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Genetic and Epigenetic Analyses of Multiple Sclerosis

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Genetic and Epigenetic Analyses of Multiple Sclerosis Genetic and epigenetic analyses of multiple sclerosis Chris Cotsapas PhD Yale School of Medicine Stanley Center/Broad Institute [email protected] GWAS SNPs enriched in accessible chromatin Maurano et. al, Science 2012 Gusev et. al, AJHG 2014 Trynka et. al, AJHG 2015 IMSGC, Science, to appear IMSGC, Science, to appear Regulatory fine-mapping PositionPosition on Chromosome on Chromosome 1 (Mbp) 6 (Mbp) Position on Chromosome 1 (Mbp) Posi8on"on"Chromosome"1"(Mbp)" 116.08 89.98 116.5890.48 117.0890.98 117.5891.48 91.98118.08 116.08" 116.58" 117.08" 117.58" 118.08" 24 Posterior 0.77 2424" 6 Posterior 18 Position on Chromosome 1 (Mbp) 0.95 GWAS data 116.08 116.58 117.08 117.58 118.08 12 1818" log10(P) − MS GWAS 24 4 Posterior 6 1212" 0.77 log10(P) 18 Gene 1 Gene 2 Gene 3 0 − MS GWAS 0 log10(P) 12 P"Value"(/log10)" 6" log10(P) 6 − − MS GWAS 2 ATD GWAS ATD 6 0 0 00" 0 0 CASQ2 SLC22A15 ATP1A1 IGSF3 PTGFRN TRIM45 VANGL1 NHLH2 MAB21L3 CD58 CD2 TTF2 MAN1A2 DHS ρTotal'='0.988' 1 2 0.1'<'FDR' ρCD3+'='0.77' 0.05'<'FDR'≤'0.1' per-SNP posteriors ' FDR'≤'0.05'' CI SNPs Gene VANGL1 CASQ2 NHLH2 SLC22A15 MAB21L3 ATP1A1 CD58 IGSF3 CD2 PTGFRN TTF2 TRIM45 MAN1A2 DHS ​�↓� Per-DHS posterior probability in tissue t 13 DHS State Absent Present 11 9 7 ​�↓�,� DHS State by Correlation between DHS d and gene g Gene Expression 5 ​�↓� = ∑�∈�↑▒​�↓� ×​�↓�,� DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 Association posterior transmitted to gene g in 0.73 0.15 0.69 0.78 Gene 1 0.42 0.53 0.95 0.54 0.06 0.99 0.52 0.7 Gene 2 0.04* 0.08 0.29 0.29 0.17 0.38 0.56Gene 3 0.21 0.46 0.59 0.29 0.55 0.44 0.81 tissue t P Value Shooshtari et al AJHG 2017 Aligning DHSs Over Cell Types 56 x 2 DHS REP tissues Hotspot - Peak Calling DHS peaks for 112 samples Markov Clustering 1,079,138/1,994,675 clusters (~54%) 1,994,675 DHS clusters pass QC 8% of genome (cf. 14% all peaks) Replication Test A' Position on Chromosome 1 (Mbp) 116.08 116.58 117.08 117.58 118.08 24 Posterior 0.77 18 12 log10(P) − MS GWAS 6 0 0 CASQ2 SLC22A15 ATP1A1 IGSF3 PTGFRN TRIM45 VANGL1 NHLH2 MAB21L3 CD58 CD2 TTF2 MAN1A2 B' CD3+' DHS ρTotal'='0.988' 1 2 0.1'<'FDR' ρCD3+'='0.77' 0.05'<'FDR'≤'0.1' ' FDR'≤'0.05'' CD3+' Gene VANGL1 CASQ2 NHLH2 SLC22A15 MAB21L3 ATP1A1 CD58 IGSF3 CD2 PTGFRN TTF2 TRIM45 MAN1A2 C' 13 