Converging on a theme: autoimmune genetic architecture across diseases Chris Cotsapas PhD Daly Lab MGH/Broad Institute [email_address] broad.mit.edu/~cotsapas/autoimm.html

Acknowledgements Mark Daly Steve Rich David Hafler Sarah Krause John Todd Jeff Barrett Tim Behrens Rob Graham John Harley Carl Langefeld Pat Gaffney Kathy Moser JT Elder Goncalo Abecasis Peter Gregersen Lars Klareskog Leonid Padyukov Robert Plenge David van Heel Judy Cho Michel Georges John 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

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

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

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

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

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

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

Loci ascertained in T1D: Association in RA

Next steps Account for shared controls Composite likelihood method Incorporate further imputed data Validate directionality Additional studies and loci Within-disease meta-analyses Replication

Account for shared controls

Composite likelihood method

Incorporate further imputed data

Validate directionality

Additional studies and loci

Within-disease meta-analyses

Replication

Overlap between diseases