How to use the scientific literature to infer implicit links between genes and diseases.

1. k.m.hettne@lumc.nl
The implicitome: a resource for inferring gene-disease
associations
Kristina Hettne
Human Genetics Department, LUMC
NVHG FALL SYMPOSIUM, PAPENDAL, ARNHEM

2. Problem: biological complexity and data overload
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Goh, K.-I. et al. The human disease network. Proceedings of the National Academy of Sciences 104, 8685-8690 (2008)

3. Solution: Literature-wide association study (LWAS)
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Slide adapted from Erik Schultes

4. Concept profile matching enables implicit links
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(Co-occurrence)
(No co-occurrence)

5. The gene-disease implicitome
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= Max number of
associations

6. Can LWAS predict GWAS?
Retrospective study:
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https://www.ebi.ac.uk/gwas/LWAS (literature)
January 1980 - July 2012 January 2013 - August 2014

7. LWAS meets GWAS
• 238 gene-disease pairs from GWAS, representing 35 diseases
• 194 had concept profiles and could be exposed from LWAS
• The best 5% LWAS: 45 gene-disease pairs overlap with GWAS
• 23%, 4.6-fold enrichment, 5% would be random
• The best 1% LWAS: 12 gene-disease pairs overlap with GWAS
• 6%, 6-fold enrichment, 1% would be random
• Take home message: we can predict now proven associations!
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Slide adapted from Erik Schultes

8. Example: ERAP1 and Behçet’s disease
LWAS connecting Y concepts in 2012:
• HLA-B
• Ankylosing spondylitis
Confirmed in 2013:
Nature Genetics 2013 Feb;45(2):202-7: HLA-B interacts with ERAP1. ERAP1 is
one of the three risk loci shared with Ankylosing spondylitis and psoriasis, which
are thought to involve pathogenic pathways similar to Behçet’s disease.
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Image source: http://www.arthritisresearchuk.org/arthritis-information/conditions/behcets-syndrome/symptoms.aspx
Slide adapted from Erik Schultes
ERAP1 Behçet’s disease

9. LWAS association type classification: top 105
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For example the gene-
disease pair TTBK1-SCA11,
where TTBK1 and TTBK2
are isoforms of the TTBK
gene, and a mutation in
the TTBK2 form is causing
the disease.

10. Example novel (Type IV) association
CYP2R1 had a strong association with Smith-Lemli-Opitz syndrome (SLOS)
Connecting Y concepts:
• DHCR7 (defects cause SLOS)
• cholesta-5,7-dien-3beta-ol (=7-dihydrocholesterol)
Reasoning:
• Pathological hallmark of SLOS is increased levels of
7-dihydrocholesterol
• 7-dihydrocholesterol is a precursor of vitamin D3
• Defects in CYP2R1 are known to affect vitamin D3
levels
• Thus, LWAS implicates CYP2R1 in SLOS since defects may potentially lead to
7-dihydrocholesterol accumulation
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Image source: http://www.nature.com/ejhg/journal/v16/n5/fig_tab/ejhg200810f3.htmlSlide adapted from Erik Schultes

11. Explore the implicitome with http://knowledge.bio
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12. Contact us!
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Code is open source, and data are available for
download
http://biosemantics.humgen.nl/
k.m.hettne@lumc.nl

13. Acknowledgements
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LUMC:
Erik Schultes
Mark Thompson
Herman H.H.B.M. van Haagen
Eelke van der Horst
Rajaram Kaliyaperumal
Eleni Mina
Zuotian Tatum
Jeroen F.J. Laros
Emmelien Aten
Johan den Dunnen
Gert-Jan J.B. van Ommen
Marco Roos
Peter A.C. 't Hoen
Barend Mons
EMC:
Erik M. van Mulligen
Jan A. Kors
Martijn Schuemie
SCRIPPS:
Li S. Tong
Richard Bruskiewich
Benjamin M. Good
Andrew Su
Funding: Dutch Center of Medical Systems
Biology, ODEX4all, Melton Foundation, John
Templeton Foundation, Open PHACTS, National
Institutes of Health, SURF Foundation, RD-
Connect
NVHG Fall Symposium 2015