DHS State Absent Present 11 9 7 by DHS State by Gene Expression 5 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 DHS1 DHS2 0.73 0.15 0.69 0.78 0.42 0.53 0.95 0.54 0.06 0.99 0.52 0.7 0.04* 0.08 0.29 0.29 0.17 0.38 0.56 0.21 0.46 0.59 0.29 0.55 0.44 0.81 P Value A% Position on Chromosome 6 (Mbp) 89.98 90.48 Position on Chromosome90.98 6 (Mbp) 91.48 91.98 Position on Chromosome 1 (Mbp) 89.98 90.48 Position on Chromosome90.98 6 (Mbp) 91.48 91.98 A% 6 Posterior 116.08 116.58 117.08 117.58 118.08 0.95 89.98 90.48 Position on Chromosome90.98 6 (Mbp) 91.48 91.98 Posterior Position on Chromosome 1 (Mbp) 4 0.85 6 89.98 90.48 Position on Chromosome90.98 6 (Mbp) 91.48 91.98 6 Posterior Posterior 24 116.08 116.58 117.08 117.58 118.08 Posterior0.95 log10(P) 0.95 89.98 0.77 90.48 90.98 91.48 0.480.8591.98 − 2 Position on Chromosome 6 (Mbp) ATD GWAS ATD 3log10(P)% Posterior AITD%GWAS% 4 18 4 0.85 log10(P) 4 6 89.98 90.48 Position on Chromosome90.98 6 (Mbp) 91.48 0 91.98 − T1D GWAS 06 Posterior Posterior 24 Posterior0.48 log10(P) 89.98 90.48 90.98 91.48 0.9591.98 12 log10(P) 0.85 log10(P) 0.77 0.48 log10(P) 0 − 2 − 2 − − log10(P) ATD GWAS ATD 3log10(P)% MS GWAS ATD GWAS ATD RRAGD GJA10 MAP3K7 T1D GWAS 04 Posterior AITD%GWAS% 4 − 18 MS GWAS 0.85 log10(P) 4 log10(P) 6 0 6 0 − − T1D GWAS T1D GWAS 0 GABRR2RRAGD MDN1 GJA10 BACH2 MAP3K7 Posterior 0 0 0.48 log10(P) 12 log10(P) log10(P) 2 log10(P) 2 0 0 B% − − 2 MS GWAS − − log10(P) MS GWAS ATD GWAS ATD RRAGD GJA10 MAP3K7 T1D GWAS 04 GABRR2RRAGD MDN1 GJA10 BACH2 MAP3K7 − MS GWAS Position on Chromosome 6 (Mbp) log10(P) ρ %=%0.95% 6 AITD% AITDDHS 1 2 3 4 5 6 7 8 9 10 11 12 13 14 150 CASQ2 SLC22A15 ATP1A1 IGSF3 PTGFRN TRIM45 − T1D GWAS %0 GABRR2RRAGD MDN1 GJA10 BACH2 MAP3K7 0 GABRR289.97 0 MDN190.47 PositionPositionBACH2 onon ChromosomeChromosome90.97 66 (Mbp)(Mbp) 91.47 91.97 log10(P) Position on Chromosome 6 (Mbp) T1D% ρ2T1D%=%0.86% 1 2 3 4 5 6 7 8 9 10 11 12 13 14 150 0 B% − DHS VANGL1 NHLH2 MAB21L3 CD58 CD2 TTF2 MS GWAS %0 MAN1A2RRAGD GJA10 MAP3K7 GABRR289.9789.8189.98 RRAGD MDN190.4790.3190.48 GJA10PositionPositionPositionPosition onPositionPositionPosition on PositionChromosome BACH2on Chromosome on Chromosome onononChromosome on ChromosomeChromosomeChromosome Chromosome90.9790.8190.98 6 (Mbp)6 (Mbp)6 6(Mbp) (Mbp) 666 (Mbp)(Mbp)(Mbp)6 (Mbp)MAP3K7 91.4791.3191.48 91.9791.8191.98 AITD% ρAITDDHS%=%0.95% 1 2 3 4 5 6 7 8 9 10 11 12 13 14 150 CASQ2 SLC22A15 ATP1A1 IGSF3 PTGFRN TRIM45 MS% ρMS%=%0.58%DHS 