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Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Integrative and translational analysis of thephenome
Robert Hoehndorf
Department of Physiology, Development and NeuroscienceUniversity of Cambridge
26 September 2012
2004 2005 2006 2007 2008 2009 2010 2011 2012
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Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Translational research
National Cancer Institute:
Translational research transforms scientific discoveries arising fromlaboratory, clinical, or population studies into clinical applicationsto reduce [disease] incidence, morbidity, and mortality.
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Genetic diseasesAlmost 4,000 genetic diseases in OMIM have an unknown molecular basis.
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Genetic diseasesOrphaNet
5,917 orphan diseases
2,543 genes linked to 2,544 diseases
2,700 diseases indexed with clinical signs
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Genetic diseasesAnimal models have been shown to be highly successful in studying human disease
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Approach
Can we use phenotypes of mutant animal organisms to findcandidate genes for orphan diseases?
1 make animal and human phenotypes comparable
2 systematically analyze the phenome for possible causativemutations
3 evaluate using real biomedical data
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Approach
Can we use phenotypes of mutant animal organisms to findcandidate genes for orphan diseases?
1 make animal and human phenotypes comparable
2 systematically analyze the phenome for possible causativemutations
3 evaluate using real biomedical data
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Genetic diseasesPATO and the EQ method enable the integration of phenotype ontologies across species.
use of Entity-Quality definitions
homologous anatomical structures
integration based on species-independent ontologies
Gene OntologyChEBI, Protein ontology, Celltype ontology
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Genetic diseasesIntegration of phenotypes enables direct comparison between species
Proximal fibular overgrowth(HPO):
E: Proximal epiphysis offibula (FMA)
Q: hypertrophic
Abnormal fibula morphology(MP):
E: fibula (MA)
Q: morphology (abnormal)
UBERON: fibula (MA) orthologous to Fibula (FMA)
FMA: Proximal epiphysis of fibula part-of Fibula
PATO: hypertrophic is-a morphology
Proximal fibular overgrowth is-a Abnormal fibula morphology
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Genetic diseasesExperimental data can be integrated through ontologies and explored using automatedreasoning.
integration of phenotype ontologies
yeast, fly, slime mold, worm, fish, mouse, rat, human
ontology-based integration of phenotypes
mutant phenotypes for yeast, fly, slime mold, worm, fish,mouse, rathuman disease phenotypes from OMIM and OrphaNet
OWL ontology with more than 500,000 classes
OWL reasoner reveals connections between phenotypes
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Genetic diseasesSemantic similarity over phenotype ontologies measures phenotypic similarity.
semantic similarity: metric based on information contained inthe axioms of an ontology
pairwise comparison of disease and animal phenotypes
sim(P,D) =
∑x∈Cl(P)∩Cl(D)
IC (x)
∑y∈Cl(P)∪Cl(D)
IC (y)
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Genetic diseasesSimilarity-based comparison
Evaluation against known gene–disease associations:
OMIM
MGI
OrphaNet
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Genetic diseasesOMIM phenotypes
AUC (OMIM): 0.78
AUC (MGI): 0.87
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Genetic diseasesOrphaNet phenotypes
AUC (OrphaNet):0.73
AUC (OMIM): 0.76
AUC (MGI): 0.80
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Genetic diseasesOntology-based integration and analysis can reveal disease genes for orphan diseases.
Adam19 and Fgf15 in mice are strong candidates forTetralogy of Fallot
Gene disease associations for orphan diseases
Slc34a1 (MGI:1345284) and Fanconi renotubular syndrome 1(OMIM:134600)
Disease pathways
Cytokine-cytokine receptor interaction pathway (ko04060) issignificantly correlated with Tetralogy of Fallot (p = 5 · 10−7,Wilcoxon signed-rank test)
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Bassoe SyndromeSigns and symptoms
skeletal:
kyphosis, hypertensible joints, cubitus valgus
muscular:
hypotonia, muscle hypotrophy, amyotrophy
behavior:
abnormal gait, amimia
visual:
cataract, strabismus
reproductive:
hypogonadism, hypogenitalism, abnormal ovaries, hypoplastictestis, reduced fertility
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Bassoe Syndromehttp://phenomebrowser.net
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Bassoe SyndromeHIP1 knockout mice
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Bassoe SyndromeHIP1 mouse phenotypes
Bassoe Syndrome:
kyphosis, hypertensiblejoints, cubitus valgus
amyotrophy, hypotonia,muscle hypotrophy
abnormal gait, amimia
cataract, strabismus
testicular atrophy,hypogonadism,hypogenitalism,abnormal ovaries,reduced fertility
Mouse phenotypes:
kyphosis, abnormal spine curvature,lordosis
abnormal muscle morphology
, musclehypotrophy, muscle wasting
abnormal gait, hypoactivity, tremors
,failure to thrive, ataxia
nuclear cataracts, microphthalmia
testicular atrophy, male infertility
,ovarian abnormalities, testiculardegeneration, increased apoptosis ofpostmeiotic spermatids, oligospermia
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Bassoe SyndromeHIP1 mouse phenotypes
Bassoe Syndrome:
kyphosis, hypertensiblejoints, cubitus valgus
amyotrophy, hypotonia,muscle hypotrophy
abnormal gait, amimia
cataract, strabismus
testicular atrophy,hypogonadism,hypogenitalism,abnormal ovaries,reduced fertility
Mouse phenotypes:
kyphosis, abnormal spine curvature,lordosis
abnormal muscle morphology, musclehypotrophy, muscle wasting
abnormal gait, hypoactivity, tremors,failure to thrive, ataxia
nuclear cataracts, microphthalmia
testicular atrophy, male infertility,ovarian abnormalities, testiculardegeneration, increased apoptosis ofpostmeiotic spermatids, oligospermia
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Bassoe Syndrome
Computational analysis of mouse phenotypes provides a strongindication that HIP1 may be involved in Bassoe syndrome.
