Mapping pathogenic regulatory regions and genes Chris Cotsapas - - PowerPoint PPT Presentation

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Mapping pathogenic regulatory regions and genes Chris Cotsapas - - PowerPoint PPT Presentation

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Mapping pathogenic regulatory regions and genes Chris Cotsapas Yale/Broad Mapping pathogenic regulatory regions Chris Cotsapas Yale/Broad Mapping pathogenic regulatory regions Chris Cotsapas Yale/Broad cotsapaslab.info/positions

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SLIDE 1

Mapping pathogenic regulatory regions and genes

Chris Cotsapas Yale/Broad

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SLIDE 2

Mapping pathogenic regulatory regions

Chris Cotsapas Yale/Broad

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SLIDE 3

Mapping pathogenic regulatory regions

Chris Cotsapas Yale/Broad cotsapaslab.info/positions

http://biorxiv.org/content/early/2016/05/19/054361

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SLIDE 4
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SLIDE 5

Common risk variants localize to DHS

Maurano et. al, Science 2012 Gusev et. al, AJHG 2014 Trynka et al, AJHG 2015

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SLIDE 6

Regulatory fine-mapping model

SNPs% DHS%Clusters% Genes% DHS1% DHS2% Gene1% Gene2% Gene3% DHS1% Gene3%

Per3DHS%posterior%probability% Normalized%correla>on% coefficient% Per3gene%posterior%probability% Per3SNP%posterior%probability%

βd,g

ρd = X

s∈CI

PPs × Od(s)

γg = X

d∈D

ρd × βd,g

CI

PPs × Summary%P%values%from%gene>cs% associa>on%data%

  • ●
  • ●
  • ●
  • 2

4 6 90.50 90.75 91.00 91.25 91.50 Position on Chromosome (Mbp) −log10(P)

Posterior(Probability( Associa/on((PPs)(

0.0 0.1 0.2 0.3 0.4

  • bability of Association

0" 0.1" 0.2" 0.3" 0.4"

Posi%on'on'Chromosome'(Mbp)' Posterior'Probability'of' Associa%on'(PPs)'

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SLIDE 7

56 x 2 DHS REP tissues Markov Clustering Hotspot - Peak Calling DHS peaks for 112 samples 1,994,675 DHS clusters Replication Test

Aligning DHSs Over Cell Types

Foreskin_Keratinocyte Foreskin_Fibroblast Pancreas H9 H1_Neuronal_Progenitor H1_Mesenchymal H1_BMP4_Trophoblast H1_BMP4_Mesendoderm H1 Gastric Skin_Upper_Back Skin_Scalp Skin_Quadriceps_Right Skin_Quadriceps_Left Skin_Biceps_Right Skin_Biceps_Left Skin_Back Skin_Abdomen Testes Stomach Spinal_Cord Renal_Pelvis_Right Renal_Pelvis_Left Renal_Pelvis Renal_Cortex_Right Renal_Cortex_Left Renal_Cortex Placenta Kidney_Right Kidney_Left Kidney Intestine_Small Intestine_Large Heart Brain Adrenal_Gland Breast Muscle_Trunk Muscle_Leg Muscle_Back Muscle_Arm Lung_Right Lung_Left Lung Mobilized_CD4 Mobilized_CD3 Mobilized_CD34 IMR90 CD8 CD56 CD4 CD3 CD19 CD14 Thymus 0.0 0.2 0.4

Proportion of Heritability Cell Types

Status

Proportion of Heritability DHS_Peaks_Hotspot DHS_Clusters

1,079,138/1,994,675 clusters (~54%) pass QC 8% of genome (cf. 14% all peaks)

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SLIDE 8

Posterior probabilities of association

SNPs DHSs Gene s

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4 6 90.50 90.75 91.00 91.25 91.50 Position on Chromosome (Mbp) −log10(P)

Association Plot for rs72928038

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  • ●
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  • 2

4 6 90.50 90.75 91.00 91.25 91.50 Position on Chromosome (Mbp) −log10(P) 0.0 Posterior Probability of Association

0.0 0.1 0.2 0.3 0.4

  • bability of Association

DHS1 DHS2 Gene1 Gene2 Gene3 DHS1 Gene3

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SLIDE 9

10 20 30 39.47 39.97 40.47 40.97 41.47

Position on Chromosome 21 (Mbp) IBD GWAS −log10(P)

0.18 Posterior

DSCR4 DSCR8 KCNJ15 ERG ETS2 AF064858.6 PSMG1 WRB LCA5L SH3BGR B3GALT5 PCP4 DSCR4 DSCR8 KCNJ15 ERG ETS2 PSMG1 WRB SH3BGR B3GALT5 PCP4 1