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Posterior15 %0 GABRR289.81 RRAGD MDN190.31 GJA10 BACH2 90.81 MAP3K7 91.31 0.5991.81 89.9889.98%689.9889.98GABRR289.9789.8189.9889.98 90.4890.4890.48MDN190.4890.4790.3190.4890.48 PositionPositionBACH290.98 on90.98on90.98 ChromosomeChromosome90.9890.9790.8190.9890.98 66 (Mbp)(Mbp) 91.4891.4891.4891.4891.4791.3191.4891.48 91.9891.9891.9891.9891.9791.8191.9891.98 T1D% ρ6T1D%=%0.86% 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 ρ '='0.988' DHS 1 2 3 4 5 6 7 8 9 10 11 12 13 14 PosteriorPosterior15 DHS Total 1 2 0.1'<'FDR'Gene RRAGD GABRR2 RRAGDGJA10 MDN1 GJA10 MAP3K7 BACH2 MAP3K7 0.59 VANGL1 NHLH2 MAB21L3 CD58 CD2 TTF2 %6 GABRR289.9789.8189.98MAN1A2 MDN190.4790.3190.48 BACH2 90.9790.8190.98 91.4791.3191.48 0.230.8591.9791.8191.98 4 PositionPositionPositionPosition onPositionPositionPosition on PositionChromosome on Chromosome on Chromosome onononChromosome on ChromosomeChromosomeChromosome Chromosome 6 (Mbp)6 (Mbp)6 6(Mbp) (Mbp) 666 (Mbp)(Mbp)(Mbp)6 (Mbp) ρCD3+'='0.77' 0.05'<'FDR'≤'0.1'66 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 6 6 MS%6 6 ρ6MS%=%0.58%6DHS 1 2 3 4 5 6 7 8 9 10 11 12 13 Posterior14PosteriorPosteriorPosteriorPosteriorPosteriorPosteriorPosterior15 ' FDR'≤'0.05''4 GeneGABRR289.81 GABRR2 MDN190.31RRAGD BACH2MDN1 90.81 GJA10 BACH291.31 MAP3K7 0.950.950.950.950.230.590.230.9591.810.95 89.98log10(P) 89.98% 89.9889.9889.8189.9889.98 90.4890.4890.4890.4890.3190.4890.48 90.9890.9890.9890.9890.8190.9890.98 91.4891.4891.4891.4891.3191.4891.48 91.9891.9891.9891.9891.8191.9891.98 106 DHS State − 4 IBD GWAS 26 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 ρ '='0.988' 1 2 4 DHSAbsent PosteriorPosterior DHS Total 0.1'<'FDR'4 Gene GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 0.590.85 4 4 AITD%4 4log10(P) 4 4Gene GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 0.23 log10(P) Gene GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 log10(P) 6 GenePresent 0 − 1024 DHS State ρ '='0.77' − 6 CD3+ 0.05'<'FDR'≤'0.1'− 6 IBD GWAS 2 1 2 3 4 5 6 7 8 9 10 11 12 13 14 Posterior15 T1D GWAS DHS 6 6 CEL GWAS 6 6 06 6 PosteriorPosteriorPosteriorPosteriorPosteriorPosteriorPosterior FDR'≤'0.05''84 Absent GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 0.23 ' log10(P) Gene GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 0.950.950.950.950.230.950.95 log10(P) Gene log10(P) log10(P) log10(P) log10(P) log10(P) log10(P) T1D%log10(P) 102 Present 00 − 2 DHS State 0 − 4 − − − − − − 