common genetic association in autoimmune diseases

Converging on a theme:autoimmune genetic architecture

across diseases

Chris Cotsapas PhDDaly Lab

MGH/Broad Institute

cotsapas@broad.mit.edubroad.mit.edu/~cotsapas/autoimm.html

Acknowledgements

Mark Daly

Steve RichDavid Hafler

Sarah Krause

John ToddJeff Barrett

Tim BehrensRob Graham

John HarleyCarl Langefeld

Pat GaffneyKathy Moser

JT ElderGoncalo Abecasis

Peter GregersenLars KlareskogLeonid PadyukovRobert Plenge

David van Heel

Judy ChoMichel GeorgesJohn Rioux

Chris Amos

Familial aggregation of autoimmunity

SLE/T1D/RA/Hashimoto (Criswell et al 05)

PTPN22 (protective for others?)

RA/T1D/AITD (Torfs et al 86; Lin et al 98)

SLE/RA (Alarcon-Segovia et al 05)

AITD (Marwaha et al 03)

Autoimmune Disease Db (Karopka et al 06)

IBD/GD/Psor/AS

Autoimmune associations

Genes common to >1 disease

Motivations

Over-arching theme Cohort and GWAS availability Low power (as yet) Potential for signal boosting

Auto-immune GWAS RA

BRASS

NARAC/EIRA

WTCCC MS

IMSGC SLE

SLEGEN

Genentech

MNSLE

Crohn's

NIDDK

WTCCC

Liege Type I diabetes

WTCCC Psoriasis

GAIN

Bowcock et al AS

AAASC

Cases ControlsMS 1851 4900 †

Ps 1359 1400RA 3398 4856 †

T1D 2800 3000 †

SLE 2462 8015 *†‡

CelD 778 3000IBD 3230 4829 †

* 2185 unique cases† includes 3K WTCCC controls‡ approx 4K unique controls

FOCiS/NOC meta-analysis

Locus selection

Replicated GWAS hit Combined p < 5 x 10-7

Not in the MHC! Extensive LD structure in region

52 loci 216 proxy SNPs on common platforms

Data collection

Participant studies share genotype counts Imputed genotypes (if available) No overlapping cases Shared controls can be a problem Calculate association as (meta) Z score

directional

Discovery Gene Genotyped T1D RASNP SNP P P

rs6679677 PTPN22 rs6679677 2e-23 9e-48rs1230666 2e-17 1e-30rs2488457 6e-13 3e-19

rs1990760 IFIH1 rs13023380 8e-03 5e-01rs7608315 2e-02 3e-01

rs3087243 CTLA4 rs3087243 4e-05 7e-05rs11571293 1e-04 2e-04rs11571304 6e-05 3e-04rs6748358 1e-03 3e-01rs7596727 1e-02 2e-03

rs17388568 Tenr-IL2 rs17388568 1e-07 5e-03rs6897932 IL7R rs6897932 9e-03 7e-02

rs6881706 1e-02 8e-02rs11746643 6e-02 1e-01rs13436926 4e-02 8e-02rs10040617 1e-01 1e-01

rs1445898 CAPSL rs1025039 5e-05 1e-01rs4024109 7e-05 4e-01

rs12251307 IL2R rs12251307 4e-05 4e-01rs2292239 ERBB3 rs2292239 1e-09 4e-02

rs705698 2e-06 2e-02rs11171739 2e-11 1e-02

rs12708716 KIAA0350 rs12708716 7e-08 2e-01rs7198004 3e-05 2e-01rs9746695 2e-08 8e-02rs3901386 1e-04 4e-01rs12924729 4e-08 1e-01rs17229044 3e-04 4e-01

rs17696736 C12orf30 rs17696736 2e-14 4e-02rs2542151 PTPN2 rs2542151 1e-07 9e-05

rs2847297 2e-05 4e-04rs16939895 8e-05 5e-05rs7234029 1e-04 5e-05

Loci ascertained in T1D:Association in RA

Discovery Gene Genotyped T1D RA CD Psoriasis SLE MS CeliacSNP SNP Z p Z p Z p Z p Z p Z p Z p

rs6679677 PTPN22 rs6679677 -9.9 2e-23 14.5 9e-48 4.2 2e-05 -0.4 4e-01 -4.5 3e-06 3.0 1e-03 -2.2 1e-02rs1230666 -8.4 2e-17 11.5 1e-30 3.6 2e-04 0.2 4e-01 -2.7 3e-03 -- -- -1.3 1e-01rs2488457 -7.1 6e-13 -8.9 3e-19 2.5 6e-03 -0.5 3e-01 -1.5 6e-02 -0.3 4e-01 -0.7 2e-01

rs1990760 IFIH1 rs13023380 2.4 8e-03 -0.1 5e-01 -0.9 2e-01 0.8 2e-01 4.6 2e-06 -- -- 0.3 4e-01rs7608315 2.0 2e-02 -0.4 3e-01 -0.1 5e-01 0.7 2e-01 4.7 2e-06 -2.9 2e-03 -0.4 3e-01

rs3087243 CTLA4 rs3087243 3.9 4e-05 -3.8 7e-05 1.2 1e-01 0.2 4e-01 1.3 9e-02 0.7 3e-01 2.0 2e-02rs11571293 3.7 1e-04 3.5 2e-04 1.5 7e-02 -0.4 4e-01 1.4 8e-02 0.0 5e-01 2.0 2e-02rs11571304 3.9 6e-05 -3.4 3e-04 0.9 2e-01 0.2 4e-01 1.5 7e-02 0.4 3e-01 2.1 2e-02rs6748358 3.0 1e-03 0.4 3e-01 0.9 2e-01 0.7 2e-01 1.2 1e-01 0.1 4e-01 1.6 5e-02rs7596727 -2.2 1e-02 -2.8 2e-03 -0.7 3e-01 0.3 4e-01 -1.4 9e-02 -0.8 2e-01 -1.8 4e-02