DHS Gene DHS and Gene Correlation Gene Expression by DHS State

4 6 8 10 12 DHS1 DHS1 DHS1 DHS1 DHS1 DHS1 DHS1 DHS1 DHS1 DHS1 Absent Present

P Value of Correlation

0.98 0.11 0.69 0.3 0.23 0.92 0.37 0.19 0.66

*

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SLIDE 10

6 12 18 24 116.08 116.58 117.08 117.58 118.08

Position on Chromosome 1 (Mbp) MS GWAS −log10(P)

0.77 Posterior

VANGL1 CASQ2 NHLH2 SLC22A15 MAB21L3 ATP1A1 CD58 IGSF3 CD2 PTGFRN TTF2 TRIM45 MAN1A2 VANGL1 CASQ2 SLC22A15 MAB21L3 ATP1A1 CD58 CD2 PTGFRN TTF2 MAN1A2 1 2

DHS Gene DHS and Gene Correlation Gene Expression by DHS State

5 7 9 11 13 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 Absent Present

P Value of Correlation

0.73 0.15 0.69 0.78 0.95 0.54 0.06 0.99 0.52 0.7 0.04 0.08 0.17 0.38 0.56 0.21 0.46 0.59 0.44 0.81

*

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SLIDE 11

2 4 6 85.02 85.52 86.02 86.52 87.02

Position on Chromosome 16 (Mbp) RA GWAS −log10(P)

0.36 Posterior

ZDHHC7 KIAA0513 LINC00311 GINS2 C16orf74 COX4NB COX4I1 IRF8 FOXC2 FOXL1 ZDHHC7 KIAA0513 LINC00311 GINS2 C16orf74 COX4NB COX4I1 IRF8 FOXC2 FOXL1 1 2 3 4 5

DHS Gene Gene Expression by DHS State

6 8 10 12 DHS1 DHS2 DHS3 DHS5 DHS1 DHS2 DHS3 DHS5 DHS1 DHS2 DHS3 DHS5 DHS1 DHS2 DHS3 DHS5 DHS1 DHS2 DHS3 DHS5 DHS1 DHS2 DHS3 DHS5 DHS1 DHS2 DHS3 DHS5 DHS1 DHS2 DHS3 DHS5 DHS1 DHS2 DHS3 DHS5 DHS1 DHS2 DHS3 DHS5 DHS State Absent Present

P Value

0.09 0.12 0.53 0.16 0.04 0.08 0.23 0.26 0.35 0.93 0.91 0.07 0.38 0.23 0.76 0.08 0.47 0.76 0.18 0.28 0.44 0.3 0.62 0.61 0.98 1 0.72 0.63 0.03 0.43 0.89 0.02 0.01 0.01 0.12 0.88 0.12 0.06 0.77

* * * * * *

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SLIDE 12
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  • DHS Clusters

1 2 3 4 5 10 20 50 200 1100 MS IBD RA CEL T1D JIA PSO AITD PBC Number of DHS Clusters (log scale)

A

  • Genes

Number of Genes (log scale)

B

1 2 3 4 5 10 20 40 65

  • Regulatory Potential Per Locus

0.2 0.4 0.6 0.8 1 MS IBD RA CEL T1D JIA PSO AITD PBC Total Posterior Probability Attributable to DHS Clusters

C

  • Posterior Probability of Association Per Gene

0.1 0.3 0.5 0.7 0.9 Normalized Posterior Probability of Association of the Top Genes

D

Allelic Imbalance in DHS Accessibility

Number of CI SNPs with Imbalanced DHS Accessibility (5% FDR) MS IBD RA CEL T1D JIA PSO AITD PBC 20 40 60 80 100 120

7e−03 1e−08 3e−02 3e−03 3e−02 4e−03 4e−03 8e−02 3e−01

E

Expected Observed

Tissue Activity of Prioritized DHS Clusters

P Value of Enrichment (−log10) MS IBD RA CEL T1D JIA PSO AITD PBC 5 10 15 20

F

Tissue Immune Non−Immune

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SLIDE 13
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4 6 90.0 90.5 91.0 91.5 Position on Chromosome (Mbp) −log10(P)

GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 Chromosome 6

BACH2 locus (chr6:91Mb) in MS

  • p=0.33

p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.33 p=0.43 p=0.43 p=0.43 p=0.43 p=0.43 p=0.43 p=0.43 p=0.43 p=0.43 p=0.43 p=0.43 p=0.43 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p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.12 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9 p=0.9