2 2 2 2− 102 2DHS State IBD GWAS CEL GWAS 2 DHS State ATD GWAS ATD ATD GWAS ATD ATD GWAS ATD GWAS ATD GWAS ATD GWAS ATD Gene VANGL1 CASQ2 NHLH2 SLC22A15 MAB21L3 ATP1A1 CD58 IGSF3 CD2 PTGFRN TTF2 CEL GWAS TRIM45040 Absent MAN1A2RRAGD GJA10 MAP3K7 MS% 4 GeneAbsent GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 4 4 AITD%4 4log10(P) 84 4Gene GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 log10(P) Gene GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 log10(P) GenePresent 0 0 0 0 000 0 − 102 PresentDHS State − − DHS State IBD GWAS 2 T1D GWAS 0 0 0 CEL GWAS 0 0 6000 0 GABRR2GABRR1RRAGD RRAGD MDN1 GJA10 GJA10BACH2 MAP3K7 MAP3K7 8 Absent log10(P) Gene GABRR2 RRAGD MDN1 GJA10 BACH2 MAP3K7 log10(P) log10(P) log10(P) log10(P) log10(P) log10(P) T1D%log10(P) 8 82 Present 00 − 13 DHS State DHS State by 102 0 − − − − − − 2 2C%2 2− 102 2DHS State CEL GWAS DHS State ATD GWAS ATD ATD GWAS ATD ATD GWAS ATD GWAS ATD GWAS ATD GWAS ATD VANGL1 CASQ2 NHLH2 SLC22A15 MAB21L3 ATP1A1 CD58 IGSF3 CD2 PTGFRN TTF2 CEL GWAS TRIM450 RRAGDMAN1A2GABRR1RRAGDRRAGD RRAGD GJA10 GJA10GJA10 GJA10 MAP3K7MAP3K7MAP3K7MAP3K7MAP3K7MAP3K7MAP3K7 MAP3K7MAP3K7 Gene Gene Expression 600 RRAGDGABRR2RRAGDRRAGDGABRR1RRAGD RRAGD MDN1GJA10GJA10GJA10GJA10 GJA10BACH2 Absent MS% GeneAbsentSRSF12GABRR2 GABRR2GABRR2 MDN1 RRAGDMDN1 BACH2MDN1 BACH2 GJA10 BACH2 MAP3K7 8 Present 0 Present IBD% 10ρIBD%=%0.59%DHSPresent 1 2 3 4 5 6 7 8 9 10 11 12 13 14 0 0 0 01500 0 by DHS State by 4 DHS State 11 0 0 GABRR20 0GABRR2%GABRR26000 GABRR20 SRSF12SRSF12GABRR2GABRR2GABRR2GABRR1RRAGDGABRR2GABRR2RRAGDMDN1MDN1MDN1MDN1MDN1MDN1MDN1 GJA10MDN1MDN1BACH2BACH2BACH2GJA10BACH2BACH2BACH2BACH2 BACH2BACH2 MAP3K7 MAP3K7 Gene Expression 6 Absent 86 8 Present 13 DHS State C%CEL% DHS State by 10ρ %=%0.21%DHSDHS State 11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515 by DHS State by CEL DHS by DHS State by 4 by DHS State by RRAGDGABRR1RRAGD RRAGD GJA10 GJA10 GJA10 MAP3K7MAP3K7MAP3K7MAP3K7MAP3K7MAP3K7 MAP3K7MAP3K7 Absent Gene Expression 6 RRAGDAbsentSRSF12GABRR2RRAGDRRAGDGABRR1RRAGDGABRR2RRAGD MDN1GJA10GJA10GJA10MDN1GJA10 GJA10BACH2 BACH2 Gene Expression Gene Expression % DHS2 DHS9 DHS2 DHS9 DHS2 DHS9 DHS2 DHS9 DHS2 DHS9 DHS2 DHS9 Gene Expression 8 DHS12 DHS12 DHS12 DHS12 DHS12 DHS12 9 Present IBD% ρIBD%=%0.59%DHSPresent1 1 1 1 1121 12 2 2 222 32 3 34 3 4 3334 34 4544 45 56 56 5565 65 666 76 7 7 7 777 87 8 8 89 8988 98 910 91099 109111011101010111011
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