The common architecture of autoimmune disease

The genetics of autoimmunity Chris Cotsapas MGH/Broad chrisc@chgr.mgh.harvard.edu

March 2008

See also Zhernakova, van Diemen and Wijmenga NRG 2009.

Co-occurrence in Denmark T1D Celiac MS CD Ps RA SLE T1D -- 108 147 217 442 616 46 Celiac 4.2 -- 6 101 13 21 3 MS 1.2 1.0 -- 36 39 43 14 CD 1.7 16.7 1.2 -- 95 148 13 Ps 3.2 2.3 1.4 3.3 -- 372 19 RA 1.9 1.7 0.8 2.8 6.4 -- 226 SLE 2.2 2.7 2.5 2.5 4.1 24.0 -- Lower tri is pairwise OR Upper tri is overlapping cases condensed from Eaton et al J Autoimm 2007

Systematically test genetic overlaps • Independent discovery implies false negatives • Compile multiple GWAS – Cross-phenotype “meta” analysis

Participating studies Disease Study Cases Controls Celiac Disease 778 3000 † Crohn's Disease IBDGC 3230 4829 †† Multiple Sclerosis IMSGC 1851 4900 †† Psoriasis CASP 1359 1400 Rheumatoid Arthritis EIRA 660 658 NARAC 873 1196 WTCCC 1860 10606 †† 3398 12460 Type I Diabetes WTCCC 2800 3000 †† FOCiS NoC † includes 1958 Birth Cohort †† includes 3K WTCCC

Locus selection • Replicated GWAS hit (03/2008) – Combined p < 5 x 10-7 • Not in the MHC! – Extensive LD structure in region • Sufficient data for 43 of 48 loci – Others not captured across platforms

How to analyze across diseases? Celiac Crohn’s MS Psoriasis RA T1D 0.5 1 x 10-20 0.46 0.98 0.7 0.35 0.04 0.0009 0.9 0.006 0.03 0.02 0.76 0.04 0.54 0.38 0.04 0.02 with Ben Voight

Binning p-values P value range Bin Probability 1 – 0.05 0 0.95 0.05 – 0.001 1 0.049 0.001 – 1x10-6 2 9 x 10-4 < 1x10-6 3 9 x 10-7 with Ben Voight

How to analyze across diseases? Celiac Crohn’s MS Psoriasis RA T1D 0.5 1 x 10-20 0.46 0.98 0.7 0.35 0.04 0.0009 0.9 0.006 0.03 0.02 0.76 0.04 0.54 0.38 0.04 0.02 with Ben Voight

How to analyze across diseases? Celiac Crohn’s MS Psoriasis RA T1D 0 3 0 0 0 0 1 3 0 1 1 1 0 1 0 0 1 1 with Ben Voight

CPMA SNP 0 1 2 3 statistic rs2076756 4 1 0 0 1.44 rs1464510 4 1 0 0 1.44 rs6441961 4 1 0 0 1.44 rs2188962 4 1 0 0 1.44 rs4613763 4 1 0 0 1.44 rs3761847 4 1 0 0 1.44 rs12251307 4 1 0 0 1.44 rs4963128 5 1 0 0 1.14 rs9888739 5 1 0 0 1.14 rs844644 6 0 0 0 0.62 rs30187 6 0 0 0 0.62 rs11264798 6 0 0 0 0.62 rs1990760 5 0 0 0 0.51 rs7574865 5 0 0 0 0.51 rs2241880 5 0 0 0 0.51 rs17810546 5 0 0 0 0.51 rs3924462 5 0 0 0 0.51 rs11747270 5 0 0 0 0.51 rs1445898 5 0 0 0 0.51 rs4263839 5 0 0 0 0.51 rs2024092 5 0 0 0 0.51

CPMA SNP 0 1 2 3 statistic rs11209032 3 1 0 2 49.46 rs6679677 3 0 1 1 32.25 rs17388568 2 1 2 0 23.32 rs17696736 1 3 1 0 22.51 rs2542151 3 0 2 0 21.21 PCPMA < 0.01 rs12722489 2 3 0 0 11.57 rs6822844 2 3 0 0 11.57 expect 0 by chance rs2816316 3 1 1 0 10.65 rs12708716 3 1 1 0 10.65 rs3087243 3 1 1 0 10.65 rs10045431 3 1 1 0 10.65 rs6920220 3 1 1 0 10.65 rs11465804 4 0 1 0 9.22 rs917997 4 0 1 0 9.22 rs10499194 4 0 1 0 9.22 rs13277113 5 0 1 0 8.92 rs11190140 3 2 0 0 5.64 rs10995271 3 2 0 0 5.64 rs2292239 3 2 0 0 5.64 rs6897932 3 2 0 0 5.64 rs1738074 3 2 0 0 5.64

Patterns in association across diseases Celiac Crohn’s MS Psoriasis RA T1D 0 3 0 0 0 0 1 3 0 1 1 1 0 1 0 0 1 1

Disease categories P < 1e-6 1e-6 < P < 1e-3 1e-3 < P < 0.05 0.05 < P < 0.95 1e-3 < P < 0.05 1e-6 < P < 1e-3

P < 1e-6 1e-6 < P < 1e-3 1e-3 < P < 0.05 0.05 < P < 0.95 1e-3 < P < 0.05 1e-6 < P < 1e-3

