrainHack 2013) Analysis -> Gene Expression Decoding functionality in NeuroVault -tSNE visualization Freesurfer mapping HBASet Visualization of polygenic expression patterns

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14 For a gene of interest: What is its regional expression pattern across the FreeSurfer cortical regions?

15 Using the Allen Human Brain AtlasDownload from the website for CNR1 provides 3 data files: A matrix 329,478 expression values A spreadsheet with information about the expression probes (89 rows) A spreadsheet with information for each sample (3702 rows) Hawrylycz, et al. (2012) An anatomically comprehensive atlas of the adult human brain transcriptome, Nature 489: Wikipedia: Ildar Sagdejev (Specious)

16 Solution: summarize the expression data into a commonly used cortical parcellation.Image from: Cortical thickness or grey matter volume? The importance of selecting the phenotype for imaging genetics studies. Winkler, Kochunov, Blangero, Almasy, Zilles, Fox, Duggirala, Glahn. Neuroimage 2010.

17 Methods Semi-automatically mapped the provided MNI coordinates to the FreeSurfer Desikan-Killiany atlas (34 regions per hemisphere) For each gene, expression was averaged across: Expression probes Samples within a cortical region Individual donor brains Data available online French, L., & Paus, T. (2015). A FreeSurfer view of the cortical transcriptome generated from the Allen Human Brain Atlas. Frontiers in Neuroscience, 9, 323.

18 Example use case We observed group differences in cortical thickness that were associated with cannabis use Are these differences across the cortex correlated with CNR1 expression levels?

19 CNR1 expression shown in TkSurferconsistency across the six individual brains is high – 98th percentile

20 CNR1 expression across cortical regions correlates with inter-regional differences associated with cannabis use R = -0.66, n = 34, p < Group differences in regional cortical thickness between those who never and ever used cannabis show a gradient as a function of the regional differences in CNR1 expression. French, L., Gray, C., Leonard, G., … Paus, T. (2015). Early Cannabis Use, Polygenic Risk Score for Schizophrenia and Brain Maturation in Adolescence. JAMA Psychiatry, 72(10), Group differences in regional cortical thickness between those who never and ever used cannabis show a gradient as a function of the regional differences in CNR1 expression [1].

21 For a set of genes of interest:What is its regional expression pattern?

22 Citalopram or escitalopram responders vs nonresponders -10 genes* Corrected for 236 regions tested

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24 MyConnectome

25 MyConnectome Single subject: Dr. Russel PoldrackBrain scans twice a week for 18 months Focused on fMRI data Key condition: coffee + breakfast Multi-center (two) Transcriptomic and metabolomic data https://github.com/poldrack/myconnectome/ https://github.com/poldrack/myconnectome-vm/

26 Long-term neural and physiological phenotyping of a single humanLong-term neural and physiological phenotyping of a single human. Poldrack et al. Nat Commun Dec 9;6:8885. doi: /ncomms9885.

27 + many other variables like sleep and surveysLong-term neural and physiological phenotyping of a single human. Poldrack et al. Nat Commun Dec 9;6:8885. doi: /ncomms9885.

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29 Fully Reproducible Analysis pipelines provided as a virtual machineMotivated by a linux specific bug in a R library Takes a few hours to run I was able to get it running on Mac OSX Just ask me for copy of the pipeline results One analysis didn’t complete – looking into it

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32 Multi-centre, Multimodal & Multi-speciesBonus dataset: Allen Mouse Brain atlases Gene expression 3d – sagittal and coronal slices Developmental data for 2,000 genes Normalized to standardized coordinates Connectivity Images of axonal projections (using viral tracers) Registered and normalized Cre lines used to focus on specific neuronal populations

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34 Allen Mouse Brain toolsAllen API and website Allen Atlas Brain toolbox (Matlab) I can share normalized gene expression images (~30gb) Excross For visualization of polygenic signal Allen Brain Atlas hackathon excross.chibi.ubc.ca

35 For a set of genes of interest:What is its regional expression pattern?

36 http://excross.chibi.ubc.ca Parkinson’s associated genes as input

37 Summary Two human multi-omic datasets are online and ready to be studied Code is available to parse the vast transcriptomic, metabolomic, and connectomic data The Allen Mouse Brain Atlases allow cross-species comparisons

38 Thanks for sharing Allen Institute for Brain ScienceDr. Russel Poldrack and co-authors Thanks to the BrainHack organizers Dr. Tomas Paus and lab at Baycrest Dr. Paul Pavlidis and lab at UBC