Fully powered polygenic prediction using summary statistics · Fully powered polygenic prediction...
Transcript of Fully powered polygenic prediction using summary statistics · Fully powered polygenic prediction...
Fully powered polygenic prediction
using summary statistics
Alkes L. Price
Harvard T.H. Chan School of Public Health
October 7, 2015 To download slides of this talk: google “Alkes HSPH”
Summary statistics are widely available
—Nat Genet editorial, July 2012
Outline
1. A brief history of summary statistic genetics
2. Introduction to polygenic prediction using summary statistics
3. LDpred method for polygenic prediction using summary statistics
4. Application of LDpred to real data sets
Outline
1. A brief history of summary statistic genetics
2. Introduction to polygenic prediction using summary statistics
3. LDpred method for polygenic prediction using summary statistics
4. Application of LDpred to real data sets
Definition of summary statistics
Definition: Summary statistics consist of:
• GWAS association z-scores for each typed or imputed SNP +
• Sample sizes on which z-scores were computed (may vary by SNP)
Note: Many applications also require LD information computed from
a reference panel (e.g. 1000 Genomes or UK10K) using a population
“very similar” to the target sample.
Meta-analysis can be performed
using summary statistics
Evangelou & Ioannidis 2013 Nat Rev Genet
Joint and conditional analysis can be
performed using summary statistics
Yang et al. 2012 Nat Genet
Imputation can be performed
using summary statistics
Lee et al. 2013 Bioinformatics; Pasaniuc et al. 2014 Bioinformatics
also see Park et al. 2015 Bioinformatics, Lee et al. 2015 Bioinformatics
Rare variant meta-analysis can be
performed using summary statistics
Lee et al. 2013 AJHG; Hu et al. 2013 AJHG; Liu et al. 2014 Nat Genet
also see Clarke et al. 2013 PLoS Genet, Tang & Lin 2015 AJHG
Genetic variance and covariance can be
inferred using summary statistics
Palla & Dudbridge 2015 AJHG; Bulik-Sullivan et al. 2015 Nat Genet
Functional enrichment can be
inferred using summary statistics
Pickrell 2014 AJHG; Kichaev & Pasaniuc 2015 AJHG; Finucane et al. 2015 Nat Genet
Many projects at ASHG 2015
using summary statistics
• Invited talks Pickrell, Pasaniuc, Im (this session)
• Platform talks 11 Gusev, 77 Cichonska, 220 Golan, 272 Park
• Posters 791 Kichaev, 797 Shi, 807 Roytman, 860 Salem,
868 Pare, 1301 Wu, 1334 Zhu, 1357 Chatterjee, 1477 Brown,
1618 Li, 1668 Khawaja, 1686 Lee, 1687 Zhao, 1728 Torres,
1867 O’Connor
Outline
1. A brief history of summary statistic genetics
2. Introduction to polygenic prediction using summary statistics
3. LDpred method for polygenic prediction using summary statistics
4. Application of LDpred to real data sets
Erbe et al. 2012 J Dairy Sci; Goss et al. 2011 New Engl J Med
Genetic prediction: why care?
Using only genome-wide significant SNPs
is a Stone Age genetic prediction method
i
ikik x ˆˆ
(published SNPs)
φk = phenotype for sample k
βi = effect size for SNP i
xik = genotype for SNP i, sample k
How should we conduct
genetic prediction, Fred?
Prediction r2 is less than half the r2 attained by polygenic prediction
PGC-SCZ 2014 Nature; Vilhjalmsson et al. 2015 AJHG
Polygenic prediction can be performed
using genome-wide summary statistics
i
ikik x ˆˆ
(all GWAS SNPs)
φk = phenotype for sample k
βi = effect size for SNP i
xik = genotype for SNP i, sample k
Is polygenic prediction using raw genotypes
more accurate than using summary statistics?
Answer: slightly.
NMh
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NMrh
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= heritability explained by SNPs
M = number of (unlinked) SNPs
N = number of training samples
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using summary statistics: using raw genotypes:
fit each SNP individually fit all SNPs simultaneously
(BLUP prediction; Henderson 1975 Biometrics)
Daetwyler et al. 2008 PLoS ONE; Wray et al. 2013 Nat Rev Genet
also see Speed & Balding 2014 Genome Res (multiBLUP)
Accounting for non-infinitesimal architectures
can improve polygenic prediction
Infinitesimal (Gaussian) architecture:
=>
Uniform shrink on estimated effect sizes is appropriate
MhN gi /,0~ 2
NNii /1,0~ˆ
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i
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iiNMh
hE ˆ
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Accounting for non-infinitesimal architectures
can improve polygenic prediction Non-infinitesimal architecture:
(e.g. point-normal mixture, mixture of normals, etc.)