Genetic diseasesROC analysis quantifies the performance of the approach.
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Question
Is there a similarity between a knock-out/knock-down of a gene(through targeted mutation) and the inhibition/negative regulationof a gene (through a drug action)?
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
PhenomeNET compares phenotypes across species
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Statistical testing to rank drug–disease pairs
one-sided Wilcoxon signed rank test
result: ranking of drugs for each disease based on p-value
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Phenotype-based comparison can provide some informationabout drug indications
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AUC (CTD): 0.61AUC (FDA): 0.67
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Future: phenotype-based drug repurposing
similarity between inhibition (drug action) andknock-out/knock-down (mutation)
effectsindicationstargets
combination with interaction networks
D inhibits G1 and G1 positively regulated G2 ⇒ D inhibits G2.
drug pathways
pharmacodynamicspharmacokineticsphysiological pathways
Pharmacogenomics databases
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Aims: queries and integrated analysis
integrate and query knowledge in pharmacogenomics
identify aberrant pathways and patho-physiology underlyingdisease
identify drug pathways (pharmacokinetics andpharmacodynamics)
personalized treatment and dosage guidelines
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Approach to data integration in pharmacogenomics
integration of databases containing drug, gene, genotype,disease and pathway information
DrugBank: drugs and drugs targetsPharmGKB: genotype and drug responsePathway Interaction Database: biological pathwaysCTD: toxicogenomics information (chemical–gene–disease)
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Queries
What drugs can be used to treat parasitic infectious diseases(DOID:1398)?
Chloroquine
Arthemeter
...
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Queries
What drugs are effective for diseases affecting the joints(FMA:7490)?
Folic acid (for arthritis)
Chloroquine (for Chikungunya virus)
...
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Queries
What genotypes are related to diseases affecting the joints(FMA:7490)?
RSID:rs70991108 (with arthritis)
RSID:rs1207421 (Osteoarthritis, Knee)
...
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Queries
What genotypes are related to response to steroids(CHEBI:35341)?
RSID:rs45566039 (with estrogen)
RSID:rs1042713 (with budesonide)
...
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Disease and drug pathwaysOntology enrichment analysis can identify over-represented ontology classes.
ontology-based, statistical approach to identify drug anddisease pathways
use graph structure of ontology to identify statistically over-and under-represented ontology classes
aims:
identify over-represented disease classes (in disease ontology)for genes in a pathway (disease pathways)identify over-represented chemical classes (from chemicalontology) for genes in a pathway (drug pathways)
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Disease and drug pathwaysOntoFUNC enables enrichment analyses over OWL ontologies.
OntoFUNC: http://ontofunc.googlecode.com
based on FUNC (http://func.eva.mpg.de)
supports
hypergeometric testWilcoxon rank testbinomial testMcDonaldKreitman (2x2 contingency) testcorrection for multiple testing (FWER, FDR)
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Disease and drug pathwaysOntoFUNC identifies disease classes that are enriched in pathways.
hypergeometric test over Disease Ontology
genes participating in pathway P vs. all other genes
carcinosarcoma (DOID:4236) and Zidovudine Pathway(PharmGKB:PA165859361) (p < 10−10).
mood disorder (DOID:3324) and Zidovudine Pathway(PharmGKB:PA165859361) (p < 0.01).
(All results at http://pharmgkb-owl.googlecode.com)
Species Inferred p-valueFish 1717 0.240Yeast 14047 0.162Fly 1633 0.041Worm 9221 0.003
Mouse 15693 7 · 10−5
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S. cerevisiae
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Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
SummaryOntologies can be used to enable integrative biology.
1 integration of ontologies
2 integration of data through ontologies3 ontology-based data analysis
semantic similaritystatistical testsgraph-/network-based algorithms
4 quantitative evaluation on real biological data
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Acknowledgements
George Gkoutos
Paul Schofield
Michel Dumontier
Heinrich Herre
Janet Kelso
DietrichRebholz-Schuhmann
Dan Cook
John Gennari
Anika Oellrich
Nico Adams
Bernard de Bono
Pierre Grenon
Midori Harris
Pascal Hitzler
Simon Jupp
Frank Loebe
Kay Pruefer
Gabrielle Rustici
Stefan Schulz
Robert Stevens
Sarala Wimalaratne
...
Introduction Animal and disease phenotypes Pharmacogenomics Pathways Summary
Thank you!
http://phenomebrowser.net