rs17388568 Tenr-IL2 rs17388568 -5.2 1e-07 2.6 5e-03 -3.8 9e-05 -0.6 3e-01 -2.5 6e-03 1.5 6e-02 -2.3 1e-02rs6897932 IL7R rs6897932 2.4 9e-03 1.5 7e-02 -0.5 3e-01 1.3 1e-01 -0.3 4e-01 4.0 4e-05 2.4 9e-03

rs6881706 2.3 1e-02 1.4 8e-02 -0.4 4e-01 1.3 1e-01 0.1 5e-01 3.5 2e-04 2.4 9e-03rs11746643 1.5 6e-02 1.2 1e-01 0.3 4e-01 2.4 7e-03 0.6 3e-01 -- -- -- --rs13436926 1.8 4e-02 1.4 8e-02 0.3 4e-01 2.6 5e-03 0.7 2e-01 3.5 3e-04 1.7 5e-02rs10040617 1.1 1e-01 1.1 1e-01 -1.4 8e-02 0.9 2e-01 1.0 2e-01 2.0 2e-02 1.7 4e-02

rs1445898 CAPSL rs1025039 -3.9 5e-05 -1.2 1e-01 -0.3 4e-01 -0.9 2e-01 1.0 2e-01 -0.4 4e-01 -0.4 4e-01rs4024109 -3.8 7e-05 0.3 4e-01 -0.2 4e-01 0.8 2e-01 0.9 2e-01 -1.1 1e-01 -0.3 4e-01

rs12251307 IL2R rs12251307 4.0 4e-05 0.1 4e-01 -1.7 5e-02 -1.0 2e-01 -0.4 3e-01 -0.2 4e-01 -1.6 6e-02rs2292239 ERBB3 rs2292239 -6.0 1e-09 1.8 4e-02 -1.2 1e-01 -1.8 4e-02 -0.5 3e-01 0.7 2e-01 -1.0 2e-01

rs705698 -4.6 2e-06 -2.0 2e-02 -1.1 1e-01 2.0 2e-02 -0.3 4e-01 1.2 1e-01 -0.5 3e-01rs11171739 -6.6 2e-11 -2.2 1e-02 -1.0 2e-01 2.9 2e-03 -0.7 2e-01 0.4 4e-01 -1.4 8e-02

rs12708716 KIAA0350 rs12708716 5.3 7e-08 0.9 2e-01 0.6 3e-01 0.2 4e-01 1.3 9e-02 -- -- -0.4 4e-01rs2867880 2.5 7e-03 -- -- -- -- -0.5 3e-01 1.5 7e-02 -- -- -0.5 3e-01rs7198004 4.0 3e-05 0.9 2e-01 1.7 5e-02 -0.1 4e-01 2.0 2e-02 2.4 7e-03 -0.8 2e-01rs9746695 5.5 2e-08 -1.4 8e-02 1.1 1e-01 0.5 3e-01 1.7 5e-02 3.9 6e-05 -0.6 3e-01rs3901386 3.7 1e-04 -0.3 4e-01 1.0 2e-01 0.3 4e-01 2.1 2e-02 1.1 1e-01 -1.3 1e-01rs12924729 5.4 4e-08 -1.2 1e-01 1.1 1e-01 0.4 3e-01 1.4 9e-02 3.5 3e-04 -0.6 3e-01rs17229044 3.5 3e-04 0.3 4e-01 -0.3 4e-01 -1.1 1e-01 0.8 2e-01 1.0 2e-01 -0.9 2e-01

rs17696736 C12orf30 rs17696736 -7.6 2e-14 -1.7 4e-02 -3.2 6e-04 -2.2 1e-02 -1.3 9e-02 -3.0 1e-03 -- --rs2542151 PTPN2 rs2542151 -5.2 1e-07 3.7 9e-05 -6.6 1e-11 2.1 2e-02 -1.7 5e-02 0.7 2e-01 -2.8 2e-03

rs2847297 -4.1 2e-05 -3.3 4e-04 -3.7 1e-04 -0.5 3e-01 -1.3 1e-01 1.7 4e-02 -1.1 1e-01rs16939895 -3.8 8e-05 3.9 5e-05 -5.8 3e-09 2.0 2e-02 -1.5 7e-02 1.2 1e-01 -2.9 2e-03rs7234029 -3.6 1e-04 -3.9 5e-05 -5.8 3e-09 -1.7 4e-02 -0.7 2e-01 -0.4 3e-01 -2.7 3e-03

Next steps

Account for shared controls Composite likelihood method

Incorporate further imputed data Validate directionality Additional studies and loci Within-disease meta-analyses Replication

Celiac SLE T1D MS CD RA PsoriasisP < 0.01 P < 0.01 P < 0.01 P < 0.01 P < 0.01 P < 0.01 P < 0.01

Celiac 7 1 2 1 2 2 0SLE 0 4 0 0 0 1 0T1D 0 4 8 4 4 4 0MS 1 0 1 2 1 0 0CD 2 2 1 3 12 2 3RA 1 4 2 2 0 4 1

Overlap between diseases