Celi CD MS Psor RA T1D 0.69 1.68 2.03 1.43 1.46 6.50 2.17 2.54 1.01 1.43 5.10 5.00 3.36 2.01 1.15 0.91 1.82 0.97 0.62 6.21 2.68 2.50 1.61 1.11

• Are these groups meaningful? – molecular processes – “mechanisms” • If so, might expect proteins in loci to interact – snp-snp distances should correlate – ppi paths should be short

Assessing locus protein connection L1 0.2 0.75 1.0 0.3 0.78 0.68 L2 0.4 0.1 0.4 0.98 with Kasper Lage and Lizzy Rossin

SNP-SNP distance correlation DZ DPPI 1 1 0.3 1 0.4 1 0.6 0.7 1 0.4 0.8 1 with Kasper Lage, Lizzy Rossin and Anthony Philippakis

with Kasper Lage and Lizzy Rossin

Celi CD MS Psor RA T1D 0.69 1.68 2.03 1.43 1.46 6.50 2.17 2.54 1.01 1.43 5.10 5.00 3.36 2.01 1.15 0.91 1.82 0.97 0.62 6.21 2.68 2.50 1.61 1.11

Genome-wide data • Define functional clusters – Complete – Accurate – Interpretable • Define sets of diseases with shared liability – Set-specific mechanisms – Leverage power for new insight – Mechanistic hypotheses

Joint analysis: Crohn’s and MS • Epidemiologically linked • Minuk & Lewkonia 86, Sadovnick et al 89 • GWAS meta-analysis data: – Barrett et al 2008 – De Jager et al 2009 • Criteria – Joint p < 1 x 10-5 – Per-disease p < 0.01 – Consistent effects

CHR BP SNP JointP clumpSNPs CD.P MS.P Direction Genes (100kb window) 1 67437141 rs10889677 3.20E-19 15 1.33E-21 0.00177 ++ IL23R 1 197613252 rs7522462 7.73E-09 24 8.31E-06 0.000208 -- C1ORF106 2 61129193 rs10188217 2.32E-06 16 2.66E-05 0.0132 -- PUS10 2 230983017 rs6710297 3.03E-07 7 0.000124 0.000663 -- SP140 4 42949449 rs1436475 9.65E-06 24 0.0206 8.10E-05 -- 4p13 4 47416600 rs6447568 2.12E-06 14 0.000392 0.00157 ++ ATP10D/KIAA1487 5 40437266 rs17234657 5.75E-17 2 2.87E-19 0.00418 -- PTGER4 5 40473705 rs9292777 3.85E-23 24 3.42E-19 4.25E-07 ++ PTGER4 5 40534334 rs1505992 4.18E-10 27 4.96E-11 0.0236 -- PTGER4 5 158615778 rs254837 1.69E-07 3 0.00123 3.09E-05 ++ UBLCP1/RNF145/IL12B 5 159062555 rs16750 5.15E-06 9 2.46E-05 0.0258 ++ 5q33 9 547340 rs10975130 4.72E-06 20 0.0558 5.11E-06 -- KANK1 9 4971602 rs10758669 1.88E-08 32 3.94E-06 0.000846 -- JAK2 10 6142018 rs12722489 1.11E-06 6 0.00922 1.82E-05 -- IL2RA 10 101314426 rs1332102 1.20E-08 18 3.04E-08 0.0117 -- NKX2.3 11 60570507 rs12276967 1.62E-06 10 0.0134 1.64E-05 ++ CD6 * 16 11260805 rs243327 9.27E-06 17 0.00203 0.00145 ++ SOCS2/C16ORF75/TNP2/PRM2/PRM1/PRM3 16 11311394 rs12928822 6.16E-06 17 0.000362 0.0047 -- SOCS2/C16ORF75/TNP2/PRM2/PRM1/PRM3 16 47211576 rs1872656 3.23E-07 1 0.000352 0.00026 ++ N4BP1 16 84549206 rs11642873 8.44E-08 8 1.11E-05 0.00146 ++ IRF8 * 17 9529440 rs9906593 4.49E-06 7 0.0039 0.000316 -- WDR16/USP43 17 35294289 rs2872507 6.70E-07 15 1.06E-05 0.0087 ++ IKZF3/ZPBP2/GSDMB/ORMDL3 20 44188518 rs3746821 1.81E-06 9 0.00132 4.00E-04 ++ CD40

Acknowledgements Mark Daly Goncalo Abecasis Ben Voight Jeff Barrett Elizabeth Rossin Judy Cho Kasper Lage JT Elder Ben Neale Michel Georges Anthony Philippakis Peter Gregersen David van Heel David Hafler Lars Klareskog Steve Rich Leonid Padyukov Robert Plenge Cristin Aubin Soumya Raychaudhuri Phil de Jager John Rioux John Todd Sarah Krause Cisca Wijmenga

TH17 cell involvement in MS? IL12 B NKX2.3 IL12B IL23R JAK2 STAT3

Analysis! Celiac Crohn’s MS Psoriasis RA T1D CPMA 0.5 1e-20 0.46 0.98 0.7 0.35 No 0.05 1e-3 0.9 0.006 0.05 0.02 Yes 0.76 0.05 0.54 0.38 0.04 0.06 Yes

12/19 loci P ~ 1e-3 connected P ~ 4.3e-3 P ~ 0.057 P ~ 7.8e-4 with Kasper Lage and Lizzy Rossin

The common architecture of autoimmune disease

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