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

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

Common risk variants localize to DHS Maurano et. al, Science 2012 Gusev et. al, AJHG 2014 Trynka et al, AJHG 2015

Regulatory fine-mapping model ● 6 Posterior(Probability( Posterior'Probability'of' Associa/on((PP s )( ● ● ● ● Associa%on'(PP s )' ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● obability of Association ● ● ● ● ● 4 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0" 0.1" 0.2" 0.3" 0.4" ● − log 10 (P) 0.0 0.1 0.2 0.3 0.4 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● Summary% P %values%from%gene>cs% ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●● ● ● ● ● associa>on%data% ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 ● ● ● ● ● ● ● ● ● ● ● ● ● 90.50 90.75 91.00 91.25 91.50 Posi%on'on'Chromosome'(Mbp)' Position on Chromosome (Mbp) Per3SNP%posterior%probability% PP s × SNPs% CI X Per3DHS%posterior%probability% ρ d = PP s × O d ( s ) DHS1% DHS1% DHS2% DHS%Clusters% s ∈ CI Normalized%correla>on% β d,g coefficient% X γ g = ρ d × β d,g Per3gene%posterior%probability% Genes% Gene1% Gene2% Gene3% Gene3% d ∈ D

Aligning DHSs Over Cell Types Proportion of Heritability Thymus CD14 56 x 2 DHS REP tissues CD19 CD3 CD4 CD56 CD8 IMR90 Hotspot - Peak Calling Mobilized_CD34 Mobilized_CD3 Mobilized_CD4 Lung Lung_Left Lung_Right Muscle_Arm DHS peaks for 112 samples Muscle_Back Muscle_Leg Muscle_Trunk Breast Adrenal_Gland Brain Markov Clustering Heart 1,079,138/1,994,675 clusters Intestine_Large Intestine_Small Kidney Cell Types (~54%) pass QC Kidney_Left Status Kidney_Right 1,994,675 DHS clusters Placenta Renal_Cortex Renal_Cortex_Left Renal_Cortex_Right 8% of genome (cf. 14% all peaks) Renal_Pelvis DHS_Peaks_Hotspot Renal_Pelvis_Left Replication Test Renal_Pelvis_Right Spinal_Cord DHS_Clusters Stomach Testes Skin_Abdomen Skin_Back Skin_Biceps_Left Skin_Biceps_Right Skin_Quadriceps_Left Skin_Quadriceps_Right Skin_Scalp Skin_Upper_Back Gastric H1 H1_BMP4_Mesendoderm H1_BMP4_Trophoblast H1_Mesenchymal H1_Neuronal_Progenitor H9 Pancreas Foreskin_Fibroblast Foreskin_Keratinocyte 0.0 0.2 0.4 Proportion of Heritability

Posterior probabilities of association Association Plot for rs72928038 ● ● 6 6 Posterior Probability of Association ● ● ● 0.0 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● obability of Association ● ● ● ● ● ● ● ● 4 ● ● ● ● ● ● ● ● ● ● 4 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0.0 0.1 0.2 0.3 0.4 ● − log 10 (P) − log 10 (P) ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 2 2 ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ●● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● 0 0 ● ● ● ● ● ● ● ● ● ● ● 90.50 90.50 90.75 90.75 91.00 91.00 91.25 91.25 91.50 91.50 Position on Chromosome (Mbp) Position on Chromosome (Mbp) SNPs DHSs DHS1 DHS1 DHS2 Gene Gene1 Gene2 Gene3 Gene3 s

Position on Chromosome 21 (Mbp) 39.47 39.97 40.47 40.97 41.47 30 Posterior 0.18 IBD GWAS − log10(P) 20 10 0 0 DSCR8 ERG AF064858.6 WRB SH3BGR PCP4 DSCR4 KCNJ15 ETS2 PSMG1 LCA5L B3GALT5 DHS 1 DHS and Gene Correlation Gene DSCR4 DSCR8 KCNJ15 ERG ETS2 PSMG1 WRB SH3BGR B3GALT5 PCP4 12 Absent Gene Expression Present by DHS State 10 8 6 4 DHS1 DHS1 DHS1 DHS1 DHS1 DHS1 DHS1 DHS1 DHS1 DHS1 Correlation P Value of * 0.98 0.11 0.69 0.23 0.92 0.37 0.19 0.66 0.3 0

P Value of Gene Expression DHS and Gene MS GWAS Correlation by DHS State Correlation − log10(P) 11 13 12 18 24 5 7 9 0 6 Gene DHS 116.08 Present Absent VANGL1 VANGL1 0.73 DHS1 CASQ2 0.15 DHS2 NHLH2 CASQ2 0.69 DHS1 0.78 DHS2 SLC22A15 SLC22A15 116.58 0.95 DHS1 MAB21L3 0.54 DHS2 MAB21L3 0.06 DHS1 Position on Chromosome 1 (Mbp) 0.99 DHS2 ATP1A1 ATP1A1 0.52 DHS1 1 0.7 DHS2 117.08 CD58 IGSF3 2 * 0.04 DHS1 CD58 0.08 DHS2 CD2 0.17 DHS1 CD2 0.38 DHS2 PTGFRN 0.56 DHS1 PTGFRN 117.58 TTF2 TRIM45 0.21 DHS2 0.46 DHS1 TTF2 0.59 DHS2 0.44 DHS1 MAN1A2 MAN1A2 Posterior 0.81 DHS2 0 0.77 118.08

Position on Chromosome 16 (Mbp) 85.02 85.52 86.02 86.52 87.02 6 Posterior 0.36 RA GWAS − log10(P) 4 2 0 0 KIAA0513 GINS2 COX4NB IRF8 FOXL1 ZDHHC7 LINC00311 C16orf74 COX4I1 FOXC2 DHS 1 2 3 4 5 Gene ZDHHC7 KIAA0513 LINC00311 GINS2 C16orf74 COX4NB COX4I1 IRF8 FOXC2 FOXL1 12 DHS State Absent Gene Expression Present by DHS State 10 8 6 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 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 0.62 0.61 0.98 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 0.3 1 0