Non-uniform shrink on estimated effect sizes is appropriate
i
Accounting for non-infinitesimal architectures
can improve polygenic prediction
Infinitesimal (Gaussian) architecture:
=>
Uniform shrink on estimated effect sizes is appropriate
Non-infinitesimal architecture:
(e.g. point-normal mixture, mixture of normals, etc.)
Non-uniform shrink on estimated effect sizes is appropriate
Standard heuristic approach: P-value thresholding
MhN gi /,0~ 2
NNii /1,0~ˆ
i
i
i
ikik x ˆˆ
P-value < PT
(Note: requires optimization of
PT threshold in validation samples)
Purcell et al. 2009 Nature; Chatterjee et al. 2013 Nat Genet; Dudbridge 2013 PLoS Genet
i
g
g
iiNMh
hE ˆ
/)ˆ|(
2
2
Accounting for linkage disequilibrium
can improve polygenic prediction
Problem: does not account for LD b/t SNPs
Standard heuristic approaches:
Random LD-pruning: prune SNPs (e.g. r2 < 0.2),
removing one of each pair of linked SNPs
(decide randomly which SNP to remove)
Informed LD-pruning (LD-clumping): prune SNPs,
removing one of each pair of linked SNPs
(remove SNP with less significant P-value in training data)
i
ikik x ˆˆ
P-value < PT
Purcell et al. 2009 Nature; Stahl et al. 2012 Nat Genet
also see Rietveld et al. 2013 Science (COJO)
Pruning + Thresholding is widely used …
Purcell et al. 2009 Nature; Lango Allen et al. 2010 Nature; Ripke et al. 2011 Nat Genet;
Stahl et al. 2012 Nat Genet; Deloukas et al. 2013 Nat Genet; Ripke et al. 2013 Nat Genet;
Chatterjee et al. 2013 Nat Genet; Dudbridge 2013 PLoS Genet; PGC-SCZ 2014 Nature
Pruning + Thresholding is widely used, but
does not attain maximum prediction accuracy
Vilhjalmsson et al. 2015 AJHG
2
gh
Simulations at different proportions p of causal SNPs:
Infinitesimal Infinitesimal
Non-infinitesimal Non-infinitesimal
Outline
1. A brief history of summary statistic genetics
2. Introduction to polygenic prediction using summary statistics
3. LDpred method for polygenic prediction using summary statistics
4. Application of LDpred to real data sets
LDpred computes posterior means under a
point-normal prior, accounting for LD
Vilhjalmsson et al. 2015 AJHG
i
ikiik xE )ˆ|(ˆ
(all GWAS SNPs)
φk = phenotype for sample k
βi = effect size for SNP i
xik = genotype for SNP i, sample k
where are posterior mean effect sizes )ˆ|( iiE
LDpred computes posterior means under a
point-normal prior, accounting for LD
Vilhjalmsson et al. 2015 AJHG
i
ikiik xE )ˆ|(ˆ
(all GWAS SNPs)
φk = phenotype for sample k
βi = effect size for SNP i
xik = genotype for SNP i, sample k
where are posterior mean effect sizes based on
• point-normal prior with 2 parameters:
= heritability explained by SNPs (estimated from training data)
p = proportion of causal SNPs (optimized in validation samples)
• LD from a reference panel
Use validation samples as LD reference
(restrict to SNPs with validation data)
)ˆ|( iiE
2
gh
In the special case of no LD between SNPs,
posterior means can be computed analytically
= heritability explained by SNPs
p = proportion of causal SNPs
M = number of (unlinked) SNPs
N = number of training samples
2
gh
ii
g
g
ii pNMph
hE ˆ
/)ˆ|(
2
2
where
is the posterior probability that , i.e. SNP i is causal
(generalizes uniform shrink when p = 1: infinitesimal prior, no LD)
)/1(2
ˆ
)/1/(2
ˆ
2
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NMph
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NMph
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eNMph
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0i
In the special case of infinitesimal prior (with LD),
posterior means can be computed analytically
= heritability explained by SNPs
M = number of (unlinked) SNPs
N = number of training samples
2
gh
i
g
ii INh
MDE ˆ)ˆ|(
1
2
where D is an LD matrix from a reference panel
(generalizes uniform shrink when D = I: infinitesimal prior, no LD)
General case of non-infinitesimal prior with LD:
posterior means cannot be computed analytically
General case of non-infinitesimal prior with LD:
posterior means cannot be computed analytically
Possible solutions:
• Assume 1 causal variant per locus
General case of non-infinitesimal prior with LD:
posterior means cannot be computed analytically
Possible solutions:
• Assume 1 causal variant per locus
• Iterative approach
General case of non-infinitesimal prior with LD:
posterior means cannot be computed analytically
Possible solutions:
• Assume 1 causal variant per locus
• Iterative approach
• MCMC
General case of non-infinitesimal prior with LD:
posterior means cannot be computed analytically
Solution: use MCMC.