4 6 8 10 12

GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7

Genes Gene Expression

D7.Activity Absent Present

0.0 Posterior Probability of Association

0.0 0.1 0.2 0.3 0.4

  • bability of Association

D1 (0.07) D2 (0.003) D3 (0.003) D4 (0.003) D5 (0.002) D6 (0.002) D7 (0.48) D8 (0.005) D9 (0.005) D10 (0.02)

GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7

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SLIDE 14 2 4 6 89.81 90.31 90.81 91.31 91.81 Position on Chromosome 6 (Mbp) CEL GWAS −log10(P) 0.23 Posterior SRSF12 GABRR1 GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 SRSF12 GABRR1 GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 1 2 3 4 5 6 7 8 10 11 12 13 14 DHS Gene Gene Expression by DHS State 4 6 8 10 DHS2 DHS12 DHS13 DHS14 DHS2 DHS12 DHS13 DHS14 DHS2 DHS12 DHS13 DHS14 DHS2 DHS12 DHS13 DHS14 DHS2 DHS12 DHS13 DHS14 DHS2 DHS12 DHS13 DHS14 DHS2 DHS12 DHS13 DHS14 DHS2 DHS12 DHS13 DHS14 DHS State Absent Present P Value . 5 7 . 3 5 . 2 7 . 7 9 . 9 1 . 8 9 . 9 9 . 4 4 . 1 3 . 3 4 . 9 . 3 9 . 5 . 4 3 . 5 5 . 6 5 . 3 6 . 2 * . 1 9 . 2 1 . 8 . 7 4 . 9 3 . 3 * . 3 5 . 1 2 . 9 . 9 2 . 8 8 . 9 . 8 8 . 5 1 2 4 6 89.97 90.47 90.97 91.47 91.97 Position on Chromosome 6 (Mbp) IBD GWAS −log10(P) 0.59 Posterior GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 3 4 6 9 DHS Gene Gene Expression by DHS State 4 6 8 10 DHS9 DHS9 DHS9 DHS9 DHS9 DHS9 DHS State Absent Present P Value . 7 8 . 4 1 . 3 8 . 2 7 . 8 6 . 1 2 2 4 6 89.98 90.48 90.98 91.48 91.98 Position on Chromosome 6 (Mbp) MS GWAS −log10(P) 0.48 Posterior GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 2 3 4 6 7 8 10 11 12 13 14 15 DHS Gene Gene Expression by DHS State 4 6 8 10 DHS2 DHS12 DHS15 DHS2 DHS12 DHS15 DHS2 DHS12 DHS15 DHS2 DHS12 DHS15 DHS2 DHS12 DHS15 DHS2 DHS12 DHS15 DHS State Absent Present P Value . 1 2 . 3 3 . 1 3 . 5 1 . 4 3 . 2 6 . 3 5 . 2 * . 8 5 . 8 1 . 7 5 . 6 3 . 3 5 . 1 2 . 1 4 . 8 7 . 9 . 5 3 89.98 90.48 90.98 91.48 91.98 Position on Chromosome 6 (Mbp) T1D GWAS −log10(P) 0.85 Posterior GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 7 12 13 14 DHS Gene Gene Expression by DHS State 4 6 8 10 DHS12 DHS12 DHS12 DHS12 DHS12 DHS12 DHS State Absent Present P Value . 3 3 . 4 3 . 2 * . 7 5 . 1 2 . 9 2 4 6 89.98 90.48 90.98 91.48 91.98 Position on Chromosome 6 (Mbp) ATD GWAS −log10(P) 0.95 Posterior GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 2 12 15 DHS Gene Gene Expression by DHS State 4 6 8 10 DHS12 DHS12 DHS12 DHS12 DHS12 DHS12 DHS State Absent Present P Value . 3 3 . 4 3 . 1 * . 7 5 . 1 2 . 9 CEL IBD T1D ATD MS CEL IBD T1D ATD MS Traits Traits 0.4 0.8 Value Color Key

A" B" C" D" E" F"

IBD (MAP3K7)

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SLIDE 15

Concordance Discordance Jaccard Coefficient Most Associated SNPs 6 45 0.12 CI SNPs (mean) 6.8 31.16 0.21 Prioritized CI SNPs (mean) 2.2 9.47 0.25 Prioritized DHS Clusters (mean) 2.47 8.51 0.27 Prioritized Genes 16 35 0.31

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SLIDE 16

Concordance Discordance Jaccard Coefficient Most Associated SNPs 6 45 0.12 CI SNPs (mean) 6.8 31.16 0.21 Prioritized CI SNPs (mean) 2.2 9.47 0.25 Prioritized DHS Clusters (mean) 2.47 8.51 0.27 Prioritized Genes 16 35 0.31 Fisher’s exact test P = 0.001

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SLIDE 17