Download Common trait genetics

Common trait genetics
Chris Cotsapas
Liability threshold model
Al-Chalabi and Hardiman, Nat Rev Neurology 2013
Heritability
• Proportion of differences due to genetic
factors
– From family and twin studies
• Broad sense (H2)
– Additive, dominant and epistatic
• Narrow sense (h2)
– Additive only
• How many genetic factors explain
heritability?
– Mendel v Galton
Necessary and sufficient
(BUT! expressivity, penetrance)
Minikel et al, STM 2016
http://psychology.wikia.com/wiki/Body_height
http://www.ebi.ac.uk/fgpt/gwas/images/timeseries/gwas-latest.png
Enrichment of GWAS SNPs on Regions of
Chromatin Accessibility Marked by DHSs
Maurano et. al, Science 2012
Gusev et. al, AJHG 2014
Trynka et. al, AJHG 2015
Liability threshold model
Al-Chalabi and Hardiman, Nat Rev Neurology 2013
Roep & Tree Nat Rev Imm 2014
Common and rare variant
hypotheses
GENETIC STUDY DESIGN
Family or cohort study?
Genetic data
SNP
Ind1
Ind2
Ind3
Ind4
1
AA
AG
AA
GG
2
TC
CC
CC
CC
3
GT
GG
TT
GG
4
AC
CC
AC
AC
5
AT
AA
TT
AA
Linkage analysis and TDT
Transmission
Disequilibrium
Test
Case/control association
• H0: Frequency of ‘A1’ is independent of case/control
status.
A1
A2
Cases
w
x
Controls
y
z
c2 = (O-E)2/E
[Pearson’s chi-Square]
Odds Ratio (OR): Odds of Allele
occurring in cases to the odds of
Allele occurring in controls:
w/x
y/z
=
wz
xy
Power
Small sample size
Large sample size
Freq
Freq
Cases
Controls
Cases
Controls
Regression analysis
• Analysis of the relationship between a dependent or outcome
variable (phenotype) with one or more independent or
predictor variables (SNP genotype)
Logistic Regression
ln( pi )
( 1 - pi )
= b 0 + b 1 Xi + e i
Continuous Trait Value
Linear Regression
Yi = b0 + b1Xi + ei
Slope: b1
b0
0
Pro tip Z2 = χ2
1
Number of A1 Alleles
2
QQ plot
P < 5e-8
Manhattan plot
DRILLING DOWN
http://www.ebi.ac.uk/fgpt/gwas/images/timeseries/gwas-latest.png
Effect sizes – T1D
Petretto, Liu and Aitman NG 2007
Maurano et al Science 2012
GWAS signals
are enriched in
tissue-specific
gene regulatory
sequence
Gusev et al ASHG 2014
Miki et al NG 2010
Fine mapping strategies
• If a SNP is causal, then r2
should predict association of
other SNPs in the area:
Kichaev et al. PLoS Genet. 2014
LD score
Bulik-Sullivan et al. NG 2015
Risk
variant
Molecular
trait
Cellular
trait
Disease
risk
RTC and CPSM in the CD58 Locus
6
5
3
eQTL
2
35
eqtl$BP
26
17
GWAS
9
10
gwas$BP
7
5
CPSM
2
1
pos$BP
0.75
0.5
RTC
0.25
116.5
116.63
116.75
116.88
tab$bps
117
Physical Position (Mbp)
117.13
117.25
117.38
117.5
Trait #2
M1 M2 M3 M4 M5
Trait #1
M1
M2
M3
M4
M5
GWAS
Distinct
eQTL
GWAS
eQTL
GWAS
eQTL
Shared
Shared
Number of loci
Densely
eQTL present 2
Driven by same effect 3
genotype
CD14
CD14
1
+
+
+
+
Disease
d
CD4
LCL Total CD4
LCL Total
MS
59
54
55
55
56
8
3
3
10
IBD
69
69
69
68
69
6
7
1
11
Crohn
19
18
18
18
18
2
1
0
3
UC
10
10
9
10
10
2
1
3
4
T1D
47
39
40
36
40
2
0
2
4
RA
34
34
34
34
34
1
0
0
1
CEL
34
34
34
34
34
3
1
0
4
Overall
272
258 259 255 261
24
13
9
37
* Excluding conditional hits
** Defined by immunochip's densely genotyped
fine-mapping intervals. Excluding MHC
*** Loosely identified by cis-eQTL signal within +/100kb from index SNPs. cis-eQTL is defined by the
association p-value < 0.05.
MS GWAS risk effect: NFKB1 locus
97 MS risk loci;
IMSGC, Nat Genet 2013
MS patients show altered NFκB
signaling in CD4+ T cells
Figure 1. Naïve CD4 cells from patients with MS
exhibit increased phospho-p65 NFκB. Flow
cytometry of PBMCs from age-matched healthy
+ T cells show
control
(HC) CD4
and relapsing-remitting
MS (RRMS)
ex vivo
higher
patients stained for CD4, CD45RA, CD45RO, and
p-p65
STM
2015)
pS529
p65 (Housley
NFκB. MFI of et
p65al,
results
are shown
gated on naïve CD4+CD45RA+CD45RO- T-cells.
CD4+ T cells from MS patients
proliferate more rapidly after
stimulus (Kofler et al JCI 2014)
MS risk effect near NFKB1 alters
signaling in CD4+ cells
Nuclear localization
rs228614
p= 0.037
p50 NFkB
30
20
10
0
Housley, STM 2015
GG
AA
p= 0.05
30
GG
AA
20
10
0
0
15
30
Minutes
GWAS loci harbor many NFκB
genes
Will Housley, David Hafler
Model: NFκB signaling variation
p50
External
stimulus
P-p50
p65
*NFκB
Activation
Proliferation
Survival
*NFκB
Activation
Proliferation
Survival
Broader
phenotype?
p50
P-p50
GV in NFκB pathway
New gene activation
patterns by NFκB
GV in NFκB TFBS
p65
IκB
p50
p65
Resting state
Stimulus
Phosphorylation
Nuclear translocation
P
rs228614-A
carriers
Low cytoplasmic NFκB
Gene
activation
P
Low levels
P
Moderate transcription
P
rs228614-G
carriers
P
High cytoplasmic NFκB
P
P
P
High levels
High activation threshold
Moderate proliferation
Distinct CD4+ subset fates
P
High transcription
P
Cell
phenotype
P
Other target activation
Low activation threshold
High proliferation
Plastic CD4+ subset fates