Initialize = 0
At each big iteration
For each SNP i
Re-sample based on
• Point-normal prior on
• Observed
, where
reflects point-normal prior (based on and p)
i)/,(~ˆ NDDN
i
i
)( if 2
gh
)ˆ(ˆ2
1
)(~)ˆ|(
DDD
N
ii
T
eff
General case of non-infinitesimal prior with LD:
posterior means cannot be computed analytically
Solution: use MCMC.
Initialize = 0
At each big iteration
For each SNP i
Re-sample based on
• Point-normal prior on
• Observed
100 big iterations generally suffice for convergence
Rao-Blackwellization: average the posterior means sampled
i)/,(~ˆ NDDN
Related MCMC methods for prediction from raw genotypes are described in
Erbe et al. 2012 J Dairy Sci, Zhou et al. 2013 PLoS Genet, Moser et al. 2015 PLoS Genet
i
i
LDpred performs well in simulations
Simulations with real genotypes, 1% of SNPs causal
Understanding polygenic prediction
Let’s hide away and dance.
-- Freddie K.
Let’s hide away with data.
-- Alkes
Outline
1. A brief history of summary statistic genetics
2. Introduction to polygenic prediction using summary statistics
3. LDpred method for polygenic prediction using summary statistics
4. Application of LDpred to real data sets
LDpred performs well on within-cohort
prediction of WTCCC traits …
Data from WTCCC 2007 Nature. Results are similar to MCMC-based methods that
require raw genotypes: Zhou et al. 2013 PLoS Genet, Moser et al. 2015 PLoS Genet
LDpred performs well on within-cohort
prediction of WTCCC traits …
(see Lee et al. 2012 Genet Epidemiol) 222
liabobsnag RRR
Data from WTCCC 2007 Nature. Results are similar to MCMC-based methods that
require raw genotypes: Zhou et al. 2013 PLoS Genet, Moser et al. 2015 PLoS Genet
LDpred performs well on within-cohort
prediction of WTCCC traits …
Dominated
by HLA
Data from WTCCC 2007 Nature. Results are similar to MCMC-based methods that
require raw genotypes: Zhou et al. 2013 PLoS Genet, Moser et al. 2015 PLoS Genet
LDpred performs well on within-cohort
prediction of WTCCC traits …
Do not
validate in
new cohort
Data from WTCCC 2007 Nature. Results are similar to MCMC-based methods that
require raw genotypes: Zhou et al. 2013 PLoS Genet, Moser et al. 2015 PLoS Genet
… but within-cohort prediction accuracy
may be too good to be true
2
nagR
Results presented for LDpred; similar relative results for other methods
Cryptic relatedness? Population structure? (Wray et al. 2013 Nat Rev Genet)
CAD T2D
Training: WTCCC
Validation: WTCCC
0.0451 0.0467
Training: WTCCC
Validation: WGHS
0.0048 0.0095
LDpred performs well on summary statistics
with independent validation cohorts
Training N=70K PGC-SCZ 2014 Nature; MGS replication sample
LDpred performs well on summary statistics
with independent validation cohorts
Training N=70K Training N=30K Training N=60K
LDpred performs well on summary statistics
with independent validation cohorts
Training N=70K Training N=30K Training N=60K
Training N=70K Training N=90K
LDpred performs well on summary statistics
with independent validation cohorts
Height: complexities due to population stratification.
Including PCs can improve prediction accuracy.
(Chen et al. 2015 Genet Epidemiol)
Training N=130K (Lango Allen et al. 2010 Nature)
• Explicitly modeling both LD and non-infinitesimal architectures
improves polygenic prediction from summary statistics.
• Polygenic prediction should be evaluated using independent
validation cohorts.
• Although polygenic predictions are not yet clinically useful,
prediction accuracies will increase as sample sizes increase
(bounded by heritability explained by SNPs; ).
Conclusions …
2
gh
• Polygenic prediction in non-European samples is challenging.
How to combine training data from Europeans (large sample size)
with training data from target population (small sample size)?
(cross-population genetic correlation; Poster 1477 Brown)
• Enrichment of heritability in functional annotation classes
could potentially be used to improve polygenic prediction
(Poster 1357 Chatterjee)
• Methods for large raw genotype data sets (e.g. UK Biobank)
should be developed in parallel with summary statistic methods
(Platform talk 38 Loh; Platform talk 170 Young)
… and Future directions
Acknowledgements
Bjarni Vilhjalmsson + Vilhjalmsson et al. 2015 AJHG co-authors
Everyone in alkesgrp. Please check out our other ASHG 2015 talks:
• Platform talk 11 Gusev “Large-scale transcriptome-wide association study …”
• Platform talk 38 Loh “Contrasting regional architectures of schizophrenia …”
• Platform talk 196 Bhatia “Haplotypes of common SNPs explain a large …”
• Platform talk 352 Galinsky “Population differentiation analysis of 54,734 …”
• Platform talk 346 Hayeck “Mixed model association with family-biased …”
• Platform talk 354 Palamara “Leveraging distant relatedness to quantify …”