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Detecting genome-wide directional effects of transcription factor
binding on polygenic disease risk
Yakir ReshefHarvard/MIT MD/PhD Program
Harvard University Computer ScienceOctober 18, 2017
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GWAS + genomics biology
[Liu et al 2015 Nat Genet]
“inflammation”
Crohn’s GWAS
genes expressed in immune cells
[Pasaniuc & Price 2016 Nat Rev Genet; Maurano et al. 2012 Science;Pickrell 2014 AJHG;Gusev et al. 2014 AJHG; Farh et al. 2015 Nature; Finucane et al. 2015 Nat Genet; …]
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Signed annotations: stronger inference
“inflammation”
Crohn’s GWAS
genes expressed in immune cells
.
.
.
[Degner et al. 2012 Nature; Lee et al. 2015 Nat Genet; Zhou et al. 2015 Nat Meth;Tehranchi et al. 2016 Cell; Tewhey et al. 2016 Cell; Kelley et al. 2016 Genome Res]
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Signed annotations for transcription factors
“binding of IRF1”
Crohn’s GWAS
IRF1 Crohn’scausality
IRF1 “Inflammation” Crohn’smechanism
“Genome-wide, alleles increasing IRF1 binding tend to increase Crohn’s risk”
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Outline
• Description of method
• Validation in simulations
• Proof of concept: analysis of molecular traits
• Analysis of 46 diseases and complex traits
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Outline
• Description of method
• Validation in simulations
• Proof of concept: analysis of molecular traits
• Analysis of 46 diseases and complex traits
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A thought experiment
What if oracle gave us
true causal effect of SNPs on disease
true causal effect of SNPs on TF binding
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A thought experiment
effects on disease effects on TF binding
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What do we have in practice?(Signed) marginal GWAS summary statistics
(Signed) binding predictions from DNA sequence
LD matrix from reference panel
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Method: signed LD profile regression(Signed) marginal GWAS summary statistics
(Signed) binding predictions from DNA sequence
LD matrix from reference panel
[Details: p-values, generalized least-squares, minor allele effects]
Under model:
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Outline
• Description of method
• Validation in simulations
• Proof of concept: analysis of molecular traits
• Analysis of 46 diseases and complex traits
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SLDP is well-calibrated
[Reshef et al. 2017 BioRxiv]
no enrichment
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SLDP is robust to unsigned enrichment
[Reshef et al. 2017 BioRxiv]
confounding byunsigned enrichment
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Outline
• Description of method
• Validation in simulations
• Proof of concept: analysis of molecular traits
• Analysis of 46 diseases and complex traits
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382 TF binding annotations analyzed
ENCODE ChIP-seq + Basset CNN model
Transcription factor Cell line
CTCF A459...
.
.
.
IRF1 GM12878
[ENCODE Project; Kelly et al. 2016 Genome Res]
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Trait: gene expression, across genes
Seeking:
TFs that affect expression inconsistent direction across genes
Strategy:
Meta-analysis across genes
GENE1
GENE2
GENE3
GENE4
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SLDP reproducibly identifies activating TFs
[Reshef et al. 2017 BioRxiv; Hansen et al. 1994 Mol Chem Bio; Kimura et al. 1994 Science]
Known activator (UniProt)
Other
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SLDP links TFs to epigenetic marks
[Reshef et al. 2017 BioRxiv; Ogryzko et al. 1996 Cell; Laiosa et al. 2006 Ann Rev Immun]
Known activator (UniProt)
Other
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Outline
• Description of method
• Validation in simulations
• Proof of concept: analysis of molecular traits
• Analysis of 46 diseases and complex traits
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46 diseases and complex traitsUKB + public (sumstats) avg N=289k, ~1M SNPs
Phenotype Sample size
Height N≈450k
Rheu. arthritis N≈36k...
.
.
.
Lupus N≈14k
Schizophrenia N≈70k
[Loh et al. BioRxiv; BOLT-LMM UK Biobank summary statistics are publicly available]
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SLDP identifies 77 TF-trait annotations
[Reshef et al. 2017 BioRxiv]
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SLDP identifies 77 TF-trait annotations
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…that form 12 independent signalsTotal results: 77Indep. signals: 12
Significant results at per-trait FDR < 5%, grouped into approx. independent signals.
[Reshef et al. 2017 BioRxiv]
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0
20
BCL11A
[DDD 2015 Nature; Okbay et al. 2016 Nature; Bazak et al. 2016 JCI; Dias et al. 2016 AJHG]
Rare LOFsin BCL11A
intellectual disability
BCL11A EDU+
Genome-wide GWAS signalvs signed LD profile EDU Manhattan plot
0
0
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[DDD 2015 Nature; Okbay et al. 2016 Nature; Bazak et al. 2016 JCI; Dias et al. 2016 AJHG]
CTCF Lupus-
Genome-wide GWAS signalvs signed LD profile Lupus Manhattan plot
0
0
0
20
CTCF
CTCF slows myeloiddifferentiation
Fine-mapped SLE SNPsmodify CTCF binding
ExAC:pLI(CTCF) = 1.00(> 99.9% of genes)
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IRF1 Crohn’s+
Genome-wide GWAS signalvs signed LD profile Crohn’s Manhattan plot
0
0
-20
20
IRF1
[Jostins et al. 2012 Nature; Wright et al. 2014 Nat Genet]
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IRF1 Crohn’s+
Genome-wide GWAS signalvs signed LD profile
0
0
[Jostins et al. 2012 Nature; Wright et al. 2014 Nat Genet]
-20
20
IRF1
IRF1
eQTL
z-s
core
Crohn’s Manhattan plot
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Conclusions
• Signed annotations enable strong inference about disease mechanism
• Signed LD profile regression links signed annotations to GWAS
• Evidence for genome-wide directional effects of TFs on molecular and complex traits
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AcknowledgementsHilary Finucane
David KelleyAlexander Gusev
Dylan KotliarJacob Ulirsch
Farhad Hormozdiari
Pier-Francesco Palamara
Luca Pinello
Nick Patterson
Ryan Adams
Alkes Price
CGTA, HMS research computing, C de Boer, L Dicker, J Engreitz, N Friedman, X Liu, M Mitzenmacher, J Perry, D Reshef, S Reilly, S Raychaudhuri, A Schoech, P Sabeti, R Tewhey, P Turley
Luke O’ConnorBryce van de Geijn
Po-Ru LohShari GrossmanGaurav BhatiaSteven Gazal
Detecting genome-wide directional effects of transcription factor binding on polygenic disease risk Reshef et al. 2017 bioRxiv:204685
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Thank you